Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:18][N:17]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added isopropylamine (18 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (0.096 g, 0.30 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4), filtered and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (51 mg, 65%) as a colorless oil. MS: m/e=369.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:35][S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:35][S:36]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:25][C@H:10]2[C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[O:44])=[CH:46][CH:47]=1)(=[O:37])=[O:38]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C(N)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(S(N)(=O)=O)cc2)C1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
1-tert-butoxycarbonyl-3-amino-4-(benzyloxycarbonyl)amino-piperidine (151b) (300 mg) was dissolved in DMF (5 mL) prior to addition of Hunig's base (0.45 mL). 4-(aminosulfonyl)benzoic acid (210 mg) was added followed by BOP (420 mg). The solution was stirred for 8 h then quenched with aqueous NH4Cl. The mixture was partitioned between EtOAc and water. The organic layer was washed with NaHCO3, 5% LiCl (3×), and brine. The organic layer was dried, filtered, and concentrated. Flash chromatography of the residue provided tert-butyl (cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-{[(benzyloxy)carbonyl]amino}-1-piperidinecarboxylate (210 mg). MS found: (M−H)−=531.3.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12]C)[CH:9]=[C:8]([F:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(Br)(Br)Br>>[F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([F:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)cc(OC)cc1F
Agent: BrB(Br)Br
Product: COC(=O)c1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To the above methyl 2,6-difluoro-4-methoxybenzoate (90 g) was added boron tribromide (224 g) under cooling, and then the mixture was stirred for 2 hours at room temperature. After the reaction, the reaction mixture was extracted with ethyl acetate (300 ml). The organic layer separated was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give methyl 2,6-difluoro-4-hydroxybenzoate (56 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:40])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36](O)=[O:37])=[N:20][C:19]=2[CH3:39])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:50]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.O>[C:36]([C:21]1[C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:18]([C:14]2[C:13]([CH3:40])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:17]=[CH:16][CH:15]=2)=[C:19]([CH3:39])[N:20]=1)=[CH:28][CH:27]=[C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])[CH:25]=3)(=[O:37])[NH2:50]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)nc(C)c(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.5025 g, 0.931 mmol), ammonium chloride (0.199 g, 3.73 mmol), BOP (0.535 g, 1.211 mmol), DIPEA (0.781 ml, 4.47 mmol) and N-methylmorpholine (0.399 ml, 3.63 mmol) in DMF (Volume: 4.66 ml) was stirred under nitrogen for 2.5 h. Water (50 mL) was added, and the solution was stirred for 1 h. The precipitate was filtered, rinsed with water and dried over Drierite to give benzyl 3-(1-carbamoyl-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.4856 g, 0.902 mmol, 97% yield) as a tan solid, LC/MS (M+H)=539.24.
Reaction SMILES: CO.[Na].[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:9][NH2:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:15]=[CH:16][C:17]=1[CH:18](Cl)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:15]=[CH:16][C:17]=1[CH:18]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[NH:10][CH2:9][C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: NCc1ncc[nH]1
Agent: [Na]
Solvent: CC#N
Solvent: CO
Product: O=c1cnn(-c2ccc(C(NCc3ncc[nH]3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Yield: 16.5 %

Procedure:
Methanol (100 ml) was stirred at RT and sodium (0.09 mol) was added. The mixture was stirred until complete dissolution. (1H-imidazol-2-yl)methanamine (0.045 mol) was added. The mixture was stirred for 30 minutes. NaCl was removed by filtration and the filtrate was evaporated. Toluene was added and azeotroped on the rotary evaporator. 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) and acetonitrile (50 ml) were added. The resulting reaction mixture was stirred and refluxed for 20 hours. The solvent was evaporated, the residue was stirred in water, and extracted with CH2Cl2/CH3OH (90/10). The separated organic layer was dried, filtered, and the solvent evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was stirred in CH3CN, filtered off, washed with DIPE, then dried, yielding 1.1 g (16.5%) of (±)-2-[3-chloro-4-[(4-chlorophenyl)[(1H-imidazol-2-ylmethyl)amino]methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 50).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([O:13]C(C)C)(=[O:12])=[O:11].[OH-].[Na+:20]>O1CCCC1.O>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([O-:13])(=[O:11])=[O:12].[Na+:20]
Reactant: Cc1cccc(C(F)(F)F)c1S(=O)(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(F)(F)F)c1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A solution of 83 g of the crude isopropyl 2-trifluoromethyl-6-methylbenzenesulfonate (which contained about 10% of isopropyl 2-trifluoromethylbenzenesulfonate) in 300 mL of tetrahydrofuran was treated with a solution of 24.8 g of 50% aqueous sodium hydroxide in 150 mL of water and heated to reflux for 4 hours, then stirred at room temperature overnight. The mixture was assayed by capillary GC (10 m DB-1, 100°-250° C. at 20° C./min) to ascertain that the isopropyl 2-trifluoromethyl-6-methylbenzenesulfonate was consumed. The tetrahydrofuran was removed in vacuo, then the remainder was poured into 100 mL of water and 200 mL of hexane. The aqueous phase was washed with hexane, then the water removed in vacuo to yield 71 g sodium 2-trifluoromethyl-6-methylbenzenesulfonate as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOCC3)c2n1
Temperature: 60 °C
Yield: 55.8 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in anhydrous N,N-dimethylformamide (5 mL) was treated with anhydrous potassium carbonate (0.315 g) and then heated to 60° C. for 1 hour. On cooling to room temperature, to the above was added 4-(2-bromoethyl)tetrahydro-2H-pyran (0.110 g) and the reaction was warmed to 50° C., overnight. The reaction mixture was quenched with water (5 mL) and extracted into ethyl acetate (3 times, 100 mL combined total volume). The separated organic layers were combined and passed through a hydrophobic frit to dry. The organic phase was stripped to give a gum which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (111 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:14]
Reactant: C[Mg]Br
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To an ice cooled solution of 2-chloro-3-trifluoromethylbenzaldehyde (1 g, 4.8 mmol) in THF (16 mL) was added methylmagnesium bromide (3M in THF, 1.8 mL, 5.3 mmol). The reaction was allowed to warm to rt and stirred overnight. Saturated aqueous NH4Cl was added, and the mixture was extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford the desired product as a clear oil (1.1 g, 98%). 1H NMR (500 MHz, CDCl3) δ 7.86-7.82 (m, 1H), 7.62 (dd, J=7.8, 1.5 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 5.40 (q, J=6.4 Hz, 1H), 2.14 (s, 1H), 1.50 (d, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=[O:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[CH2:24]([Mg]Br)[CH3:25]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]([OH:23])[CH2:24][CH3:25])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Cn1ncc2cc(Cc3cnc4ccc(C=O)nn34)c(F)cc21
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine-6-carbaldehyde (52 mg, 0.168 mmol) in THF (4 mL) at 0° C., was added a solution of ethylmagnesium bromide in THF (1M, 0.336 mL) dropwise. After stirring for 16 h, the reaction mixture was quenched with NH4Cl(aq), extracted with EtOAc, dried over Na2SO4. Filtered through Celite and concentrated in vacuo to give a crude product (14 mg, 10%). LCMS (method B): [MH]+=340, tR=2.04 min.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9]P(=O)(OCC)OCC)[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:29]\[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:8]=1)([CH3:2])[CH3:3]
Reactant: CCOP(=O)(Cc1coc(C(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C\c1coc(C(C)C)n1
Reaction time: 0.5 h
Yield: 1.3 %

Procedure:
To a solution of diethyl [(2-isopropyl-1,3-oxazol-4-yl)methyl]phosphonate (1.16 g) in tetrahydrofuran (15 mL) was added sodium hydride (60% in oil, 0.24 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.57 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:2, v/v) to give 2-isopropyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.02 g, yield 1.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=[O:6].[CH2:14](O)[CH2:15][OH:16]>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]1[O:16][CH2:15][CH2:14][O:6]1
Reactant: OCCO
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: COc1ccc([N+](=O)[O-])cc1C1OCCO1
Yield: 80.5 %

Procedure:
A solution of 2-methoxy-5-nitrobenzaldehyde (100 g, 550 mmol), ethylene glycol (36.9 ml, 660 mmol) and CSA (5.00 g) was heated at reflux under dehydrating condition for 5 hr. After removal of the solvent, triethylamine (6 ml) was added to the residue and the mixture was recrystallized from first ethyl acetate and from next isopropanol to give 2-(2-methoxy-5-nitrophenyl)-1,3-dioxolane (99.7 g, 80.5%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CC(O)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20]3[N:21]([C:25]([CH:26]([CH3:28])[CH3:27])=[N:24][N:23]=3)[CH:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: CC(C)C=O
Reactant: NNc1ncc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CC(C)c1nnc2ncc(-c3c(-c4ccc(F)cc4F)nc4occn34)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To a flask was added 6-(2,4-difluorophenyl)-5-(2-hydrazinylpyrimidin-5-yl)imidazo[2,1-b]oxazole (0.120 g, 0.366 mmol) and DCM (8 mL). Isobutyraldehyde (0.026 g, 0.366 mmol) and HOAc (0.000021 mL, 0.000366 mmol) were added. The reaction mixture was stirred at ambient temperature for about 2 h. Then iodobenzene diacetate (0.124 g, 0.384 mmol) was added. The reaction mixture was stirred at ambient temperature for about 2 h. The crude material was purified by silica gel flash chromatography using a gradient of 0-20% MeOH in DCM to give the title compound (0.085 g, 61%): LC/MS (Table 1, Method a) Rt=2.62 min; MS m/z: 381.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+]>CC(C)=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:34])=[O:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Reaction time: 16 h

Procedure:
An amount of 345 mg (0.73 mmol) of the compound from Example 14A and also 0.58 ml (5.45 mmol) of 2-methyl-2-butene were dissolved in 3 ml of acetone and admixed at RT with a solution of 376 mg (2.73 mmol) of sodium dihydrogenphosphate-1-hydrate and 460 mg (4.07 mmol) of sodium chlorite in 9 ml of water. The mixture was stirred at this temperature for 16 hours thereafter and then diluted with 15 ml of water and with 15 ml of ethyl acetate. After the phases had been separated, the aqueous phase was further extracted with 15 ml of ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulphate. Following filtration, the solvent was concentrated and the residue was dried in a high vacuum. This gave 337 mg (104% of theory) of the target compound, which was reacted further without additional purification.
Reaction SMILES: C[C:2]1[N:3]([C@H:30]2[C@H:34]([OH:35])[C@H:33]([OH:36])[C@@H:32]([CH2:37][OH:38])[O:31]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:7]=[C:6]([CH2:26][C:27]([NH2:29])=[O:28])[N:5]=2.[CH2:39](N)[CH2:40][NH2:41]>ClCCl>[NH2:41][CH2:40][CH2:39][NH:29][C:27]([CH2:26][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[CH:2][N:3]2[C@H:30]2[C@H:34]([OH:35])[C@H:33]([OH:36])[C@@H:32]([CH2:37][OH:38])[O:31]2)=[C:8]([NH:11][CH2:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:7]=1)=[O:28]
Reactant: NCCN
Reactant: Cc1nc2c(NCC(c3ccccc3)c3ccccc3)nc(CC(N)=O)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: ClCCl
Product: NCCNC(=O)Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 105 °C
Yield: 76.2 %

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxyamide (Preparation 16) (0.52 g, 1.03 mmol) and 1,2-ethylenediamine (0.6 g, 10 mmol) was heated at 105° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.43 g, 78%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>O1CCCC1.CCCCCC>[OH:8][CH2:9][CH2:10][N:11]([CH:42]1[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amide (333) in tetrahydrofuran (3 ml) was added 1N HCl (1 ml) at room temperature and the reaction mixture was stirred for 30 min at room temperature while silica thin layer chromatography was performed (ethyl acetate:hexane=3:2, Rf=0.4). After completion of the reaction, solid NaHCO3 was added and the mixture basified up to about pH 8. After extraction with ethyl acetate (3×30 mL), the combined extracts were dried and concentrated to get 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-(tetrahydro-pyran-4-yl)-amide (334) which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:10]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>CCOC(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.C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:13]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=[C:11]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)[CH:12]=2)=[CH:35][CH:34]=1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 43.2 %

Procedure:
A flask is charged with trifluoromethanesulfonic acid 2-(2-methoxy-phenyl)-5-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl ester (1.10 g, 3.70 mmol), 4-chlorophenyl boronic acid (0.630 g, 4.07 mmol), Pd(PPh3)4 (0.24 g, 5 mol %), 2 M Na2CO3 (16 mL), EtOH (16 mL) and toluene (32 mL) and heated at 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), and the organic layer dried over Na2SO4 and evaporated. The crude product was purified by flash silica gel chromatography eluting with 10% EtOAc/hexanes to give 0.68 g (66%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]([OH:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[S:21][CH2:20][CH2:19][C:18]3([CH3:26])[CH3:25])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14](=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[S:21][CH2:20][CH2:19][C:18]3([CH3:25])[CH3:26])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCS3)cc1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCS3)cc1O
Reaction time: 8 h

Procedure:
2 g (5.2 mmol) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoate and 50 ml of dichloromethane were introduced into a round-bottomed flask. 2.6 g (6.9 mmol) of pyridinium dichromate were added and stirring was carried out at room temperature for 8 hours. The reaction mixture was evaporated to dryness and the residue obtained purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporating the solvents, 1.3 g (65%) of the expected ester was recovered in the form of a brown oil.