Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([CH3:8])[N:3]1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[N:13]=1.[Li+].C([O-])(O)=O.[Na+].Cl[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29].Cl>C(Cl)(Cl)Cl.O>[CH2:31]([O:30][C:28]([N:6]1[CH2:5][C@H:4]([CH3:8])[N:3]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)[C@@H:2]([CH3:1])[CH2:7]1)=[O:29])[CH:32]([CH3:34])[CH3:33]
Reactant: C[C@H]1CNC[C@H](C)N1c1nc2c(C(=O)[O-])cccc2o1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)N1C[C@H](C)N(c2nc3c(C(=O)O)cccc3o2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously stirred suspension of lithium 2-((2S,6S)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate (97 mg, 0.346 mmol) and NaHCO3 (87 mg, 1.037 mmol) in chloroform (6 mL) and H2O (6 mL) was added dropwise isobutyl chloroformate (54 mL, 0.415 mmol). The reaction mixture was stirred at room temperature for 2 h, then neutralized with 1N aqueous HCl, and concentrated under reduced pressure to provide 2-((2S,6S)-4-(isobutoxycarbonyl)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylic acid. MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[O:9][CH2:10][C:11]#[CH:12])=[CH:4][CH:3]=1.[C-:14]#[N:15].[Na+].O.[OH-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:9][CH2:10][C:11]#[CH:12])[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: C#CCOC(Cl)c1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
1-Chloro-4-(chloro-prop-2-ynyloxy-methyl)-benzene (13.0 g) is added to sodium cyanide (3.1 g) in N,N-dimethylformamide (40 ml) over 2 hours at room temperature. The reaction mixture is stirred at room temperature for 3 hours and then poured into water (200 ml), which contained sodium hydroxide (4 g). The aqueous phase is extracted with tert butyl methyl ether (2×200 ml). The organic phases are washed with water (2×50 ml), combined, dried (sodium sulfate) and evaporated. (4-Chloro-phenyl)-prop-2-ynyloxy-acetonitrile (9.2 g) is obtained which is purified by flash column chromatography on silica gel using ethyl acetate/hexane as eluant.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].Cl.[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>O1CCCC1>[C:3]([CH2:2][NH:1][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])#[N:4]
Reactant: N#CCN
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)NCC#N

Procedure:
To a stirring mixture of 18.7 g (0.2 mole) aminoacetonitrile·HCl in 300 ml. dry tetrahydrofuran under a nitrogen atmosphere, there is added 20.4 g. (0.2 mole) t-butyl isocyanate (97%), followed by 28 ml. (0.2 mole) triethylamine. The resulting mixture is heated at reflux for five hours, cooled and the tetrahydrofuran removed at reduced pressure. The solid is recrystallized from ethyl acetate to give N-cyanomethyl-N'-(1,1-dimethylethyl)urea, m.p. 128°-32° (Anal. Calcd. for C7H13N3O: C: 54.17, H: 8.44, N: 27.07; Found: C: 53.84, H: 8.33, N: 26.86.
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:17]=2)=[CH:13][CH:12]=1.[NH2:34][C:35]1[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=1>O>[Cl:10][C:11]1[S:15][C:14]([C:16]2[C:20]([C:39]3[N:38]=[CH:37][N:36]=[C:35]([NH2:34])[CH:40]=3)=[CH:19][N:18]([CH2:30][CH:31]([CH3:32])[CH3:33])[N:17]=2)=[CH:13][CH:12]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)Cn1cc(-c2cc(N)ncn2)c(-c2ccc(Cl)s2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
To a degassed solution of acetonitrile (4 mL) and water (1 mL) were added potassium carbonate (4 eq, 2.8 mmol), 3-(5-chloro-2-thienyl)-1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq, 0.7 mmol), 4-amino-6-chloropyrimidine (1.1 eq, 0.77 mmol) and 1,1′-bis(diphenylphosphinoferrocene)palladium(II)dichloride (0.1 eq, 0.07 mmol). The mixture was stirred at 130° C. in the microwave for 60 min. At room temperature, the mixture was filtered over celite and the filtrate was evaporated. The residue was purified by chromatography on silica gel (dichloromethane:methanol 1:0 to 9:1) to afford 12 mg of 6-[3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazol-4-yl]pyrimidin-4-amine (5% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][OH:28]>C(#N)C>[OH:28][CH2:27][CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:16])([F:17])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1
Reactant: OCCI
Reactant: Oc1c(OC(F)(F)F)cccc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CCC(c2cccc(OC(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethoxy)phenol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 g). MS m/z (relative intensity, 70 eV) 305 (M+, 1), 275 (15), 274 (bp), 117 (5), 70 (20).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Cl)=[CH:10][CH:9]=1)=[CH2:7].C(C1C=CC(Cl)=CC=1)=C.[Mg]>C1COCC1>[CH3:1][Si:2]([CH3:5])([CH3:4])[C:11]1[CH:12]=[CH:13][C:8]([CH:6]=[CH2:7])=[CH:9][CH:10]=1
Reactant: C=Cc1ccc([Mg]Cl)cc1
Reactant: C[Si](C)(C)Cl
Agent: C=Cc1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc([Si](C)(C)C)cc1
Temperature: 10 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
A solution of trimethylchlorosilane (7.82 g, 72.4 mmole) in dry tetrahydrofuran(THF) (40 mL) was added dropwise over a 90 minute period to a solution of (4-vinylphenyl)magnesium chloride, prepared from 4-vinylphenylchloride (10 g, 72.4 mmole) and magnesium (2.43 g, 100 mmole) in dry THF (100 mL). Temperature was maintained at 10° C. during the addition. The reaction mixture was stirred at room temperature over 20 hours under nitrogen atmosphere. The crude product was obtained by direct distillation at 45°-48° C./0.5 mm in 45% yield.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:25])[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O

Procedure:
To a solution of 5.0 g (0.0147 mole) of 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one in 300 ml of ethanol was added 0.25g of 5 percent palladium on charcoal. It was subjected to hydrogenation in a Paar apparatus and filtered. This solvent was removed by evaporation under vacuum and the residue was recrystallized from a 5:2 (v/v) ethanol-water mixture to provide light-orange crystals of 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid, m.p. 241°-243° C. Analysis: Calculated for C21H27NO3 : %C, 73.9; %H, 8.0; %N, 4.1; Found: %C, 73.9; %H, 7.9; %N, 3.8.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[OH-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@@H](O)[C@@H](c1ccccc1)N3
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1nc2c3c(ccn2c1C)C(=O)[C@](O)(Cc1ccccc1)[C@@H](c1ccccc1)N3

Procedure:
2 g of (8S,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one, 1 g of Adogen 464, 7 ml of 50% strength aqueous sodium hydroxide solution and 0.8 ml of benzyl bromide are intensively stirred at room temperature for 16 h in 10 ml of dichloromethane. The mixture is then adjusted to pH 7 using ½ conc. aqueous hydrochloric acid with cooling and extracted three times with 100 ml of dichloromethane each time, and the organic phases are combined and washed twice with a little water. After stripping off the volatile components in vacuo, the residue obtained is chromatographed on silica gel (eluent: dichloromethane/methanol 100/3). 1.2 g of the title compound are obtained as yellowish crystals of melting point 248-51° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].S(O[CH2:20][CH2:21][CH2:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1)(=O)(=O)C>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1O
Reactant: CS(=O)(=O)OCCCOc1ccnc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccnc2ccccc12
Reaction time: 1 h
Yield: 100.6 %

Procedure:
2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.3963 g, 2.6 mmol) was added to a stirred solution of lithium hydroxide monohydrate (497.2 mg, 11.8 mmol) in DMF (2 mL) and the reaction mixture was stirred for 1 hour. A solution of 3-(quinolin-4-yloxy)-propyl mesylate (0.3868 g, 1.37 mmol) in DMF (1 mL) was slowly added and the reaction mixture was left stirring at 25° C. overnight. The reaction was diluted with dichloromethane and extracted with water. The dichloromethane layer was evaporated followed by crystallization of the residue from aqueous methanol. The product was obtained as a slightly yellow solid (0.4677 g, 53%). 1H NMR (400 MHz, DMSO-d6): 0.87 (3H, t, J=7.0 Hz), 2.24 (2H, q, J=7.0 Hz), 2.30 (2H, m), 3.85 (2H, t, J=5.5 Hz), 4.43 (2H, t, J=5.5 Hz), 5.53 (2H, s), 6.11 (2H, s), 7.06 (1H, d, J=5.2 Hz), 7.54 (1H, t, J=8.0 Hz), 7.72 (1H, ddd, J=1.4, 6.9, 8.3 Hz), 7.93 (1H, d, J=8.3 Hz), 8.15 (1H, d, J=8.5 Hz), 8.72 (1H, d, J=5.2 Hz).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([S:10]([CH3:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:20]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O.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].O1CCOCC1>[CH3:14][C:15]1[C:16]([C:2]2[S:6][C:5]([C:7]([S:10]([CH3:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=2)=[C:17]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=[CH:33][N:32]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(c1ncc(Br)s1)S(C)(=O)=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(Nc2nccc(C(F)(F)F)n2)c1-c1cnc(C(C)(C)S(C)(=O)=O)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
The product of Step 1 (112 mg, 0.40 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 150 mg, 0.40 mmol), and PdCl2(dppf).CH2Cl2 (29 mg, 0.040 mmol) were combined in a flask, sealed, and purged with nitrogen (2×). Dioxane (2.4 mL) and 2 M Na2CO3 (0.59 mL, 1.19 mmol) were added, and the reaction was purged again with nitrogen (2×). The mixture was stirred in an oil bath at 100° C. overnight. The dark brown reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded N-(3-methyl-{2-[2-(methylsulfonyl)propan-2-yl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (140 mg, 78%) as a colorless solid. MS ESI: [M+H]+ m/z 457.0. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.84 (d, J=4.9, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.49 (s, 1H), 7.29 (d, J=4.9, 1H), 7.22 (s, 1H), 2.96 (s, 3H), 2.32 (s, 3H), 1.83 (s, 6H). rhSYK activity=+++
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])/[C:5](OC)=[O:6].[CH3:24][NH2:25]>>[CH3:24][NH:25][C:5](=[O:6])/[C:4](=[N:3]/[O:2][CH3:1])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: CN
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccccc1C
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccccc1C
Temperature: 40 °C

Procedure:
250 g of methyl E-2-methoxyimino-2-[(2-methylphenoxymethyl)phenyl]acetate are suspended in 1 l of 40% strength aqueous methylamine solution and heated at 40° C. for 4 h. After cooling to room temperature (20° C.), the solid is filtered off with suction, washed several times with water and dried at 50° C. 229.8 g of the title compound are obtained as colorless crystals.
Reaction SMILES: Br.[Br:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([CH3:12])[C:4]=1[NH2:5].Cl.[N:14]([O-])=O.[Na+].C([O-])(=O)C.[Na+].CC(S)(C)C.CC(C)([O-])C.[K+]>O.C(O)C.CS(C)=O>[Br:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]2[C:4]=1[NH:5][N:14]=[CH:12]2
Reactant: COc1cc(C)c(N)c(Br)c1
Reactant: O=N[O-]
Agent: Br
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCO
Solvent: CC(C)(C)S
Solvent: O
Product: COc1cc(Br)c2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-bromo-4-methoxy-6-methylaniline hydrobromide (18.5 g, 62.3 mmol) in hydrochloric acid (8 M, 56 mL, 448 mmol) at 0° C. was added a solution of sodium nitrite (4.51 g, 65.4 mmol) in water (ca. 14 mL) drop wise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (7.02 mL, 62.3 mmol) in ethanol (140 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (35 mL) and transferred to a solution of potassium tert-butoxide (55.9 g, 498 mmol) in dimethylsulfoxide (350 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Preparative HPLC gave 10.1 g (86%) as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 8.05 (s, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 3.82 (s, 3H); Mass spec.: 226.95 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:24])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:15][C:16]([CH3:24])=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: CC(=Cc1ccccc1)CBr
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=Cc1ccccc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 41 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl) benzene, the title compound was synthesized according to Reference Example 17b. Yield: 41%. Melting point: 152-154° C. (Ethyl acetate-hexane)
Reaction SMILES: [P:1]([O-:32])([O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:13])=[CH:6][C:5]=1[O:21][CH3:22])=[O:2].[Na+:33].[O-]CC.[Na+].Cl[CH2:39][C:40]([OH:42])=[O:41]>C(O)C>[P:1]([O-:32])([O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:39][C:40]([O-:42])=[O:41])[CH:15]=2)=[O:13])=[CH:6][C:5]=1[O:21][CH3:22])=[O:2].[Na+:33].[Na+:33]
Reactant: O=C(O)CCl
Reactant: COc1cc(CCC(=O)c2cccc(O)c2)ccc1OP(=O)([O-])Oc1cc(C)cc(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCC(=O)c2cccc(OCC(=O)[O-])c2)ccc1OP(=O)([O-])Oc1cc(C)cc(C)c1
Reaction time: 1 h

Procedure:
To a mixture of 22.5 g sodium 4-(3-(3-hydroxyphenyl)-3-oxopropyl)-2-methoxyphenyl 3,5-dimethylphenyl phosphate (see Example 6) and 1000 ml of 0.22 M sodium ethoxide kept under nitrogen, 5.7 g of chloroacetic acid in 50 ml anhydrous ethanol is added dropwise with stirring and the mixture being kept boiling. After all of the acid is added the refluxing is continued for one hour. The reaction mixture is cooled and sodium chloride is removed by filtration. The solvent is evaporated under vacuum, and the residue is dissolved in water, acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated sodium sulphate solution. Water is added and pH adjusted to 7 with 2 M sodium hydroxide. The water layer is freeze-dried giving disodium 4-(3-(3-carboxylatomethoxyphenyl)-3-oxopropyl)-2-methoxypenyl 3,5-dimethylphenyl phosphate.
Reaction SMILES: [C:1]1(=[CH:7][CH2:8][C:9]2([CH3:38])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=4[S:22](=[O:36])(=[O:35])[N:21]=3)[C:10]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO.O1CCCC1>[CH:1]1([CH2:7][CH2:8][C:9]2([CH3:38])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=4[S:22](=[O:35])(=[O:36])[N:21]=3)[C:10]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(CC=C2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(CCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.9 %

Procedure:
To a solution of Example 147 (18 mg, 0.032 mmol), 10% palladium on carbon (5 mg) in methanol (5 mL) and tetrahydrofuran (5 mL) was added a hydrogen balloon. After evacuating the solution two times the mixture was stirred under the hydrogen atmosphere at room temperature for 24 hours. The solution was then filtered through celite and the filtrate concentrated to provide the title compound (18 mg, 100%). MS (ESI+) m/z=558 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 0.42 (m, 1H), 0.62 (m, 2H), 0.78 (m, 2H), 1.03 (m, 4H), 1.50 (m, 4H), 1.54 (s, 3H), 2.12 (m, 2H), 3.08 (s, 3H), 7.56 (m, 3H), 7.73 (m, 3H), 8.16 (d, J=8.1 Hz, 1H), 10.26 (s, 1H), 13.74 (s, 1H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH3:12])=[O:10].C([Li])CCC.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.O>[O:3]=[C:4]1[C:8](=[CH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1CCCC1=O
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCC(=CCCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.9 %

Procedure:
To a suspension of 60% NaH (1.2 g, 30 mmol) in anhydrous THF (30 mL) in an ice bath is added a solution of methyl 2-oxocyclopentanecarboxylate (4.26 g, 30 mmol) in 10 mL of THF dropwise over 5 minutes. The mixture is stirred at room temperature for 20 minutes. The mixture is cooled to -25° C. and 2.5 M n-butyllithium is added over 5 minutes (12 mL, 30 mmol). After stirring for 5 minutes, 1-bromo-3-phenylpropane (4.6 mL, 30 mmol) is added. The mixture is stirred at room temperature for 3 hours. The mixture is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (6:1 hexane:ethyl acetate) to afford methyl 2-oxo-3-(3-phenylpropyl-1-yl)cyclopentanecarboxylate (1 g, 13%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.22-1.50 (m, 2H), 1.62-1.90 (m, 4H), 2.12-2.38 (m, 4H), 2.58-2.69 (m, 2H), 3.75 (s, 3H), 7.10-7.32 (m, 5H); MS (EI) m/e 260 (M+).
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]3[O:20][C:13]4=[C:14]([NH2:19])[N:15]=[CH:16][C:17](I)=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.C([Si](C)(C)[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([N:33]2[CH2:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][NH:34]2)[CH2:28]1)(C)(C)C.[SiH3]O[SiH3]>>[NH2:19][C:14]1[N:15]=[CH:16][C:17]([C:36]2[CH:35]=[N:34][N:33]([C@H:29]3[CH2:30][CH2:31][CH2:32][C@H:27]([OH:26])[CH2:28]3)[CH:37]=2)=[C:12]2[CH:11]=[C:10]([C:6]3[C:5]4[S:1][N:2]=[CH:3][C:4]=4[CH:9]=[CH:8][CH:7]=3)[O:20][C:13]=12
Reactant: CC1(C)OB(C2=CNN(C3CCCC(O[Si](C)(C)C(C)(C)C)C3)C2)OC1(C)C
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnsc34)oc12
Agent: [SiH3]O[SiH3]
Product: Nc1ncc(-c2cnn([C@H]3CCC[C@H](O)C3)c2)c2cc(-c3cccc4cnsc34)oc12

Procedure:
The title compound was prepared from 2-(1,2-benzothiazol-7-yl)-4-iodofuro[2,3-c]pyridin-7-amine and 2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole by a procedure analogous to Example 68 followed by silyl ether deprotection by a procedure analogous to Example 229. 1H NMR (400 MHz, CD3OD): δ 9.48 (s, 1H), 9.09 (s, 1H), 8.84 (d, J=5.9 Hz, 1H), 8.71 (d, J=5.9 Hz, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 4.73 (m, 1H), 3.30 (m, 1H), 2.20 (m, 2H), 2.03 (m, 1H), 1.92 (m, 1H), 1.84 (m, 1H), 1.76 (m, 1H), 1.63 (m, 1H), 1.40 (m, 1H); MS (ESI): 432.60 [M+H]+; HPLC tR=0.60 min (HPLC: Analytical—2 min)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([CH3:23])=[C:9]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](O)=[C:16]3[CH:15]=[N:14]2)[CH:10]=[CH:11][CH:12]=1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=3[CH3:23])[N:14]=[CH:15][C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(Cl)cccc1-n1ncc2c(O)ncnc21
Product: Cc1c(Cl)cccc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Phosphoryl trichloride (16.09 mL, 172.63 mmol) was added in one portion to 1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate AE6) (3.0 g, 11.51 mmol) and the resulting suspension was heated to 100° C. to give a solution and stirred for 4 hours. Evaporated, the residue poured into ice/water and stirred for 30 minutes. The solids were filtered, washed with water (4×20 mL), dissolved in ethyl acetate (100 mL), dried (MgSO4), filtered and evaporated to afford the product (2.8 g) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 2.06 (3H, s), 7.41-7.54 (2H, m), 7.71-7.73 (1H, m), 8.79 (1H, s), 8.89 (1H, s); m/z (ESI+) (M+H)+=279; HPLC tR=2.59 min.