Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])[CH2:6][CH2:5]1)(=O)C.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[O:14]([CH:12]([CH3:13])[CH2:11][O:10][CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: CC(=O)N1CCC(OCC(C)O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(COC1CCNCC1)Oc1ccccc1
Reaction time: 3 h
Yield: 3.6 %

Procedure:
N-Acetyl-4-(2-hydroxy-n-propoxy)piperidine (12 g.) in dry D.M.F. (50 ml.) was added dropwise to a stirred suspension of sodium hydride (5.0 g., 50% dispersion in mineral oil) in D.M.F. (50 ml.) at 60°-70° C. under an atmosphere of nitrogen. The suspension was stirred for 3 hours, then fluorobenzene (6.4 g.) in D.M.F. (50 ml.) added dropwise and the suspension stirred at 100° C. for 50 hours. The cooled solution was treated with isopropanol (20 ml.) then water (200 ml.), extracted with petroleum ether (3×200 ml.) and chloroform (3×200 ml.). The combined chloroform extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue (9.0 g.) in sodium hydroxide solution (20 ml., 5N) and methanol (20 ml.) to bring about solution was heated under reflux for 5 hours. The methanol was evaporated, the residue diluted with water then extracted with chloroform (3×50 ml.). The combined chloroform extracts were washed with 2N HCl (3×30 ml.), the combined aqueous extracts basified to pH 12 with sodium hydroxide solution and extracted with chloroform (3×50 ml.). The combined chloroform layers were dried (Na2SO4), solvent evaporated in vacuo, then the residue triturated with ether and filtered. The filtrate was concentrated then distilled to give 4-(2-phenoxy-n-propoxy)piperidine (0.5 g.), b.p. 118°-122° C./0.3 mm., characterized spectroscopically.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[SH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([S:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C)c(S)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Sc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of 2,4,6-trimethylbenzene-1-thiol (231 mg, 1.52 mmol) in 1-methyl-2-pyrridone (2 mL) was added NaH (58 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (131 mg, 0.51 mmol) in 1-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 60° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 180 mg (94%) of 7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[C:23]([N:35]2[CH2:36][CH2:37][CH:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH2:33][CH2:34]2)[CH:22]=[CH:21][C:20]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)nc(-c1cc(Br)ccc1F)n2C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(F)c(-c3nc4cc(OC)ccc4n3C(=O)OC(C)(C)C)c2)CC1
Temperature: 80 °C
Yield: 65.9 %

Procedure:
Method 9—Step a 2-(5-Bromo-2-fluoro-phenyl)-5-methoxy-benzoimidazole-1-carboxylic acid tert-butyl ester (obtained as described in general method 6, step c) (1.05 g, 2.50 mmol), piperidine-4-carboxylic acid ethyl ester (0.51 g, 3.25 mmol) and cesium carbonate (4.07 g, 12.50 mmol) were placed into a dried schlenk tube and 3 cycles of vacuum/nitrogen were performed, then dry toluene (4 mL) was added. At the same time palladium(II)acetate (0.11 g, 0.50 mmol), and BINAP (0.48 g, 0.75 mmol) were placed into a dried schlenk tube under nitrogen and 3 cycles of vacuum/nitrogen were performed. Then dry toluene (2 mL) was added, at room temperature under nitrogen, and the mixture was added to the first schlenk. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, EtOAC (20 mL) was added and the mixture filtered off. Solvent was removed and the crude was purified by flash chromatography (eluent gradient: cyclohexane:EtOAc from 4:1 to 3:1), to obtain 0.82 g of the title compound (69%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:32](=[O:34])[CH3:33])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Yield: 72 %

Procedure:
To a stirred solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (250 mg, 0.753 mmol) and triethylamine (200 μl. 1.88 mmol) in dichloromethane (2 ml) was added dropwise acetic anhydride (78 μl, 0.828 mmol). Reaction left at ambient temperature until reaction complete. Dichloromethane (10 ml) added to the reaction, the organic phase extracted with saturated NaHCO3 (3×10 ml). Organic washings were dried over Na2SO4 and concentrated in vacuo to give the title compound as an oil (203 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H), 6.94 (d, 2H), 4.95-5.02 (broad, 1H), 4.24-4.38 (m, 1H), 3.79-3.88 (m, 2H), 3.52-3.64 (m, 2H), 3.45 (d, 2H), 2.70-2.88 (m, 3H), 2.36-2.45 (m, 2H), 1.98-2.10 (m, 4H), 1.78-1.90 (m, 7H), 1.05 (d, 6H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Si:4]([O:21][C@H:22]1[CH2:26][CH2:25][O:24][C:23]1=[O:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[Si:4]([O:21][C@@H:22]([CH2:26][CH2:25][S:2][CH3:1])[C:23]([OH:24])=[O:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[S-]
Reactant: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.98 %

Procedure:
Sodium thiomethoxide (0.187 g, 2.67 mmol) was added to (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (CAS no. 220351-82-6: Klar, U.; Schwede, W.; Skuballa, W.; Buchmann, B.; Schirner, M. Ger. Offen. 1999 DE 19735575 A1) (0.826 g, 2.43 mmol) in DMF (2 mL) at 0° C. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was neutralised with 2M HCl and diluted with ethyl acetate. The organic layer was extracted with water (3×100 mL), the organic layer was dried (MgSO4) and evaporated to afford (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 16.98%) which was used without further purification. A solution of trimethylsilyldiazomethane (2M solution in ether, 0.412 ml, 0.82 mmol) was added dropwise to a stirred solution of methyl alcohol (0.167 ml, 4.12 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 0.41 mmol) in toluene (0.174 ml) over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with acetic acid (0.071 ml, 1.24 mmol) and stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane to afford the product (0.120 g, 72.4%). 1H NMR (400 MHz, CDCl3) δ 1.09 (9H, s), 1.94-2.05 (5H, m), 2.48-2.60 (2H, m), 3.47 (3H, s), 4.33-4.36 (1H, m), 7.34-7.45 (6H, m), 7.62-7.67 (4H, m); m/z (ES+) (M-Ph)-=325; HPLC tR=3.63 min
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([CH3:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[C:40]([C:39]1[CH:42]=[CH:43][C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)=[CH:37][C:38]=1[CH3:44])#[N:41]
Reactant: Cc1cc(-c2ccn(C[C@H](C)N)n2)ccc1C#N
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4cnn(C)c4)on3)n2)ccc1C#N
Reaction time: 24 h
Yield: 18.1 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (48 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 15 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.28 (m, 1H), 4.42-4.49 (m, 1H), 4.55-4.66 (m, 1H), 6.62 (d, 1H), 6.67 (s, 1H), 7.49 (d, 1H), 7.63 (d, 1H), 7.72-7.75 (m, 1H), 7.81 (m, 2H), 7.96 (s, 1H), 8.14 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](Cl)=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28].C([O-])(O)=O.[Na+]>C(O)CO>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15]([NH2:28])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2c(Cl)nccc2cc1N(Cc1ccccc1)Cc1ccccc1
Reactant: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: Nc1nccc2cc(N(Cc3ccccc3)Cc3ccccc3)c(F)cc12
Temperature: 165 °C
Yield: 99 %

Procedure:
To a steel bomb charged with N,N-dibenzyl-1-chloro-7-fluoroisoquinolin-6-amine (3.953 g, 10.49 mmol, see WO 2007/002313 for preparation) was added 15 mL of 7N NH3 in ethylene glycol (prepared by condensing ammonia in ethylene glycol) and the reaction sealed and heated at 165° C. overnight (20 h). The reaction mixture was poured into sat. NaHCO3 (200 mL) and extracted with DCM (3×200 mL). The combined organics were washed with brine (150 mL) and dried (Na2SO4), filtered and concentrated to leave Intermediate 4A (3.71 g, 99% yield) as a yellow solid. MS (ESI) m/z: 358.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:18])=[C:16]([CH3:17])[C:3]=12.CC(C)([O-])C.[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>CN(C=O)C.C(OCC)(=O)C.O>[Br:18][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)(=[O:34])=[O:33])=[C:3]2[C:16]=1[CH3:17]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
To a stirred solution of ethyl 4-amino-2-bromo-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (Description 31) (500 mg, 1.519 mmol) in DMF (10 mL) was added sodium tert-butoxide (365 mg, 3.80 mmol) and 3-chlorobenzenesulfonyl chloride (0.428 mL, 3.04 mmol). The whole mixture was stirred at RT under nitrogen for ca. 1.5 h. The reaction mixture was then diluted with ethyl acetate (ca. 30 mL) and water (ca. 50 mL). The organic phase was separated and the aqueous phase re-extracted with ethyl acetate (ca. 30 mL×2). The combined organic phase was dried over Na2SO4 and the solvent concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (350 mg). LCMS (A) m/z: 504/506 [M+1]+, Rt 1.59 min (acidic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:20][O:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:31]3=[N:32][CH:33]=[CH:34][C:35](Cl)=[C:30]3[C:29]([CH3:37])=[N:28]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:35]1[CH:34]=[CH:33][N:32]=[C:31]2[N:27]([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:39][CH:38]=3)[N:28]=[C:29]([CH3:37])[C:30]=12
Reactant: O=C1Nc2ccccc2CN1c1ccc(O)c(F)c1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N5Cc6ccccc6NC5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a round bottom flask were added 3-(3-fluoro-4-hydroxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (19 mg, 0.074 mmol) and DMF (0.7 mL). 1-(4-Methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (25.4 mg, 0.088 mmol), prepared according to the procedure of Example 43, Step E, was added followed by potassium carbonate (12.2 mg, 0.088 mmol) and a 1 M solution of potassium t-butoxide in THF (0.088 mL, 0.088 mmol). The mixture was stirred at 110° C. for 4 hours under nitrogen. The reaction was cooled to room temperature and the reaction mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with a second portion of ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give 29.8 mg of brown oil. The crude oil was triturated with a dichloromethane:ether mixture and the resulting solid was filtered and dried to afford the desired product as a tan solid (17.6 mg, 47%). LRMS (APCI pos): m/e 510.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@@H:33]([CH2:37][OH:38])[C@@H:34]([CH3:36])[OH:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:38][CH2:37][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[C@H:34]([OH:35])[CH3:36]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](O)[C@@H](N)CO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.63 g, 3.64 mmol) synthesized in Example (106c) was dissolved in methanol (20 mL), and D-allo-threoninol (1.05 g, 9.99 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.00 g, 7.23 mmol) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (1.70 g, yield 87%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:9][C:3]1[C:2]([Cl:1])=[N:7][C:6]([Cl:8])=[CH:5][N:4]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ncc(Cl)nc1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 3,5-dichloro-2-pyrazinamine (2.0 g) and 2,3-dichloro benzenesulphonyl chloride (2.94 g). Yield 3.0 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=C1NCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CCNC2=O

Procedure:
To a solution of 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (23.8 g, 146 mmol) in acetone (350 mL) is added K2CO3 (34.6 g, 219 mmol) and allyl bromide (19.3 g, 161 mmol). The reaction mixture is then heated to reflux for 24 hours. After this time the solution is filtered and subsequently concentrated in vacuo. The resulting material is washed with hexanes (1×200 mL) and Et2O (1×100 mL) to give 6-allyloxy-1,2,3,4-tetrahydroisoquinolin-1-one as a tan solid, m.p. 105°-107°.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:24][N:23](COCC[Si](C)(C)C)[C:20]3=[N:21][CH:22]=2)=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[O:4].Cl(O)(=O)(=O)=O.O>C(O)(=O)C>[Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)CBr)c(C(=O)N(C)C)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)CBr)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 68.1 %

Procedure:
300 mg of 2-(2-bromo-acetylamino)-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 5 mL of glacial acetic acid. 400 μL of 70% perchloric acid was added and the resulting solution stirred at ambient temperature for 23 h. 85 mL of water was added and the resulting precipitate filtered off and dried by suction to afford 162 mg (0.32 mmol, 68%) of 2-(2-bromo-acetylamino)-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a yellow solid. MS: m/z 508.0+510.1 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[N+:14](=C)=[N-:15].O.NN>C1COCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][NH2:15])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: C=[N+]=[N-]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)NN)cc1
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 4-isopropoxy-benzoic acid (2.5 g, 13.8 mmol) in THF (5 ml) was treated with fresh ethereal diazomethane (ca. 20 mg/ml) (0.79 ml, 18.9 mmol, 1.4 eq.) at r.t. and stirred for 15 min. The crude product was then evaporated to dryness, dissolved in ethanol (10 ml) and heated under reflux with hydrazine monohydrate (3.5 ml, 71 mmol, 5 eq.) for 48 hrs. The volatiles were then completely evaporated and the product was dried overnight under high vacuum at 40° C. to afford the title compound (2.64 g, 99% yield) as a light brown solid. MS: m/e=194 (M+).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([N+:30]([O-:32])=[O:31])([N+:27]([O-:29])=[O:28])[CH2:8][N:9]([N+:24]([O-:26])=[O:25])[CH2:10][C:11]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[CH2:12][CH2:13][O:14]C(=O)C)(=O)C.CO.Cl>O>[N+:30]([C:7]([N+:27]([O-:29])=[O:28])([CH2:8][N:9]([N+:24]([O-:26])=[O:25])[CH2:10][C:11]([N+:18]([O-:20])=[O:19])([N+:21]([O-:23])=[O:22])[CH2:12][CH2:13][OH:14])[CH2:6][CH2:5][OH:4])([O-:32])=[O:31]
Reactant: CC(=O)OCCC(CN(CC(CCOC(C)=O)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])N(CC(CCO)([N+](=O)[O-])[N+](=O)[O-])CC(CCO)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
Crude 3,3,5,7,7-pentanitro-5-azanonane-1,9-diol-1,9-diacetate (66.5 g) was stirred in 615 ml of warm (50° C.) MeOH in a 2000 ml round-bottom flask. Distilled water (265 ml) was added followed by 19 ml of concentrated hydrochloric acid. The mixture was heated at 67°-69° C. (mild reflux) overnight before nearly all the solvent was removed under reduced pressure on a rotary evaporator (water bath at 35° C.). The white solid (mp 118°-120° C.) was removed by filtration and washed with cold water. Crystallization from methanol-water gave 50.0 g, mp 121.5°-123° C. The second crop (2.9 g, mp 118°-120° C.) raised the yield to 52.9 g (97 percent). 1H NMR (acetone-d6 +1 dr. D2O): δ3.00 (t, 2H), 2.90 (t, 2H), 5.57 (s, 2H).