Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][O:12][C@@H:13]1[C@@H:21]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][NH2:29])[C@@H:20]([O:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][NH2:37])[C@@H:19]([CH2:38][O:39][CH2:40][CH2:41][S:42][CH2:43][CH2:44][CH2:45][NH2:46])[O:18][C@@H:14]1[O:15][CH2:16][CH3:17].COC([C:51]1[C:52](N[C:55](=[O:57])[CH:56]=1)=[O:53])=O>C([O-])(O)=O.[Na+].O.C(#N)C.C(Cl)Cl>[C:19]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][O:12][C@@H:13]2[C@@H:21]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][N:29]3[C:52](=[O:53])[CH:51]=[CH:56][C:55]3=[O:57])[C@@H:20]([O:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][N:37]3[C:52](=[O:53])[CH:51]=[CH:56][C:55]3=[O:57])[C@@H:19]([CH2:38][O:39][CH2:40][CH2:41][S:42][CH2:43][CH2:44][CH2:45][N:46]3[C:52](=[O:53])[CH:51]=[CH:56][C:55]3=[O:57])[O:18][C@@H:14]2[O:15][CH2:16][CH3:17])[C:13](=[O:12])[CH:21]=[CH:20]1
Reactant: CCO[C@H]1O[C@H](COCCSCCCN)[C@H](OCCSCCCN)[C@H](OCCSCCCN)[C@H]1OCCSCCCN
Reactant: COC(=O)C1=CC(=O)NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCO[C@H]1O[C@H](COCCSCCCN2C(=O)C=CC2=O)[C@H](OCCSCCCN2C(=O)C=CC2=O)[C@H](OCCSCCCN2C(=O)C=CC2=O)[C@H]1OCCSCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 351 %

Procedure:
A solution of amine 8 (23.9 mg, 29.0 μmol) dissolved in 1 M aqueous solution of NaHCO3 (1 mL) was treated with methoxycarbonylmaleimide (27.03 mg, 17.4 μmol) at 0° C. After 5 min, the mixture was diluted with water (1 mL) and acetonitrile (2 mL), and then stirred at room temperature for 1 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with brine (3×10 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The oily residue was purified by flash chromatography (CH2Cl2/MeOH 96:4) to give maleimide 9 (20.3 mg, 71%); Rf 0.45 (CH2Cl2/MeOH 96:4); 1H-NMR (CDCl3/TMS): δ6.72 (s, 8H, CH═CH), 4.94 (d, 1H, J=3.4 Hz, H-1), 3.95-3.82 (m, 2H, H-4, and OCHHCH2CH2N), 3.80˜3.45 (m, 22H, H-2, H-3, H-5, H-6, H-6′, OCH2CH2CH2S, SCH2CH2N, and OCH2CH3), 2.90-2.60 (m, 16H, OCH2CH2CH2SCH2CH2N), 1.96-1.82 (m, 8H, OCH2CH2CH2S), 1.23 (t, 3H, J=7.1 Hz, OCH2CH3); ES-MS: 1019.49 (M+Na)+, 951(M-OEt)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[N:24]=1>>[Br:25][C:23]1[N:24]=[C:20]([N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]2=[O:1])[S:21][CH:22]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2nc(Br)cs2)c2ccccc21

Procedure:
Essentially following the procedures described for Intermediate 7, but using 2,4-dibromothiazole in place of 2-bromopyridine, the title compound was prepared. MS: m/z=412 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-:34].[Na+].[Na+]>C(COC)OC.ClCCl.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C:5]1[C:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:34])=[N:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:21]([F:31])([F:32])[F:20])=[CH:23][CH:24]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cnc(Cl)nc1Cc1cccc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(=O)c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
The title compound of Example 1, Step A (0.6 g, 2 mmol), 4-trifluoromethyl-benzeneboronic acid (1.1 g, 6 mmol), and bis(triphenylphosphine)palladium dichloride were dissolved in dimethoxyethane (15 mL) and aqueous sodium carbonate (2 M, 4 mmol). The resulting mixture was heated at 80° C. for 3 h. The mixture was diluted with dichloromethane (50 mL) and water (50 mL). The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography using hexaneslethyl acetate (85:15). The title compound of Step A, a compound of the invention, was isolated as a white solid (0.56 g) melting at 159-161° C. 1H NMR (CDCl3/200 MHz) 2.47 (s, 3H), 7.62-7.78 (m, 3H), 7.94 (d, 1H), 8.17 (d, 1H), 8.34 (s, 1H), 8.5 (d, 2H), 8.9 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13](Br)[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1[CH2:41][O:40][CH2:39]C1.C(N(CC)CC)C.C[OH:50]>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]>[C:32]([O:31][C:30]([NH:29][C:25]1([C:22]2[CH:23]=[CH:24][C:19]([C:8]3[N:9]=[C:10]4[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:39]([O:40][CH3:41])=[O:50])=[N:12][N:11]4[C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:20][CH:21]=2)[CH2:28][CH2:27][CH2:26]1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: C1CCOC1
Reactant: COc1cc(Br)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Reactant: CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.41 g, 0.75 mmol) in MeOH (10 mL) and THF (1 mL) in an autoclave was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.12 g, 0.15 mmol, 0.20 equiv) and triethylamine (0.11 mL, 0.82 mmol, 1.1 equiv.). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.), heated to 110° C., and stirred at this temperature for 22 h. The resulting solution was concentrated under reduced pressure. The resulting material was crystallized from MeOH to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.34 g, 85%):
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#N.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.S(=O)(=O)(O)[OH:16]>C(OCC)C.O>[CH3:1][O:2][CH2:3][C:4]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)=[O:16]
Reactant: O=S(=O)(O)O
Reactant: COCC#N
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: O
Product: COCC(=O)c1ccc(Cl)cc1

Procedure:
To 25 g (281 mmole) of methoxyacetonitrile in 100 ml of diethyl ether at reflux was added 250 ml (250 mmole) of 1.0M 4-chlorophenyl magnesium bromide in diethyl ether. After refluxing for 30 minutes the reaction mixture was hydrolyzed with a solution of 30 ml of concentrated sulfuric acid in 100 ml of water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and dissolved in hexanes. The insolubles were filtered away and the resultant solution was concentrated and distilled yielding a clear liquid. bp 105°-115° C. at 1 torr. The oil solidified on standing.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1.C(NC(C(C)C)(C(C)C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([C:39]1[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]
Reactant: Clc1ncc(Br)cn1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCNC(C)(C(C)C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
{2-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (4.6 g), 5-bromo-2-chloropyrimidine (3.56 g) and N-ethyldiisopropylethylamine (4.8 ml) are dissolved in toluene (100 ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, 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→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amine (5.24 g). MS (m/z): 657/659 [M+H]+
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH:19]=[CH2:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)C(O)[O:10]1.[Cl-].[CH3:31][O:32][CH2:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:53]C(C)([O-])C.[K+]>O1CCCC1>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]([C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:53]=[CH:33][O:32][CH3:31])([OH:10])[CH:19]=[CH2:20]
Reactant: C=CC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(O)c2ccccc21
Reactant: CC(C)(C)[O-]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C=COC
Reaction time: 6 h

Procedure:
To a suspension of 3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-vinyl-1,3-dihydroisobenzofuran-1-ol (475 mg, 1.14 mmol) and (methoxymethyl)triphenylphosphonium chloride (973 mg, 2.84 mmol) in tetrahydrofuran (6 mL) at 0° C. was added potassium tert-butoxide (319 mg, 2.84 mmol). The ice bath was removed and stirring continued for 6 h. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%-->25% EtOAc/Hex) gave 210 mg (41%) as a colorless oil. Mass spec.: 469.23 (MNa)+.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32](C(Cl)(Cl)Cl)[O:31][N:30]=1)([CH3:6])([CH3:5])[CH3:4].O>CN(C=O)C>[NH2:2][C:32]1[O:31][N:30]=[C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:8]2[N:7]([C:3]([CH3:5])([CH3:6])[CH3:4])[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=4)=[CH:15][C:10]=3[N:9]=2)[N:33]=1
Reactant: [NH4+]
Reactant: CC(C)(C)n1c(-c2ccccc2-c2noc(C(Cl)(Cl)Cl)n2)nc2cc(-c3cnc(N)nc3)ccc21
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2-c2noc(N)n2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
To a stirred solution of ammonium hydroxide (0.02 mL, 0.39 mmol) in DMF (2 mL) at room temperature is added 5-{1-tert-butyl-2-[2-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-benzimidazol-5-yl}-pyrimidin-2-ylamine (395 mg, 0.26 mmol). The reaction mixture is stirred at room temperature for 0.5 hours. Water is added to the reaction mixture and the product is extracted into EtOAc (3×) and the combined organics are then dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography (10 g silica gel, 3-6% MeOH/CH2Cl2) affords the title compound (20.6 mg, 17%). LCMS (ESMS): m/z 427.29 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:9]([NH2:19])=[N:10][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:12][C:6]2=[CH:5][C:4]=1[O:20][CH3:21].[CH:22]1([N:27]=[C:28]=[S:29])[CH2:26][CH2:25][CH2:24][CH2:23]1.O1CCOC[CH2:31]1>>[CH:22]1([NH:27][C:28]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[N:10]=[C:9]([NH2:19])[C:7]4[C:6](=[CH:5][C:4]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[CH:8]=4)[N:12]=3)[CH2:14][CH2:15]2)=[S:29])[CH2:31][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: S=C=NC1CCCC1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=S)NC4CCCCC4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution prepared by dissolving 868 mg. (3 mmole) of 2-piperazine-4-amino-6,7-dimethoxyquinazoline in 30 ml of dioxane, there was added dropwise 424 mg. (13 mmole) of cyclopentyl isothiocyanate at room temperature. The mixture was stirred overnight at room temperature. After evaporation of the solvent from the reaction mixture, the residue was chromatographed on silica gel, and eluted with 2% ethanol-chloroform to obtain 1.26 g. of the desired product. The product was dissolved in 10 ml of iso-propanol and 2 ml of 2N hydrochloric acid was added to the resultant solution to form a hydrochloride, which was in turn isolated.
Reaction SMILES: C([O:5][C:6](=[O:49])[C@@H:7]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH2:8][NH:9][C:10]([NH:12][C:13]1[C:22](=[O:23])[N:21]2[C:16]([CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:20]2)=[CH:15][CH:14]=1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:43]1([S:40]([NH:39][C@@H:7]([CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22](=[O:23])[N:21]3[C:16]([CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])=[CH:20]3)=[CH:15][CH:14]=2)=[O:11])[C:6]([OH:49])=[O:5])(=[O:41])=[O:42])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)Nc1ccc2ccc(OCCCNC(=O)OCc3ccccc3)cn2c1=O)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)Nc1ccc2ccc(OCCCNC(=O)OCc3ccccc3)cn2c1=O
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of (S)-2-Benzenesulfonylamino-3-{3-[7-(3-benzyloxycarbonylamino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionic acid tert-butyl ester (25 mg, 0.036 mmol) in dichloromethane (3 mL) was added TFA(3 ml) at room temperature. The reaction mixture was stirred overnight and then solvents were evaporated under reduced pressure. The residue was triturated with ether(2×5 ml) and dried. The resulting solid was purified by flash chromatography (10% methanol in ethyl acetate) to give 18 mg of compound VI which was characterized by 1HNMR (300 MHz) (CD3OD) δ: 8.56 (d, 1H, J=7 Hz), 8.40 (s, 1H), 7.92 (m, 2H), 7.42-7.60 (m, 4H), 7.25 (m, 5H), 6.91-7.04 (m, 2H), 5.12 (s, 2H), 4.19 (t, 2H), 3.63 (m, 1H), 3.50 (m, 2H), 3.20 (m, 2H), 2.02 (m, 2H)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:23][CH2:24][CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[N:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].S(=O)(=O)(O)[OH:35].B1([O-])OO1.O.O.O.O.[Na+]>CO>[N:17]1([CH2:16][CH2:15][N:14]=[S:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)([CH2:23][CH2:24][CH2:25][CH2:26][S:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:35])=[O:13])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(CCCCSc2ccccc2)=NCCN2CCOCC2)cc1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(S(=O)(CCCCS(=O)c2ccccc2)=NCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of S-[4-(methanesulfonylamino)phenyl]-N-[2-(4-morpholinyl)ethyl]-S-[4-(phenylthio)butyl]sulfoximine in methanol is treated slowly with excess 30% sulfuric acid and then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide and filtered. The filter cake is washed with methylene chloride. The aqueous filtrate is extracted with methylene chloride and the extract combined with the methylene chloride used to wash the filter cake. The methylene chloride solution is washed with water, dried and concentrated to obtain the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.C([O:18][B:19](OCCCC)[O:20]CCCC)CCC>C(OCC)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of 4-iodotoluene (35 g, 160.5 mmol) in diethyl ether (400 mL) was added n-butyllithium (2 M in pentane, 88.3 mL, 176.6 mmol) at 0° C. After stirring at 0° C. for another 15 min the solution was cooled to -60° C. and tributylborate (60.6 mL, 224.7 mmol) was added. The cooling bath was removed and the reaction allowed to heat up to room temperature. The solution was acidified with hydrochloric acid (2 N, 280 mL) and the organic phase separated off. The aqueous phase was extracted with diethyl ether 2×125 mL). The combined organic phases were extracted with sodium hydroxide (1 N, 5×50 mL). The combined aqueous extracts were acidified to give 18.6 g of the desired material.
Reaction SMILES: Br.Br[CH:3]([C:5]1[O:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].C([N:42]1[CH:50]=[N:49][C:48]2[C:43]1=[N:44][CH:45]=[N:46][C:47]=2[NH:51]C(=O)OC(C)(C)C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].C(O)(C(F)(F)F)=O.C(Cl)[Cl:69]>CCOC(C)=O>[ClH:69].[N:46]1[C:47]([NH:51][CH:3]([C:5]2[O:6][C:7](=[O:22])[C:8]3[C:13]([C:14]=2[C:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:4])=[C:48]2[C:43]([NH:42][CH:50]=[N:49]2)=[N:44][CH:45]=1
Reactant: ClCCl
Reactant: CC(Br)c1oc(=O)c2ccccc2c1C1=CCN(C)CC1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(Nc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1C1=CCN(C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.3 %

Procedure:
3-(1-bromoethyl)-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one hydrobromide (C21, 100 mg, 0.233 mmol), tert-butyl 9-trityl-9H-purin-6-ylcarbamate (120 mg, 0.251 mmol) and NaH (33.6 mg, 0.699 mmol) were reacted under nitrogen at 65° C. for 2 hrs. The reaction was diluted with 15 mL of EtOAc, washed three times with 10 mL of 0.1M HClaqueous, once with saturated NaClaqueous and the solvent evaporated to give an oil. The crude was dissolved in TFA/DCM (3 mL+3 mL) and stirred for 3 h at rt and quenched by the addition of 1M HClaqueous (1 mL). The resulting mixture was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile. The combined fractions from flash chromatography were added with 1M HClaqueous (5 mL) and dried under reduced pressure to give the title compound as a yellow solid (13.6 mg, 13.3% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:18][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of compound 20 (2.0 g, 8.4 mmol) in DMF (28 mL) at room temperature was added sodium hydride (235 mg, 8.8 mmol) and ethyl bromoacetate (1.03 mL, 9.2 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture is poured onto water and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 2 g of 21 as a clear oil (2.73 g theoretical, 73% yield)
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl[CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:21].CN(C)C=O>O>[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[O:21])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CC(Cl)C(=O)OCCOCc1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCOCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
30.6 g of 4-(3,5-dichloro-2-pyridyloxy)phenol sodium salt and 30.5 g of 2-(4-fluorobenzyloxy)ethyl 2-chloropropionate were added to 100 ml of dimethylformamide, and the mixture was heated to 70° to 80° C. for 3 hours with stirring. After cooling to room temperature, the reaction solution was poured into 300 ml of water, then extracted with ether. The ether layer was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by dehydration. Upon distilling off the ether, there were obtained 38 g of a pale yellow, viscous, oily end product, 2-(4-fluorobenzyloxy)ethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:37]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=Cc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (15 ml). The stirred solution was then cooled to room temperature and treated with a solution of benzaldehyde (21 mg, 0.20 mmol) in dry tetrahydrofuran (2 ml) followed by addition of sodium triacetoxyborohydride (70 mg, 0.33 mmol). The resultant mixture was stirred at room temperature for 24 hr, diluted with ethyl acetate and then washed sequentially with saturated aqueous sodium hydrogen carbonate and brine. The organic solution was then dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (92:8) to afford the title compound as a solid (67 mg). MS: 581 (MH+).