Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[NH:29][C:28]=1[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41].CC(C)([O-])C.[K+].O>C(#N)C.C(OC(=O)C)C>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[N:29]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:28]=1[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41]
Reactant: COC(=O)c1ccccc1OCCc1c(CCNC(C)=O)[nH]c2ccc(Cl)cc12
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCCc1c(CCNC(C)=O)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12
Yield: 50.6 %

Procedure:
Bromodiphenylmethane (208.3 g 0.843 mol) and 4-{2-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy-benzoic acid methyl ester (250.0 g, 0.603 mol) were suspended in acetonitrile (10 L). The suspension was stirred and cooled to −1 C and potassium tert. butoxide (94.6 g 0.843 mol) was added in one portion. the reaction was complete by HPLC analysis after stirring for 2.5 h at −1 C. Water (125 mL) was added to the reaction mixture. The suspension was heated to 50 C and then 8.3 L solvent was removed by vacuum distillation (180 mmHg). Aqueous Potassium hydroxide (84.4 g KOH (87%) in 300 mL of water) was added and the reaction mixture was refluxed for 3 h. The solution was cooled to 35 C and acidified (pH=3) with 4N hydrochloric acid (435 mL). The suspension was stirred for 20 min. at 5 C and the precipitate was collected by filtration. The cake was washed with water (250 mL×3) and ethyl acetate (250 mL) and the wet cake was dried at 70 C/30 mmHg for 36 h to yield 253 g crude product. The solid was suspended with 1 L ethylacetate and stirred and warmed at refluxed for 4 h. This ethylacetate slurry was repeated two times. The wet product was collected by filtration and dried for 16 h at 60 C/30 mmHg to obtain 177.3 g (50%) product. The structure was determined by 1H-NMR. δ(300 MHz, DMSOd6) 1.78 (s, 3H), 2.97 (m, 2H), 3.15-3.25 (m, 4H), 4.22 (t, J=6 Hz, 2H), 6.48 (d, J=9 Hz, 1H), 6.80 (dd, J=2 Hz, J=9 Hz, 1H), 6.87 (d, J=8 Hz, 2H), 7.10-7.13 (m, 4H), 7.26 (s, 1H), 7.31-7.40 (m, 6H), 7.66 (d, J=2 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 8.15 (t, J=5 Hz, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:15])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:15][CH2:22][CH3:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Reaction time: 10 h

Procedure:
4.1 g of 4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.02 mol), 5.6 g of potassium carbonate (0.04 mol) and 3.5 g of ethyl iodide (0.022 mol) are heated in 30 ml of dimethylformamide with stirring for 10 hours at 60°. After this time, the excess potassium carbonate is filtered off and 30 ml of water is added. 4-Ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates and is recrystallized from methanol, yield 2 g (42.5%), m.p. 180°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28][O:27]1>>[C:33]([O:32][CH2:31][C@@H:29]1[CH2:28][O:27][C:26](=[O:25])[N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3)CC2)nc1C
Yield: 96.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (2.18 g) described in Preparation Example 176 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.11 g), the title compound (2.56 g) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13](Cl)[C:12]3[C:16](=[O:30])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:18][C:11]=3[C:10]=2[F:31])[CH2:6][CH2:5][O:4][CH2:3]1.[N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]2=[C:34](B(O)O)[CH:33]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13]([C:34]3[CH:33]=[N:32][N:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=34)[C:12]3[C:16](=[O:30])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:18][C:11]=3[C:10]=2[F:31])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: OB(O)c1cnn2ccccc12
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Temperature: 120 °C
Yield: 100.7 %

Procedure:
To a 5 mL microwave vial with a stir bar was added bis(triphenylphosphine)palladium chloride (11.68 mg, 0.017 mmol), 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (75 mg, 0.166 mmol), pyrazolo[1,5-a]pyridin-3-ylboronic acid (135 mg, 0.832 mmol) in dioxane (2 mL), and saturated aq NaHCO3 (2 mL). The mixture was heated in a Biotage Initiator microwave at 120° C. for 30 min. The mixture was concentrated and purified via preparative HPLC to give the title compound (89 mg, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.84 (m, 1H), 2.10-2.12 (m, 1H), 3.68-3.72 (m, 3H), 3.75 (s, 3H), 3.82 (s, 3H), 3.92-3.95 (m, 1H), 4.01-4.02 (m, 1H), 4.39 (s, 2H), 4.55-4.58 (m, 1H), 4.59 (s, 2H), 6.50 (dd, J=8.30, 1.95 Hz, 1H), 6.60 (d, J=2.44, 1H), 7.04-7.08 (m, 2H), 7.16 (d, J=5.86 Hz, 1H), 7.48-7.51 (m, 1H), 7.93 (br s, 1H), 8.37 (d, J=9.27 Hz, 1H), 8.79 (d, J=6.83 Hz, 1H), 9.36 (s, 1H). [M+H] calc'd for C28H29FN6O4, 533; found, 533.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[I:12]([O-])(=O)=O.[K+].C(OC(=O)C)(=O)C.[S:24](=[O:28])(=[O:27])([OH:26])[OH:25]>O.ClCCl>[S:24]([O-:28])([O-:27])(=[O:26])=[O:25].[C:1]([C:6]1[CH:7]=[CH:8][C:9]([IH+:12])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3].[C:1]([C:6]1[CH:7]=[CH:8][C:9]([IH+:12])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccccc1
Reactant: O=S(=O)(O)O
Reactant: [O-][I+2]([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCC(C)(C)c1ccc([IH+])cc1
Product: O=S(=O)([O-])[O-]
Reaction time: 2 h

Procedure:
Sixty grams of t-amylbenzene, 39.5 g of potassium iodate, 81 g of acetic anhydride and 170 ml of dichloromethane were mixed, and 66.8 g of concentrated sulfuric acid was slowly added thereto under ice cooling. After stirring under ice cooling for 2 hours, the mixture was stirred at room temperature for 10 hours. To the reaction solution, 500 ml of water was added under ice cooling, and the resulting solution was extracted with dichloromethane. An organic phase was washed with sodium hydrogencarbonate and water, followed by concentration to obtain (4-t-amylphenyl)iodonium sulfate. This sulfate was added to an excess amount of the solution of tetramethylammonium pentafluorobnzenesulfonate. To this solution, 500 ml of water was added, and the resulting solution was extracted with dichloromethane. An organic phase was washed with a 5% aqueous solution of tetramethylammonium hydroxide and water, followed by concentration to obtain di(4-t-amylphenyl)iodonium pentafluorobenzenesulfonate.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41].C([O-])([O-])=O.[K+].[K+]>COCCOC.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]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:36]4[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
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: [K+]
Solvent: COCCOC
Product: COc1cc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Temperature: 90 °C
Yield: 98.2 %

Procedure:
In a round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) and 3,4,5-trimethoxyphenylboronic acid (78 mg, 0.37 mmol) were dissolved in DME (2.0 mL). Aqueous K2CO3 (2.0 M, 0.37 mL, 0.74 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) were added and the mixture degassed with a gentle stream of N2 for 15 min. The reaction mixture was heated at 90° C. for 1.5 h then cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (50-100% EtOAc/heptane) to afford 146 mg (>100%) of 2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a viscous colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([O:9]C2C=CC=CC=2)=O)[CH:6]=1.[ClH:16].Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:16].[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:7]([N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[N:4]1)=[O:9])[CH2:20]2
Reactant: O=C(Oc1ccccc1)n1cc(I)cn1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)n1cc(I)cn1
Reaction time: 36 h
Yield: 83.4 %

Procedure:
Phenyl 4-iodo-1H-pyrazole-1-carboxylate (1.6 g, 5.2 mmol) and (R)-(+)-3-aminoquinuclidine dihydrochloride (1.0 g, 5.2 mmol) are suspended in 10 mL DMF. DIEA (2.7 mL, 15.5 mmol) is added dropwise. After 36 h, the solvent is removed and the residue is taken up in 1N NaOH and CHCl3. The aqueous layer is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3/MeOH/NH4OH) to provide 1.66 g (93%) of the product as a white solid. A portion of the material is converted into the hydrochloride salt and recrystallized from MeOH/EtOAc. HRMS (FAB) calcd for C11H15IN4O+H 347.0370, found 347.0357.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])OC(C)(C)C)#[N:2].Cl.N1C=CC=CC=1.[C:34]([O:37][C:38](C)([CH3:42])[C:39](Cl)=O)(=[O:36])[CH3:35]>O1CCOCC1>[C:34]([O:37][C:38]([CH3:42])([CH3:39])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:3]=1[C:1]#[N:2])=[O:19])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)OC(C)(C)C(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.8 %

Procedure:
To a solution of tert-butyl 6-(2-cyano-3-nitrophenoxy)hexylcarbamate (333 μmol, 121 mg) (Example 277c) in dioxane (2 mL) was added con. HCl (1 mL). After 15 minutes, the solution was concentrated in vacuo and dried on high vacuum. The crude HCl salt was suspended in DCM (dry, 10 mL) and treated with pyridine (2.664 mmol, 215 μL) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (1.332 mmol, 193 μL). The reaction mixture was refluxed under a nitrogen atmosphere until clear (6 h), then cooled to room temperature and the volatiles removed in vacuo. The residue was purified on silica gel (40% to 100% EtOAc in hexanes) to give the product (117 mg, 90%) as a light yellow heavy oil. MS 392 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[N:5][N:4]=[N:3]1.[NH2:15][O:16][CH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:15][O:16][CH2:17][C:18]2[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=O)c1ccccc1
Reactant: NOCc1cccc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 160 °C

Procedure:
Under protective gas (argon), a reaction tube containing a solution of (1-methyl-1H-tetrazol-5-yl)(phenyl)methanone (188 mg; 1.0 mmol), 6-[(aminooxy)methyl]pyridin-2-amine (139 mg; 1.0 mmol) and p-toluenesulfonic acid monohydrate (190 mg; 1.0 mmol) in 2-propanol (2 mL) is sealed and heated in a microwave oven at 160° C. for 90 min. For workup, the mixture is allowed to cool down, diluted with dichloromethane (10 mL) and washed twice with 3 ml each time of sat. aq. sodium bicarbonate. The aqueous phase is extracted with dichloromethane and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification on silica gel affords 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine as a colourless oil [205 mg; 66% of theory; HPLC/MS: m/z=310 (M+H); log P(HCOOH)=1.13].
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].[CH2:14]=O>C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>[CH3:11][N:12]([CH2:14][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[CH3:13]
Reactant: CNC
Reactant: C=O
Reactant: c1cnc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CN(C)Cc1c[nH]c2ncccc12

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine (18.07 g, 0.153 mol), dimethylamine hydrochloride (13.11 g, 0.161 mol) and paraformaldehyde (4.92 g, 0.164 mol) in n-butanol (500 ml) was heated at reflux for 35 minutes. The mixture was allowed to cool overnight and the precipitated solid collected by filtration. The filtrate was evaporated and the residue triturated with ethyl acetate to afford a second solid. The solids were combined, suspended in saturated aqueous potassium carbonate solution (500 ml) and extracted with dichloromethane (twice). The combined extracts were washed with saturated potassium carbonate (250 ml) then saturated sodium chloride solution (500 ml), dried (magnesium sulphate) then evaporated to a small volume, with the product crystallising out of solution during evaporation. Diethyl ether was added and the title compound collected as a solid (18.13 g, 67%). 1H NMR (360 MHz, DMSO-d6) δ2.19 (6H, s), 3.61 (2H, s), 7.03 (1H, dd, J1 =5, J2 =8 Hz), 7.36 (1H, d, J=2 Hz), 8.00 (1H, dd, J1 =2, J2 ==8 Hz), 8.20 (1H, dd, J1 =2, J2 =5 Hz), 11.47 (1H, broad s).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[NH2:19][CH2:20][C:21]([NH2:24])([CH3:23])[CH3:22]>C1COCC1>[NH2:24][C:21]([CH3:23])([CH3:22])[CH2:20][NH:19][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(N)CN
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)(N)CNC(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Yield: 38.5 %

Procedure:
4-(4′-Cyanophenoxy)benzoic acid (1.00 g, 4.2 mmol) was dissolved in THF (40 mL) followed by the addition of 1,1-carbonyldiimidazole (0.745 g, 4.6 mmol) in small portions. This mixture was stirred for 1 hour whereupon 1,2-diamino-2-methylpropane (0.48 mL, 4.6 mmol) was added and the resultant mixture stirred for 20 hours at RT. The mixture was then concentrated in vacuo and the residue chromatographed over silica (10% MeOH/CHCl3) to provide 0.50 g (38%) of the desired product. MS. (FD+) 310.2 m.p. 133–137° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16]S[C:11]=2[N:10]=[C:9]1[CH:19]([NH:23]CCC1OCCO1)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-]=[N+:32]=[N-:33].[Na+].[OH2:35]>CN(C=O)C>[N:23]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:35][C:11]=2[N:10]=1)[CH:20]([CH3:22])[CH3:21])=[N+:32]=[N-:33]
Reactant: O
Reactant: Cc1nsc2nc(C(NCCC3OCCO3)C(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A suspension of 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isoxazolo[5,4-d]pyramidin-4-one (method 44) (100 mg, 0.266 mmol) and sodium azide (34.5 mg, 0.53 mmol) in DMF (2 ml) was stirred at 60° C. for 1 h. Water (5 ml) was added to the mixture and then extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine (10 ml), dried, concentrated to obtain 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isoxazolo[5,4-d]pyrimidin-4-one which was purified by ISCO (Hexane-EtOAc). 50 mg (56%) of a colorless oil was obtained. m/z: 339 (MH+), 1H NMR (DMSO-d6): 0.60 (d, 3H), 0.95 (d, 3H), 2.25 (m, 1H), 2.45 (s, 3H), 4.19 (d, 1H), 5.30 (d, 1H), 5.42 (d, 1H), 7.12-7.30 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Cl:7].[NH2:18][C:19]1[C:27]([Br:28])=[CH:26][C:25]([Br:29])=[CH:24][C:20]=1[C:21](O)=[O:22].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]2[O:17][C:21](=[O:22])[C:20]3[CH:24]=[C:25]([Br:29])[CH:26]=[C:27]([Br:28])[C:19]=3[N:18]=2)[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Cl:7]
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: O=C(O)c1cc(Br)c(Cl)n1-c1ncccc1Cl
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)c(Cl)n2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 2-[4-bromo-5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC1(C)OC[C@H](CCO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2COC(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67699.5 %

Procedure:
To a stirred mixture of 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (50.89 g, 0.348 mol) and pyridine (113 ml, 1.39 mol) in dichloromethane (500 ml) was added gradually p-toluenesulfonyl chloride (79.65 g, 0.418 mmol) at ice-bath temperature. After removal of ice-bath, the reaction mixture was stirred at ambient temperature overnight. The mixture was poured into ice-cooled 1N-HCl (400 ml) and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 solution and brine, dried with MgSO4, and concentrated in vacuo. The residue was purified by silica gel (800 g) column chromatography eluting with toluene/ethyl acetate (50:1 to 10:1) to give 2-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl p-toluenesulfonate (85.0 g, 81.3%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:14][S:15]([C:18]1[C:19]2[CH:20]=[CH:21][NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13].CC(SCC[NH2+]C(CN)=O)=O.C([O-])(C(F)(F)F)=O.C1C(=O)N([Cl:53])C(=O)C1>CN(C=O)C.CC#N>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:14][S:15]([C:18]1[C:19]2[C:20]([Cl:53])=[CH:21][NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13]
Reactant: COC(=O)C(CCn1cccc1C#N)NS(=O)(=O)c1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(=O)SCC[NH2+]C(=O)CN
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)C(CCn1cccc1C#N)NS(=O)(=O)c1cccc2[nH]cc(Cl)c12
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A solution of 0.20 g (0.52 mmol) of 4-(2-cyano-pyrrol-1-yl)-2-(1H-indole-4-sulfonylamino)-butyric acid methyl ester (from the synthesis of I-102) and 0.070 g (0.52 mmol) of NCS in 1 mL of DMF is stirred overnight, and then diluted with MeCN and purified by preparative HPLC to provide 0.15 g (0.36 mmol; 69%) of 2-(3-chloro-1H-indole-4-sulfonylamino)-4-(2-cyano-pyrrol-1-yl)-butyric acid methyl ester. This material is stirred in 1.4 mL of THF with 1.4 mL of 1M NaOH for 3 h, and then 2N HCl is added until the pH is 3. The mixture is extracted with EtOAc, and the extract washed with brine, dried over Na2SO4, filtered, and concentrated to provide 0.12 g (85%) of I-103 as a tan powder.
Reaction SMILES: C[C:2]1(C)[O:7][CH:6]([CH2:8][S:9][CH3:10])[CH:5]([CH2:11][N:12]([CH2:14][C:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=3[NH:17][CH:16]=2)[CH3:13])[CH2:4][O:3]1.Cl>CO.C(Cl)Cl>[NH3:12].[CH3:2][OH:3].[NH2:24][C:23]1[C:18]2[NH:17][CH:16]=[C:15]([CH2:14][N:12]([CH2:11][CH:5]([CH:6]([OH:7])[CH2:8][S:9][CH3:10])[CH2:4][OH:3])[CH3:13])[C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: CSCC1OC(C)(C)OCC1CN(C)Cc1c[nH]c2c(N)ncnc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CSCC(O)C(CO)CN(C)Cc1c[nH]c2c(N)ncnc12
Product: N
Reaction time: 2 h
Yield: 158.5 %

Procedure:
To a solution of 7-(((((4RS,5RS)-2,2-dimethyl-4-(methylthiomethyl)-1,3-dioxan-5-yl)methyl)(methyl)amino)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (34 mg, 93 μmol) in MeOH (2 mL) was added conc aq HCl (0.5 mL) and the solution was allowed to stand at RT for 2 h, then was concentrated to dryness. Chromatography (15% then 25% 7N NH3/MeOH in CH2Cl2) gave (2RS,3RS)-2-((((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)(methyl)amino)methyl)-4-(methylthio)butane-1,3-diol (24 mg, 73.7 μmol, 79% yield) as a syrup. 1H NMR (CD3OD) δ 8.16 (1H, s); 7.49 (1H, s); 3.83-3.75 (3H, m); 3.67 (1H, dd, J=5.0, 10.9 Hz); 3.56 (1H, dd, J=7.1, 10.8 Hz); 2.64 (2H, m); 2.57 (1H, dd, J=4.6, 13.6 Hz); 2.41 (1H, dd, J=8.3, 13.5 Hz); 2.34 (3H, s); 2.21-2.12 (1H, m); 2.04 (3H, s). 13C NMR (CD3OD) δ 155.0, 154.0, 150.1, 133.2, 118.2, 115.3, 75.4, 66.3, 61.4, 54.8, 45.9, 45.6, 42.6, 18.9.