Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:25]([CH:26]=O)=[CH:24][N:23]=[CH:22]1>>[CH3:20][N:21]1[C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][N:23]=[CH:22]1
Reactant: Cn1cncc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cn1cncc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylimidazole-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylimidazol-4-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
Imidazole (0.816 g, 0.01 mol), ethyl 4-fluorobenzoate (2 g, 0.01 mol) and anhydrous potassium carbonate (1.43 g, 0.011 mol) was dissolved in DMSO (30 ml) and heated to 90° C. for 18 h. The solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The white solid was purified by flash column chromatography (silica, diethyl ether) to afford a white solid (1.22 g, 56%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=3)=[N:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2cc(F)c(F)c(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 83 (0.44 g, 0.91 mmol) in EtOAc (15 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O give 0.21 g of the product 84. 1H NMR (DMSO-d6) δ 9.40 (s, 1 H), 9.14 (t, 1 H), 7.88 (s, 1 H), 7.20-6.80 (m, 8 H), 6.80-6.55 (m, 4 H), 5.07 (s, 2 H), 4.70-4.50 (m, 2 H); MS: m/z 382 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2.[OH-].[Na+]>O1CCCC1.CC(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O[C@H]4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nc2c(O[C@H]3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of (−)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)-sulfonyl]-1H-benzimidazole-6-carboxamide (24.2 g, 44.7 mmol, STEP 9) in tetrahydrofuran (65 mL) and 2-propanol (220 mL) was added 2M sodium hydroxide aqueous solution (220 mL, 440 mmol) at room temperature. After stirring at room temperature for 4 hours, the mixture was diluted with ethyl acetate (1.20 L) and washed with saturated ammonium chloride aqueous solution (500 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on amino gel (ethyl acetate:methanol gradient elution from 50:1 to 20:1) to afford the title compound as a white solid (15.2 g, 87%, >99% ee).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13]4[C:14](=[CH:19][CH:20]=[CH:21][C:12]=4[C:11]2=S)[CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=1.[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][N:27]=[CH:26]1>C(O)C>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13]4[C:14](=[CH:19][CH:20]=[CH:21][C:12]=4[C:11]2=[N:33][CH2:32][CH2:31][CH2:30][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(CN2C(=S)c3cccc4cccc2c34)c1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: FC(F)(F)c1cccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)c1
Yield: 66.4 %

Procedure:
A mixture of 2.5 g of 1-[[3-(trifluoromethyl) phenyl]methyl]benz[cd]indole-2(1H)-thione (Ch), 0.95 g of 1H-imidazole-1-propanamine, 200 ml ethyl alcohol and 2.3 g of mercuric acetate is reacted as described in Example 3, giving 2.1 g of the desired product, mp. 108°-109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccccc4)c3O2)cc1
Yield: 46.6 %

Procedure:
Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with phenyl boronic acid (0.564 g, 4.60 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 provided 0.94 g of a white paste. Re-crystallization from methanol afforded 0.6 g (47%) of (±)-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 127-130° C.; Anal. calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 62.51; H, 4.48.
Reaction SMILES: Cl.CC1(C)[O:7][C@@H:6]2[C@@H:8]([CH2:21][N:22]([CH3:50])[CH2:23][CH:24]3[CH2:27][CH:26]([CH2:28][C:29]4[N:33](COCC[Si](C)(C)C)[C:32]5[CH:42]=[CH:43][C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:31]=5[N:30]=4)[CH2:25]3)[CH2:9][C@@H:10]([N:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=4[CH:13]=[CH:12]3)[C@@H:5]2[O:4]1>CO>[NH2:20][C:19]1[C:14]2[CH:13]=[CH:12][N:11]([C@@H:10]3[CH2:9][C@H:8]([CH2:21][N:22]([CH3:50])[CH2:23][CH:24]4[CH2:27][CH:26]([CH2:28][C:29]5[NH:33][C:32]6[CH:42]=[CH:43][C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:31]=6[N:30]=5)[CH2:25]4)[C@@H:6]([OH:7])[C@H:5]3[OH:4])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CN(CC1CC(Cc2nc3cc(C(F)(F)F)ccc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CN(CC1CC(Cc2nc3cc(C(F)(F)F)ccc3[nH]2)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
A solution of HCl in MeOH (1:1, 3 ml) was added to 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-({methyl[(3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl]amino}methyl)-hexahydro cyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine at 0° C. and stirred. This was then immediately stirred at 40° C. for 4 h (reaction monitored by LCMS) The reaction was continued for a further 1 h. LCMS still showed 30% acetal deprotected SM. A further 1 ml of HCl (36% aq) was added to the reaction mixture and continued at 40° C. for a further 1 h. The reaction mixture was then evaporated in vacuo. The residue was dissolve in DCM (100 ml)+MeOH (1 ml) and washed with sat. NaHCO3 (2×50 ml), dried over Na2SO4, filtered and evaporated. Purification by prep. TLC, eluting with 7N NH3 in MeOH:DCM (1:9); MS (ESI+) for C27H32F3N7O2 m/z 544 [M+H]+; HPLC purirty 96% (ret. time, 2.03 min); 1H NMR (500 MHz, MeOD) δH ppm 1.47-1.58 (1H, m), 1.58-1.69 (1H, m), 1.87-2.12 (1H, m), 2.12-2.54 (10H, m), 2.53-2.91 (3H, m), 2.93-3.15 (2H, m), 3.88-4.08 (1H, m), 4.32 (1H, dd, J=7.57, 6.15 Hz), 4.88-5.01 (1H, m), 6.59 (1H, d, J=3.63 Hz), 7.20 (1H, d, J=3.63 Hz), 7.42-7.53 (1H, m), 7.63 (1H, d, J=8.20 Hz), 7.79 (1H, s), 7.95-8.22 (1H, m).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:32](=O)[NH:33][CH2:34][CH2:35][NH:36]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[NH:12]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:57]>CO>[ClH:57].[NH2:12][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:32][NH:33][CH2:34][CH2:35][NH2:36]
Reactant: O=C(NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(CCOCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: NCCNCC(N)CCOCc1ccccc1

Procedure:
2-(2-Benzyloxyethyl)-3-oxo-1,7-bis(triphenylmethyl)-1,4,7-triazaheptane is reacted in a manner analogous to the reaction of step (c) of Example 9 up to the point where the purified product is taken up in methanol and conc. hydrochloric acid is added. From this point the method described by M. Bessodes et al., Tetr. Lett., (1986) 579 to remove the triphenylmethyl protecting groups is employed: the product is taken up in a mixture of formic acid and diethylether and refluxed for several hours. After evaporation to dryness the product is dissolved in water, the pH is adjusted to 10 and the product is extracted with chloroform. The organic phase is evaporated and the product is taken up in dry ethanol. Dry hydrogen chloride gas is bubbled through the stirred solution cooled with an ice/water bath, and 1,5-diamino-1-(2-benzyloxy-ethyl)-3-azapentane hydrochloride is collected by filtration.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:36])[CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][CH2:27][C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:25][CH2:24]1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
tert-Butyl 2-(4-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (0.020 g, 0.036 mmol) was placed in DCM (3 mL). TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid product was filtered, washed with ether and dried to give N-(4-(4-(2-aminoacetyl)piperazin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.015 g, 74% yield) as the trihydrochloride salt. MS APCI (+) m/z 459 detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reactant: N
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 339) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.575 g, 18%). mp 137–139° C. 1H NMR (300 MHz, DMSO d6) δ 0.81 (d, J=7 Hz, 6H), 1.49 (m, 2H), 1.57 (m, 1H), 4.42 (t, J=7 Hz, 2H), 7.44–7.65 (m, 5H), 7.76 (m, 1H), 7.84 (m, 2H), 7.94 (m, 2H), 8.20 (s, 1H). MS (DCI/NH3) m/z 448 (M+H)+, 465 (M+NH4)+. Anal. calc. for C21H22ClN3O4S: C, 56.31; H, 4.95; N, 9.38. Found C, 56.02; H, 4.82; N, 9.31.
Reaction SMILES: C[C@@H]1O[C@@H](OC(C[C@H](CC(O[C@H](CC(O[C@@H:37]2[C@@H:44]([C:45]([OH:47])=[O:46])[N:43]([CH3:48])[C:41](=[O:42])[C@H:40]([C@H:49]([O:65][C@@H:66]3[O:70][C@H:69]([CH2:71][NH2:72])[C@@H:68]([OH:73])[C@H:67]3[OH:74])[C@H:50]3[O:54][C@@H:53]([N:55]4[C:61](=[O:62])[NH:60][C:58](=[O:59])[CH:57]=[CH:56]4)[C@H:52]([OH:63])[C@@H:51]3[OH:64])[N:39]([CH3:75])[CH2:38]2)=O)CCCCCCCCCCCC(C)C)=O)C)=O)[C@H](OC)[C@H](OC)[C@H]1OC>C(O)(=O)C>[CH3:75][N:39]1[C@@H:40]([CH:49]([O:65][C@@H:66]2[O:70][C@H:69]([CH2:71][NH2:72])[C@@H:68]([OH:73])[C@H:67]2[OH:74])[C@H:50]2[O:54][C@@H:53]([N:55]3[C:61](=[O:62])[NH:60][C:58](=[O:59])[CH:57]=[CH:56]3)[C@H:52]([OH:63])[C@@H:51]2[OH:64])[C:41](=[O:42])[N:43]([CH3:48])[C:44]([C:45]([OH:47])=[O:46])=[CH:37][CH2:38]1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)C[C@@H](C)CC(=O)O[C@@H](CCCCCCCCCCCC(C)C)CC(=O)O[C@H]2CN(C)[C@@H]([C@H](O[C@@H]3O[C@H](CN)[C@@H](O)[C@H]3O)[C@H]3O[C@@H](n4ccc(=O)[nH]c4=O)[C@H](O)[C@@H]3O)C(=O)N(C)[C@@H]2C(=O)O)[C@@H]1OC
Solvent: CC(=O)O
Product: CN1C(=O)[C@H](C(O[C@@H]2O[C@H](CN)[C@@H](O)[C@H]2O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)N(C)CC=C1C(=O)O
Temperature: 70 °C
Yield: 100.2 %

Procedure:
The reaction of Step (1) is as shown below. Specifically, 200 mg of caprazamycin B were dissolved in 6 mL of 80% aqueous acetic acid and the resulting solution was heated at 70° C. for 2 hours. Subsequently, the reaction mixture was concentrated and acetone was added to the syrup-like concentrate. The resulting precipitate was collected by filtration, washed with acetone and dried to afford 96.3 mg of caprazene as a colorless solid (99% yield).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[CH:23]=[CH:22][S:21][C:20]=12)(=[O:15])=[O:14].[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[CH:23]=[C:22]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])[S:21][C:20]=12)(=[O:14])=[O:15]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CS(=O)(=O)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(C)(=O)=O)c2s1
Reaction time: 0.5 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (2.8 ml) was added to a solution of 404 mg of 7-methanesulfonylimidazo[5,1-b]thiazole in 20 ml of dry THF in an argon atmosphere at −40° C. The mixture was stirred at the same temperature for 30 min. Tri-n-butylstannyl chloride (0.6 ml) was added thereto. A saturated aqueous ammonium chloride solution was added to the reaction solution. Ethyl acetate was then added thereto. The mixture was washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 251 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl>[C:1]([O:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)nc1
Agent: Cl[Pt+2]Cl
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)cn1
Yield: 75.3 %

Procedure:
A mixture of methyl 6-tert-butoxycarbonylnicotinate (1.2 g, 5.06 mmol) in THF (15 ml) and 0.25 N NaOH (40 ml, 10 mol) at an ambient temperature for 0.5 hr. The mixture was poured into ice-1 N HCl (10 ml). The solid was collected, washed with water and air-dried. The crude solid was recrystallized from CHCl3-EtOH-IPE to afford 6-tert-butoxycarbonylnicotinic acid (850 mg, 76%) as needles. IR (KBr) n3095, 1728, 1705 cm−1; 1H-NMR (DMAO-d6) δ 1.63 (s, 9 H), 8.09 (m, 1 H), 8.17 (m, 1 H), 8.42 (dt, J=2.4 and 8.3 Hz, 1 H), 9.21 (t, J=2.4 and 8.8 Hz, 1 H); MS (FAB) m/z 224 (M++1); Anal. Calcd for C29H33N3O6: C, 36.18; H, 3.18; N, 3.84. Found: C, 36.85; H, 3.35; N, 3.79.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C([Li])CCC.Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].O>O1CCCC1.C(OCC)(=O)C>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH2:13][CH2:14][CH2:15][CH2:16][Cl:17]
Reactant: ClCCCCBr
Reactant: COC(=O)CS
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CSCCCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A solution of methyl thioglycolate (10.0 mL, 113 mmol) in tetrahydrofuran (200 mL) at −78° C. under argon atmosphere was treated dropwise with n-butyllithium (2.5 M hexanes solution, 45 mL, 113 mmol). After 1 h at −78° C., the cloudy solution was rapidly treated with 1-bromo-4-chlorobutane (13.0 mL, 113 mmol) and allowed to warm to room temperature overnight. It was poured into water and hexanes, washed with cold aqueous sodium hydroxide solution (0.1 M) followed with saturated aqueous ammonium chloride, and the organic layer was stored over anhydrous sodium sulfate. The volatiles were removed and the residue was purified by chromatography and eluted with 8:1 hexane:ethyl acetate to yield [(4-chlorobutyl)thio]acetic acid methyl ester (10.7 g, 54.5 mmol) as a colorless liquid: EIMS m/z 198 (M+ with 37Cl), 196 (M+ with 35Cl).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([NH:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)C>[CH2:14]([N:18]([CH2:19][CH3:20])[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNCC
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (5.0 g) and butyl-ethyl-amine (3.95 g) are dissolved in toluene (50 ml) and thereto is added potassium carbonate (10.78 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water and diethyl ether, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (6.54 g). MS (m/z): 274 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][C:24](Br)=[CH:25][CH:26]=4)[C:21]([F:33])([F:32])[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:50][C:49]2[CH:51]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:53]=[CH:54][C:48]=2[N:47]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:52]5[CH:53]=[CH:54][C:48]6[N:47]=[C:46]([CH:42]7[CH2:43][CH2:44][CH2:45][N:41]7[C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[NH:50][C:49]=6[CH:51]=5)=[CH:25][CH:26]=4)[C:21]([F:33])([F:32])[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 90 °C
Yield: 43.3 %

Procedure:
A mixture of 2-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (137 mg, 0.265 mmol), 2-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1 eq., 110 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5%, 11 mg), tetrakis(triphenylphosphine)palladium (5%, 16 mg) and potassium carbonate (2 eq., 73 mg) in 4 mL DME and 2 mL water was heated to 90° C. for 2 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{9,9-Difluoro-7-[2-(1-Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (83 mg, yield 43%). LCMS-ESI−: calc'd for C41H44F2N6O4: 722.82. Found: 723.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:35]4[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=4[O:33][CH3:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)ccc4OC)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-methoxy-5-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=605.7)=94%.