Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=O)[CH2:25][O:26][C:27]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[O:35][CH3:36])=[C:18]([CH3:38])[CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([O:35][CH3:36])[C:27]=1[O:26][CH2:25][CH2:24][NH:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:38]
Reactant: COc1cc2nccc(Oc3cc(C)c(NC(=O)COc4c(OC)cccc4OC)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc(C)c(NCCOc4c(OC)cccc4OC)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 80.2 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-2-(2,6-dimethoxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (156 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 505 (M++1)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH:12]=[O:13].[H-].[Na+]>>[CH3:10][N:11]([CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[CH:12]=[O:13]
Reactant: CNC=O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C=O)Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-picolyl chloride-HCl (15 g, 91.4 mmol) and N-methylformamide (53.4 mL, 914 mmol) in 300 mL of TMF was added 80% NaH in mineral oil (5.48 g, 183 mmol). After stirring at rt for 18 h the mixture was quenched with ice water and partitioned between CH2 Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2 Cl2 /MeOH. The title compound was obtained as a pale yellow oil (10.5 g, 76%): ESMS (m/z): 151 (M+ +H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N:12]=[C:13]=[O:14].[CH2:15]([OH:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:10])([CH3:11])[CH3:9])[C:3]=1[NH:12][C:13](=[O:14])[O:17][CH2:15][CH3:16]
Reactant: CCO
Reactant: C[Si](C)(C)c1cccc(Cl)c1N=C=O
Product: CCOC(=O)Nc1c(Cl)cccc1[Si](C)(C)C
Reaction time: 1 h

Procedure:
A mixture of the compound of Example h (10 mmol) and ethanol (75 mL) was ref luxed for 1 h. The mixture was concentrated and the residue dissolved in ethyl acetate. The solution was washed twice with water and the solvent removed to yield the crude product, which was recrystallized from hexane. GC/MS showed some remaining isocyanate so the solid was dissolved in ethanol and refluxed again with approx. 0.1 g diazobisbicyclooctane. FID/GC indicated a complete reaction and the ethanol was removed and the title compound recovered. m.p. 109-110° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11])=[O:3].[OH-].[Na+]>C(O)(C)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[F:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[CH:2]([OH:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1F
Agent: Cl[Ru]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CC(C)O
Product: CC(O)c1ccc(F)cc1F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Dichloro(p-cymene)ruthenium(II) dimer (1.2 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 85° C. After the mixture was cooled to room temperature, 2,4-difluoroacetophenone (0.4 mmol), i-propanol (2 mL) and an aqueous solution of sodium hydroxide (1.0 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (20 atm) at 0° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(2,4-difluorophenyl)ethanol was obtained and the ee value (ee=93%) was measured by GC analysis.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH3:25])[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1>C(O)C>[CH3:26][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]([CH3:25])[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: CCO
Product: C[C@@H](CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of racemic 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (37, 38.3 g, 0.1 mmol) in a mixture of ethanol and hexanes (15:85 by volume) was injected into preparative HPLC system equipped with achiral column (30×250 mm) packed with silica gel coated with cellulose tri(3,5-dimethylphenyl carbamate) (Available at Chiral technologies Inc. as Chiralcel® OD-H, 5 μm). The column was eluted with mobile phase made by a mixture of ethanol (EtOH) and hexanes in a 15 to 85 volume ratio at a flow rate of 32 mL/min at room temperature. The column elution was monitored by UV detection at a wavelength of 220 nm. Under these conditions, a baseline separation of the two enantiomers was achieved and the retention times were 15.1 minutes (Peak 1, the undesired (R)-enantiomer (R)-38) and 19.6 minutes (Peak 2, the desired (S)-enantiomer (S)-38), respectively. Each injection was 0.5 mL of feed solution at a concentration of 200 mg/mL and the cycle time for each injection was 14 minutes by using stack injections. A total of 384 injections were performed for this separation process. Fractions for Peak 1 (the undesired (R)-enantiomer, (S)-38) and Peak 2 (the desired (S)-enantiomer, (S)-38) were collected separately from each injection, and fractions collected for each peak were concentrated under reduced pressure. The residue from each evaporator was further dried under high vacuum to constant weight to afford ((S)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile ((S)-38, 17.43 g, 19.15 g theoretical, 91% yield) from Peak 2 as off-white solids and (R)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile ((R)-38, 17.8 g, 19.15 g theoretical, 93% yield) from Peak 1 as off-white solids.
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=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>[N:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]3[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccncc1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(Br)n12
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: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(-c3ccncc3)n12
Temperature: 100 °C
Yield: 19.8 %

Procedure:
Triazolopyridinone 2-4 (40 mg, 0.11 mmol) and pyridin-4-ylboronic acid (27 mg, 0.22 mmol) were placed in a microwave vial and dissolved in dioxane (1 mL). To the mixture was added 1 M aq. Cs2CO3 solution (0.22 mL, 0.22 mmol). The mixture was then sparged with N2 gas for 3 min, and bis(tri-tert-butylphosphine)palladium (5.5 mg, 0.011 mmol) was added. The vial was capped and heated at 100° C. under microwave irradiation for 30 min. After cooling, the reaction mixture was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (12 g cartridge), eluting with 0-10% MeOH/CH2Cl2. The fractions containing the desired product (5-1) were pooled, and after solvent removal in vacuo, 8.0 mg (20%) of a yellow solid were obtained. 1H NMR (400 MHz, CHCl3-d): δ 8.63 (dd, J=4.9, 1.5 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68 (ddd, J=8.4, 6.8, 1.6 Hz, 1H), 7.53-7.48 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.26 (d, J=6.0 Hz, 2H), 7.16 (d, J=9.6 Hz, 1H), 7.08 (dd, J=9.6, 6.4 Hz, 1H), 6.36 (d, J=6.4 Hz, 1H), 4.49 (t, J=7.2 Hz, 2H), 3.51 (t, J=7.2 Hz, 2H). HRMS (ES) 368.1508 (M+H) found, 368.1509 required.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.[ClH:32].C>CO>[ClH:32].[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:11]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[C:14](=[O:17])[CH2:13][CH2:12]1
Reactant: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CN(Cc3ccccc3)CC12
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CNCC12

Procedure:
A solution of (3aRS,7aRS)-2-benzyl-7,7-bis(2-fluorophenyl)perhydro-4-isoindolone (2.34 g) in methanol (100 cc), to which N hydrochloric acid (6.2 cc) is added, is hydrogenated at atmospheric pressure in the presence of palladinized charcoal (10% palladium) (0.4 g) for 5 hours at 25° C. The reaction medium is filtered and concentrated under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(2-fluorophenyl)perhydro-4-isoindolone hydrochloride (2 g) in the form of a white solid.
Reaction SMILES: Cl.[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH2:32][C@H:33]3[O:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]3)[CH:31]=2)[N:21]=1.C(N(C(C)C)CC)(C)C>>[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]5[CH:28]=[N:29][N:30]([CH2:32][C@H:33]6[O:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]6)[CH:31]=5)[N:21]=4)[CH2:17][CH2:18]3)=[N:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Reactant: C(#CC1CC1)c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C#CC6CC6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 5-(cyclopropylethynyl)-2-(piperazin-1-yl)pyrimidine HCl salt (172 mg, 0.44 mmol) and (s)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate was added diisopropylethylamine (169 mg, 1.311 mmol), and the reaction mixture was stirred at room temperature. LCMS showed the reaction was completed. The mixture was concentrated, and the residue was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=1:2, to afford (S)-tert-butyl 2-((4-(4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (240 mg, 94%) as a yellowish solid. MS (ES+): C29H37N11O3 requires: 587, found: 588 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1)=[O:28]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Product: COc1ccc(Br)c(C(=O)Nc2ccc3ncn(C(CC(=O)O)c4ccccc4)c3c2)c1

Procedure:
Using the procedure of Preparation 21, the title compound (56 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 2-bromo-5-methoxybenzoic acid, and purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.35 min, MH+ 496].
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C:9]3[NH:15][C:16]([Cl:19])=[C:17]([Cl:18])[C:8]2=3)=[CH:4][N:3]=1.BrBr.CC(O)=[O:24]>>[NH2:1][C:2]1[NH:6][C:5](=[C:7]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C:9]3[NH:15][C:16]([Cl:19])=[C:17]([Cl:18])[C:8]2=3)[C:4](=[O:24])[N:3]=1
Reactant: CC(=O)O
Reactant: Nc1ncc(C2CCNC(=O)c3[nH]c(Cl)c(Cl)c32)[nH]1
Agent: BrBr
Product: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c(Cl)c(Cl)c32)N1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-amino-3H-imidazol-4-yl)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one, prepared as in reference 2, (38 mg, 0.13 mmol) in AcOH (3 mL) is added NaOAc trihydrate (86 mg, 0.63 mmol). A solution of Br2 (40 mg, 0.25 mmol) in AcOH (1 mL) is added drop-wise, the mixture is stirred for an additional 30 minutes and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 4-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-2,3-dichloro-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one; 1H NMR (DMSO-d6) δ 3.18-3.26 (m, 2H), 3.26-3.32 (m, 2H), 8.09 (t, 1H, J=4.8 Hz), 8.68 (s, 1H), 9.37 (s, 2H), 11.11 (s, 1H), 13.46 (s, 1H); m/z [M++1] 314.0.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][CH:19]=[N:18]4)[N:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:1]3([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:18]4)[N:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: c1cnc2c(c1)ccc1ccc(C3CCCCC3)nc12
Product: OC1(c2ccc3ccc4ccc(C5CCCCC5)nc4c3n2)CCCCC1
Yield: 60 %

Procedure:
By following General Procedure I, cyclohexanone (0.094 g, 0.953 mmol) was added to 2-(cyclohexyl)-1,10-phenanthroline, prepared as described by Example 15, (0.100 g, 0.381 mmol) and 0.1 M SmI2 (8.38 mL, 0.838 mmol) yielding 0.083 g (60% yield) of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3) δ8.24 and 8.14 (two d, J=8.40 Hz, Hp3 and Hp9), 7.76 and 7.70 (two d, J=8.80 Hz, Hp5 and Hp6), 7.66 and 7.52 (two d, J=8.40 Hz, Hp4 and Hp7), 3.06 (tt, J=11.85, 3.30 Hz, (CH2)5CH (phenan)), 2.18-1.74 (m, 10H), 1.52-1.33 (m, 10H); 13C NMR (75 MHz) δ166.98, 165.25, 144.88, 143.44, 137.16, 136.01, 127.49, 127.28, 126.21, 124.85, 121.47, 118.65, 73.16, 47.24, 36.75, 32.81, 26.64, 26.12, 25.75, 22.71; IR (CHCl3) 3338 (OH), 3042 (C—H Ar), 2927 (CH), 852 (C—H Ar) cm−1; HRMS m/e Calcd for C24H29N2O (MH+): 361.2280, found, 361.2272.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40])[C@@H:3]1[OH:45].N1C=CC=CC=1.[C:52](Cl)(=[O:57])[CH2:53][CH2:54][CH2:55][CH3:56]>C(Cl)(Cl)Cl>[CH3:56][CH2:55][CH2:54][CH2:53][C:52]([O:36][CH2:35][C:33]([C@:11]1([OH:37])[CH2:12][C:13]2[C:18](=[C:17]([OH:19])[C:16]3[C:20](=[O:21])[C:22]4[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=4[C:24](=[O:25])[C:15]=3[C:14]=2[OH:32])[C@@H:9]([O:8][CH:6]2[O:7][CH:2]([CH3:1])[CH:3]([OH:45])[CH:4]([NH:38][C:39]([C:41]([F:44])([F:42])[F:43])=[O:40])[CH2:5]2)[CH2:10]1)=[O:34])=[O:57]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1
Reactant: CCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](OC2CC(NC(=O)C(F)(F)F)C(O)C(C)O2)C1)C(=O)c1c(OC)cccc1C3=O

Procedure:
A solution containing 5.0 mg. of N-trifluoroacetyladriamycin dissolved in 0.5 ml. of anhydrous pyridine was treated with 18 microliters of valeroyl chloride, which was added in small portions over a two-day period. The reaction was monitored by thin layer chromatography and when the presence of N-trifluoroacetyladriamycin could no longer be observed, the reaction mixture was diluted with 10 ml. of chloroform. The chloroform solution was extracted three times with pH 4 gaseous buffer and once with pH 7 buffer. The dried chloroform solution was then evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel G with chloroform:methanol:water (120:20:1 by volume) as the solvent system. The major orange-colored band was removed and washed free of silica gel with a mixture of methanol and ethyl acetate. Upon evaporation of the methanol and ethyl acetate, 2.19 mg. of N-trifluoroacetyladriamycin-14-valerate was obtained. This material was idential by spectral and chromatographic comparison with samples of N-trifluoroacetyladriamycin-14-valerate prepared by the earlier described methods.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(N(CC)CC)C>[CH3:2][C:3]1[C:4]([C:19]([F:20])([F:22])[F:21])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methyl-1-(4-piperidinyl)-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D60) (2.2 mmol), was dissolved in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added in that order at room temperature and the mixture was stirred at room temperature for 2 hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product. The crude obtained was dissolved again in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added at room temperature and the mixture was stirred at room temperature for three hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one, 240 mg, 30%, M++H=384, which was subsequently converted into the hydrochloride salt using HCl solution (1M in diethyl ether, 2 eq).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:8][NH:9][C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:18])([F:19])[F:20])=[N:16][C:12]=2[CH:11]=1)[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5]
Reactant: CNc1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N(C)c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
Propane-1-sulfonyl chloride (27 uL, 34 mg, 0.24 mmol) was added to a solution of N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amine (63 mg, 0.20 mmol) (see following steps B, C, D, E, F and G for preparation), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with DCM (50 mL), washed with saturated NaHCO3 (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 40 mg (47%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 1.00 (t, J=7.42 Hz, 3 H), 1.38-1.53 (m, 4 H), 1.70-1.88 (m, 2 H), 2.15-2.30 (m, 1 H), 3.01-3.11 (m, 2 H), 3.28-3.33 (m, 2 H), 3.35 (s, 3 H), 3.88-3.91 (m, 2 H), 4.30 (d, J=7.62 Hz, 2 H), 7.55 (dd, J=8.79, 1.76 Hz, 1 H), 7.75 (d, J=8.98 Hz, 1 H), 7.82 (d, J=1.56 Hz, 1 H). MS (ESI) (M+H)+=420.0. Anal. Calcd for C18H24F3N3O3S+0.20 H2O+0.30 CH3OH (432.68): C, 50.80; H, 5.96; N, 9.71. Found: C, 50.79; H, 5.91; N, 9.69.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[C:22]1(=[O:26])[CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Sn-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:22]2([OH:26])[CH2:25][CH2:24][CH2:23]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1
Reactant: O=C1CCC1
Reactant: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: OC1(c2cc3nnc(-c4ccccc4F)n3nc2Cl)CCC1
Temperature: 25 °C
Reaction time: 5.75 h
Yield: 25.5 %

Procedure:
To a stirred solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (1.04 g, 3.24 mmol) in anhydrous THF (15 ml) under nitrogen was added cyclobutanone (1.21 ml, 16.2 mmol), followed by solid tetrabutylammonium difluorotriphenylstannate (0.410 g, 0.650 mmol). The flask was evaporated and refilled with nitrogen four times, then stirred at room temperature for 5.75 h. More tetrabutylammonium difluorotriphenylstannate (0.403 g, 0.639 mmol) was added and the mixture was stirred for a further 36 h. The mixture was then partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was extracted further with dichloromethane (2×50 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in, vacuo. The residue was purified by flash chromatography (silica gel. 70-100% EtOAc/hexane) to give 0.2634 g (26%) of the title compound as a cream solid; 1H NMR (360 MHz, CDCl3) δ1.81 (1H, m), 2.27 (1H, m), 2.52 (2H, m), 2.72 (2H, m), 2.87 (1H, s), 7.30 (1H, t, J=9.3 Hz), 7.36 (1H, t, J=7.5 Hz), 7.58 (1H, m), 7.88 (1H, td, J=7.3 and 1.8 Hz), 8.12 (1H, s); MS (ES+) m/e 319/321 [MH]+, 249.