Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].[BH4-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:17]([S@:20]([NH:22][C@@H:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH3:3])=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC[C@@H](N[S@](=O)C(C)(C)C)c1ccc(NS(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a solution of titanium(IV) ethoxide (2.0 ml) and N-(4-propanoylphenyl)methanesulfonamide (280 mg, 1.2 mmol, Bioorganic & Medicinal Chemistry Letters, 2004, 14(7), 1751-1755) in THF (5.0 ml) was added (R)-(+)-2-methyl-2-propanesulfinamide (149 mg, 1.2 mmol) and the mixture was stirred for 16 hours at 70° C. Upon completion, as determined by TLC, the mixture was cooled to room temperature and then to 0° C. before the reaction mixture was added dropwise to a suspension of sodium borohydride (185 mg, 4.9 mmol) in THF (12 ml) at 0° C. The procedure described in Example 2C was performed to give the title compound (240 mg, 72%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH:18]1C=CC=CC=1>>[CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:11][CH2:13][CH2:12][CH2:18]2)=[O:8])[CH:3]1[C:14]([O-:16])=[O:15]
Reactant: c1ccccc1
Agent: CC1(C)C(C=CC(=O)OCC2CC2)C1C(=O)O
Product: CC1(C)C(C=CC(=O)OC2CCCC2)C1C(=O)[O-]

Procedure:
Using the procedure of Example 9, (1R, cis, ΔZ) 2,2-dimethyl-3-(3-cyclopentyloxy-3-oxo-1-propenyl)-cyclopropane-carboxylic acid and (RS) cyano-2-(6-phenoxy-6-pyridinyl)-methanol were reacted to obtain (RS) cyano-2-(6-phenoxy-6-pyridinyl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-cyclopentyloxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42°±1° (c=0.9% in benzene).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13](=[CH2:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:18].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl.S([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]2([O:18][CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: C=C1CCN(C(=O)OCc2ccccc2)C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CO2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution 3-methylen-pyrrolidine-1-carboxylic acid benzyl ester (WO9624593) in 5 ml of dichloromethane was treated with 2.16 g sodium bicarbonate (MW: 84.01 26.28 mmol) and 2.47 g of 80% m-chlor-perbenzoic acid (MW: 172.57, 11.48 mmol). The reaction mixture was stirred at room temperature for three hours. The reaction mixture was diluted with 20 ml of a saturated, aqueous sodium sulfite solution and 45 ml of dichloromethane. The organic layer was successively washed with 30 ml of an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate. The residue was purified by chromatography on silica (1/1 ethyl acetate/n-hexane) to afford a off white solid. Yield: 440 mg, 57%. MS: 234.1 (M+H)+, Method ESI+.
Reaction SMILES: O.[CH3:2][C:3]([CH3:23])([CH3:22])[CH2:4][C:5]([NH:7][C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19]CC)=[O:18])[C:11]=2[N:12]=1)=[O:6].[OH-].[Na+]>CO>[CH3:2][C:3]([CH3:23])([CH3:22])[CH2:4][C:5]([NH:7][C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=[O:18])[C:11]=2[N:12]=1)=[O:6]
Reactant: CCOC(=O)C1CCCc2sc(NC(=O)CC(C)(C)C)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)CC(=O)Nc1nc2c(s1)CCCC2C(=O)O
Reaction time: 24 h

Procedure:
Water (2 mL) and methanol (8 mL) were added to ethyl 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate (185 mg, 0.57 mmol) and NaOH (27 mg, 0.675 mmol), and the resultant mixture was stirred at room temperature under a blanket of nitrogen as inert gas. To complete the reaction, NaOH (200 mg, 5 mmol) was again added, and stirring was continued for a further 24 hours at room temperature. Following removal of MeOH, 2M HCl (10 mL) was added, and the resultant mixture was extracted with CH2Cl2 (3×20 mL). Following drying of the combined organic phases over Na2SO4 and filtration, there was obtained the product 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid in a yield of 144 mg (corresponding to 85% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.CN.CO.C[CH2:17][N:18](C(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:17][NH2:18]
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CO
Product: NCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 1-bromo-2-fluoro-3-nitrobenzene (3.96 g, 18 mmol), 2M methylamine in MeOH (18 mL, 36 mmol) and DIPEA (3.3 mL, 19 mmol) was stirred for 3 h at RT. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in DCM (100 mL) and washed with sat. NaHCO3 (100 mL). The aqueous layer was further extracted with DCM (100 mL). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford the title compound as bright orange oil (4.16 g, 99%). LCMS (Method C): RT 3.39 min [M+H]+ 231 (for 79Br). 1H NMR (CDCl3, 400 MHz): δ 7.86 (1H, dd, J=8.5, 1.5 Hz), 7.67 (1H, dd, J=8.0, 1.5 Hz), 6.67 (1H, dd, J=8.5, 8.0 Hz), 3.13 (1H, bs), 3.01 (3H, d, J=5.5 Hz).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:24])([CH3:23])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[C:12]([O:14]C)=[O:13])(=O)C.[OH-].[Li+].Cl>CO.C1COCC1.O>[C:19]([C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([O:8][CH2:7][C:6]([CH3:24])([CH3:23])[CH2:5][OH:4])[CH:18]=1)[C:12]([OH:14])=[O:13])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc(OCC(C)(C)COC(C)=O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)COc1cc(C(=O)O)cc(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 112.8 %

Procedure:
Methyl 3-(3-acetoxy-2,2-dimethylpropoxy)-5-tert-butylbenzoate (O5.086; 1 g) was dissolved in methanol/THF (15/30 ml), and lithium hydroxide solution (11.89 ml, 1 M in water) was added. After stirring at 40° C. for 2 h, the organic solvent was drawn off, and the residue was diluted with water and adjusted to pH 3 with 1 N hydrochloric acid. Then it was extracted with EA, and the combined organic phases were dried, filtered and concentrated. 940 mg of the title compound were obtained. LC-MS rt: 1.45 min [M+H]+: 281.1 (met. a)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].B.CSC.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: B
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1ccc(C=O)cc1O
Reaction time: 18 h
Yield: 33.4 %

Procedure:
To a solution of 3-hydroxy-4-methylbenzoic acid (15.22 g, 0.1 mole) in THF (250 mL) was added borane.dimethylsulfide (32.0 mL of a 10.0M solution, 0.32 mole) dropwise. Upon completion of addition, the reaction was stirred for 18 hrs. It was then quenched dropwise by the slow addition of aqueous 10% HCl (250 mL) and extracted with ethylacetate (3×250 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was taken up in CH2Cl2 (500 mL) and pyridinium dichromate (45.15 g, 0.12 mole) was added. The resulting mixture was stirred for 48 hrs. It was then filtered through Celite and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 30:70) to afford 4.55 g of 3-hydroxy-4-methylbenzaldehyde as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH:3]=[C:4](Br)Br.Cl[C:17]([O:19][CH3:20])=[O:18].CC(C1C=CC(OC)=CC=1)(C)C#CC>>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]#[C:4][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Agent: CC#CC(C)(C)c1ccc(OC)cc1
Product: COC(=O)C#CC(C)(C)c1ccc(OC)cc1

Procedure:
This compound was prepared from Compound 53 and ClCO2Me in the same manner of Compound 54.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][OH:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 2-aminoethanol (2.3 mL, 39 mmol), and triethylamine (16 mL, 120 mmol) in anhydrous THF (100 mL) was added 4-bromobenzene-1-sulfonyl chloride (10 g, 39 mmol) portion wise and the reaction mixture stirred at room temperature for 16 h. The reaction was filtered, the filtrate was concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (5.5 g, 50%): 1H NMR (500 MHz, CDCl3) δ 7.74 (td, J=9.0, 2.1 Hz, 2H), 7.67 (td, J=9.0, 2.1 Hz, 2H), 5.08 (s, 1H), 3.72 (t, J=5.1 Hz, 2H), 3.12 (t, J=4.8 Hz, 2H), 1.83 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]2[C:4]([CH:5]=[C:6]([N+:32]([O-])=O)[CH:7]=[CH:8]2)=[N:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][N:2]1[C:10]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]2[C:4]([CH:5]=[C:6]([NH2:32])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc2cc(N)ccc2c1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 127.3 %

Procedure:
To a solution of 2-methyl-6-nitro-3-[(trityloxy)methyl]-2H-indazole (0.50 g, 1.11 mmol) in anhydrous THF under nitrogen atmosphere at 0° C. was added LiAlH4 (2.7 ml, 1.0 M in THF, 2.7 mmol). The solution was stirred at 0° C. for ˜3 h then cooled to −78° C. and quenched with wet THF. The resulting mixture was conc. in vacuo then repeatedly triturated with CH3CN. The combined CH3CN was conc. in vacuo to give crude 2-methyl-3-[(trityloxy)methyl]-2H-indazol-6-amine (0.593 g, 108% TY). MS (ES+, m/z) 420 (M+H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2[C@]2(C(=O)c3ccccc3)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 100 mL flask was added guanosine (2.0 g, 7.06 mmol) and N,N-dimethyl-4-aminopyridine (0.017 g, 0.14 mmol). N,N-dimethylformamide (30 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (16 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and benzoyl chloride (1.2 mL, 8.5 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 72 h, the mixture was poured into 300 mL of 0.1 M sodium bicarbonate solution (warmed to 60° C.) giving a white solid which was isolated by suction filtration (using a medium glass frit), washed with 3×100 mL cold water, and air dried.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:15]=1.[NH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:21]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:16]2[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)=[N:7][C:2]=3[NH:40][C:41]3[CH:46]=[N:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[N:15]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(6-fluoro-2,3′-bipyridin-5-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (230 mg, 0.440 mmol) and 5-amino-2-methoxypyridine (0.082 mL, 0.660 mmol) (Aldrich) in THF (6.0 mL) was cooled to 0° C. in an ice bath and treated with 1 M LiHMDS (1.320 mL, 1.320 mmol) (Aldrich) resulting in a deep purple solution which was stirred at 0° C. for 30 min. The reaction was quenched by the addition of a saturated solution of NH4Cl and extracted with EtOAc (20 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude material was used in the next step without further purification. m/z (ESI, +ve ion) 627.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.89 (1H, s); 9.25 (1H, d, J=1.6 Hz); 8.91 (1H, d, J=8.2 Hz); 8.64 (1H, dd, J=4.8, 1.7 Hz); 8.37 (1H, d, J=2.5 Hz); 8.31 (1H, dt, J=8.0, 2.0 Hz); 8.01 (1H, dd, J=8.9, 2.6 Hz); 7.66 (1H, d, J=2.7 Hz); 7.39 (1H, dd, J=7.8, 4.7 Hz); 7.18-7.25 (4H, m); 7.03 (1H, dd, J=8.6, 2.9 Hz); 6.82-6.91 (4H, m); 4.85 (4H, s); 3.86 (3H, s); 3.81 (3H, s); 3.79 (3H, s); 2.60 (3H, s).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2]([O:4]CC)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.[O-]CC.[Na+].[Na]>O.C(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:2](=[O:4])[C:1]([OH:8])=[O:7])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl oxalate (29.2 g, 0.2 mol) and 4-bromo-2-nitrotoluene (21.6 g, 0.1 mol, Lancaster) were poured into a cooled sodium ethoxide solution, prepared from sodium (4.6 g, 0.2 mol) and absolute ethanol (90 mL). The mixture was stirred overnight at room temperature and then refluxed for 10 minutes at the end of the reaction. Water (30 mL) was added and the reaction refluxed for 2.5 h. The reaction mixture was cooled and concentrated to remove excess ethanol. The precipitate was collected by filtration, washed with ether and dried. The crude sodium salt was dissolved in water and acidified with conc. HCl. The solid precipitated and was collected by filtration. The crude product was recrystallized from hexane and ethyl acetate to give 12.5 g (43%) as a feathery putty-colored solid; 1H-NMR (CDCl3): δ8.40 (d, 1H, J=1.9 Hz). 7,84 (dd, 1H, J=8.0, 2.0 Hz), 7.30 (d, 1H, J=2 Hz) 4.65 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].F[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>CS(C)=O>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][O:15][C:4]1[CH:5]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:2]([O:1][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[C:3]=1[C:22](=[O:24])[CH3:23]
Reactant: COCCOCOc1cc(O)c(C(C)=O)c(OCOCCOC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCOCOc1cc(OCOCCOC)c(C(C)=O)c(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A stirred suspension of 1-{2-hydroxy-4,6-bis[(2-methoxyethoxy)methoxy]phenyl}ethanone (2.1 g, 6 mmol), potassium carbonate (0.85 g, 6 mmol) and 1-fluoro-4-nitrobenzene (0.86 g, 6.1 mmol) in DMSO (5 mL) was heated at 80° C. overnight. After dilution with ethyl acetate, the suspension was washed with brine and dried. After removal of the solvent, the residue was chromatographed on silica gel eluting with hexane/ethyl acetate 6/4 to afford the title compound (1.6 g, 54% yield).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[OH-].[Na+:19]>C(O)(C)C>[OH:17][C:4]1[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:7].[Na+:19]
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C([O-])CCCNC(=O)c1ccccc1O
Temperature: 50 °C
Yield: 104.9 %

Procedure:
A one liter, four neck round bottom flask was equipped with an overhead stirrer, reflux condenser, thermocouple temperature read out, and heating mantle. The following reaction was run under a dry nitrogen atmosphere. Isopropanol (400 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (25.0 g, 0.09 mol) were charged to the reactor and stirring was started. The reaction slurry was heated to 50° C. until a hazy brown solution was obtained. The warm solution was filtered through a warm pressure filter dressed with Whatman #1 paper into a clean 1 L reactor. The clear yellow filtrate was heated to 62° C. while stirring. Sodium hydroxide solution (50% aqueous; 7.2 g, 0.09 mol) was charged to the reactor while maintaining vigorous agitation. After the base addition was complete, the reactor was heated to reflux (72° C.) and then allowed to cool slowly to ambient temperature. The product was isolated by vacuum filtration through a sintered glass funnel and vacuum dried at 50° C. for 24 hours to give 23.16 g of sodium 4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yield was 92%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:19]1[C:23]2([CH2:28][CH2:27][C:26](B(O)O)=[CH:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(P(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd]Cl.CCOC(C)=O>[CH3:18][C:15]1[CH:16]=[CH:17][C:11]2[N:10]=[C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:26]4[CH2:27][CH2:28][C:23]5([O:22][CH2:21][CH2:20][O:19]5)[CH2:24][CH:25]=4)[N:3]=3)[NH:13][C:12]=2[CH:14]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: OB(O)C1=CCC2(CC1)OCCO2
Agent: Cl[Pd]Cl
Agent: CCP(CC)CC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3nc(C4=CCC5(CC4)OCCO5)cnc3N)[nH]c2c1
Yield: 63 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (150 mg, 0.4932 mmol), 1,4-dioxaspiro[4.5]dec-7-en-8-ylboronic acid (181.5 mg, 0.9864 mmol), dichloropalladium; triethylphosphane (10.20 mg, 0.02466 mmol) and Na2CO3 (740.0 μL of 2 M, 1.480 mmol) were heated in DMF (1.500 mL) at 130° C. in a microwave for 30 min. EtOAc was added and the organic phase washed with saturated aqueous Na2CO3, dried (MgSO4) and concentrated in vacuo. The resulting oil was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (113 mg, 63% Yield). 1H NMR (400.0 MHz, DMSO) d 1.86 (t, J=6.4 Hz, 2H), 2.45 (m, 5H), 2.76 (s, 2H), 3.95 (s, 4H), 6.61 (t, J=3.9 Hz, 1H), 7.07 (dd, J=1.3, 8.3 Hz, 1H), 7.38 (s, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.54 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 8.31 (d, J=4.0 Hz, 1H) and 8.37 (s, 1H) ppm; MS (ES+) 364
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:32][CH2:33][OH:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[CH3:35][S:36]([O:34][CH2:33][CH2:32][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]([CH3:29])[C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=2)=[N:9]1)(=[O:38])=[O:37]
Reactant: COc1cc(-c2nn(CCO)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a 0° C. mixture of N2-{4-[4-amino-1-(2-hydroxyethyl)-1H -pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.343 g, 0.750 mmol) and pyridine (7.5 mL) was added methanesulfonyl chloride (0.14 mL, 1.8 mmol) dropwise over 30 sec. The reaction mixture was stirred at 0° C. for 2 h then ice water (10 mL) was added. The precipitate was collected by filtration and dried in vacuo to afford 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate as a beige solid (0.268 g, 0.500 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.30 (1H, s), 8.13 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=8.4 Hz), 7.31-7.38 (4H, m), 7.15 (1H, t, J=7.6 Hz), 4.70 (3H, s), 4.04 (3H, s), 3.96 (3H, s), 3.37 (2H, obscured by water peak), and 3.12 (2H, s); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 11.22 min. MS: M+536.2.
Reaction SMILES: OC=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=CN=1)=[O:5].[N:19]1C=CC=C[C:20]=1NC(=O)CC1ON=C(C)C=1.[H-].[Na+].C(OCC)=O>C1COCC1.[OH-].[Na+]>[N:19]1[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[CH:20]=1
Reactant: Cc1cc(CC(=O)Nc2ccccn2)on1
Reactant: Cc1cc(C(=CO)C(=O)Nc2ccccn2)on1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC=O
Product: Cc1cc(CC(=O)Nc2cccnc2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General method for the synthesis of α-hydroxymethylene-3-methyl-N-pyridyl-5-isoxazoleacetamide: A solution of N-pyridyl-3-methyl-5-isoxazoleacetamide (1.1 g, 5 mmol) in THF (20 mL) was slowly added to a suspension of NaH (60% in oil; 0.5 g, 12.5 mmol) in 10 mL of THF. The reaction mixture was stirred at rt for 30 mins. and then ethyl formate (2 mL, 25 mmol) was added. After stirring at rt overnight, the reaction was conc. in vacuo and the residue was dissolved in 100 mL of a 1N aqueous NaOH solution and extracted with 25 mL of EtOAc. The aqueous layer was separated and brought to pH 5-6 with the addition of an aqueous 6N HCl solution. The resulting light yellow precipitate was collected and washed with cold water, affording the desired product.