Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1.[OH-].[K+]>CO>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:24])=[O:2])=[CH:11][CH:10]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)COc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
A solution of [4-(4-tert-butoxycarbonylaminobutyl)phenoxy]acetic acid methyl ester 32 (1.28 g, 3.78 mmol) in methanol (80 mL) was added with crushed potassium hydroxide (2.50 g, 85%, 37.8 mmol) and the mixture was stirred at room temperature for 5 h. Solvent was removed by rotary evaporation. The residue was taken up in water and acidified to pH ˜1 with 6N aqueous HCl, and extracted with dichloromethane. The combined organics were washed with brine, dried over Na2SO4, and concentrated to complete dryness to afford the desired product 33 as a white solid (1.19 g, 97% yield). 1H NMR (300 MHz, CD3OD) δ 1.41 (s, 9H), 1.42–1.70 (m, 4H), 2.45–2.60 (m, 2H), 3.00–3.20 (m, 2H), 4.60 (s, 2H), 6.80 (d, 2H), 7.08 (d, 2H). m/z (ESI): 322 [C17H25NO5−H]−.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1cccc(I)c1
Reactant: Sc1ccc(Cl)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1cccc(Sc2ccc(Cl)cc2)c1
Yield: 81 %

Procedure:
The general procedure in example 39 was followed. 3-Iodoanisole (234 mg, 1.0 mmol), 4-chlorothiophenol (145 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-methoxyphenyl 4-chlorophenyl sulfide (203 mg, 81% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=50/1). Rf=0.4 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.13-7.26 (m, 2 H), 6.88 (ddd, 2 H, J=1.2 Hz, 1.8 Hz, 7.8 Hz), 6.83 (t, 2 H, J=1.5 Hz), 6.78 (ddd, 2 H, J=0.9 Hz, 2.7 Hz, 8.1 Hz), 3.75 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 160.2, 136.6, 134.3, 133.4, 132.5, 130.3, 129.5, 123.4, 116.4, 113.3, 55.7. IR (neat, cm−1) 3065, 3002, 2962, 2949, 2820. MS (EI) m/z (relative intensity) 252 (30), 250 (100). Anal Cald for C13H11ClOS, Cald. C: 62.27, H: 4.42; Found C: 62.58, H: 4.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[Cl-].[NH4+].CCO.C1COCC1>[Fe].O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCC(c3ccccc3)CC2)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(F)c(N2CCC(c3ccccc3)CC2)c(F)c1
Yield: 95.8 %

Procedure:
In a 500 mL round-bottom flask was added 1-(2,6-difluoro-4-nitrophenyl)-4-phenylpiperidine (4.53 g, 14.23 mmol), iron (3.97 g, 71.2 mmol), and ammonium chloride (1.142 g, 21.35 mmol) in a solvent mixture of EtOH (60 mL)/THF (60 mL)/water (20 mL). The mixture was refluxed for 3 hours with vigorous stirring, cooled, filtered through diatomaceous earth and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to give the title compound as yellow solid (3.93 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.81 (m, 4H) 2.54-2.64 (m, 1H) 2.95-3.03 (m, 2H) 3.09 (t, J=10.57 Hz, 2H) 5.42 (s, 2H) 6.10-6.21 (m, 2H) 7.15-7.22 (m, 1H) 7.25-7.34 (m, 4H); MS (ESI+) m/z 289 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:8]([O:1][CH2:8][C:7]1[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=1)[C:7]1[CH:10]=[CH:11][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(COCc2ccccc2)cc1
Yield: 82 %

Procedure:
Compound 11a (Rb═H, 2.0 g, 6.34 mmol) was dissolved in DCM/water, 2/1, v/v (30 ml) and to this solution was added sodium hydroxide (2N, 10 ml). To this mixture was added tetrabutylammonium bromide (0.2 g, 0.63 mmol, 0.1 eq) and 4-chlorobenzyl bromide (1.43 g, 6.98 mmol, 1.1 eg). The mixture was stirred for 16 hrs at room temperature after which time TLC analysis (100% DCM, Rf 0.55) showed complete reaction. The mixture was diluted with DCM (15 ml/mmol), the layers were separated and the water layer was extracted with DCM. The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/petroleum ether, 3/1 to 1/0, v/v) to give compound 12 (Ra=4Cl, Rb═H, 2.3 g, 82%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9H); 2.75 (bs, 2H); 3.75 (bs, 2H); 4.35 (bs, 2H); 5.05 (s, 2H); 6.4 (s, 1H), 6.94 (d, 1H); 7.30-755 (m, 7H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:13]([C:17]1[CH:21]=[C:20]([NH:22][C:23]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:24])[N:19]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[CH:37]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].Cl.[Na+].[Cl-]>C(Cl)Cl>[C:13]([C:17]1[CH:21]=[C:20]([NH:22][C:23]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:24])[N:19]([C:36]2[CH:37]=[C:38]([O:42][S:2](=[O:4])(=[O:3])[NH:5][C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])[CH:39]=[CH:40][CH:41]=2)[N:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(O)c2)n1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C1CCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(OS(=O)(=O)NC(=O)N3CCCC3)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.4 %

Procedure:
To a stirring solution of chlorosulfonyl isocyanate (0.35 g, 5 mmol) in CH2Cl2 (20 mL) at 0° C. was added pyrrolidine (0.18 g, 5 mmol) at such a rate that the reaction temperature did not rise above 5° C. After stirring for 2 h, a solution of Example 41 (1.10 g, 6.5 mmol) and triethylmine (0.46 g, 9 mmol) in CH2Cl2 (20 mL) was added. When the addition was complete, the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured into 10% HCl (10 mL) saturated with NaCl, the organic layer was separated and the aqueous layer extracted with ether (20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo, purified by preparative HPLC to yield (pyrrolidine-1-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]phenyl ester (40 mg). 1H NMR (CDCl3): δ 9.12 (brs, 1H), 8.61 (brs, 1H), 7.85-7.80 (m, 3H), 7.65 (d, J=8.0 Hz, 2H), 7.53-7.51 (m, 1H), 7.45-7.25 (m, 5H), 6.89 (s, 4H), 3.36-3.34 (brs, 1H), 3.14-3.13 (brs, 2H), 1.69 (brs, 2H), 1.62 (brs, 2H), 1.39 (s, 9H); MS (ESI) m/z: 577 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[CH:42]=[CH:41][NH:40][C:37]3=[N:38][CH:39]=2)O1>>[ClH:1].[ClH:1].[ClH:1].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:34]4[CH:35]=[C:36]5[CH:42]=[CH:41][NH:40][C:37]5=[N:38][CH:39]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cnc4[nH]ccc4c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: Cl

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (60 mg, 0.17 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.25 mmol) followed by formation of the trihydrochloride salt to afford the desired product (7.5 mg, 9%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.19 (s, 1H), 9.08 (s, 2H), 8.65 (d, J=8.9 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 7.72 (d, J=3.7 Hz, 1H), 6.91 (d, J=3.6 Hz, 1H), 5.69-5.59 (m, 1H), 3.18 (d, J=6.8 Hz, 2H), 2.94 (s, 6H), 2.77 (s, 3H), 2.55-2.45 (m, 2H), 2.08-1.98 (m, 3H), 1.76-1.64 (m, 2H), 1.48-1.36 (m, 2H). ESI MS m/z 443 [M+H]+; HPLC>99% (AUC), tR=9.25 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11]O)=[CH:4][CH:3]=1.[I:22]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]([CH2:11][I:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)COc1ccc(Br)nc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCC(CI)COc1ccc(Br)nc1
Yield: 97 %

Procedure:
Iodination of alcohol 187 with I2, PPh3 and imidazole as in Example 2GGG above for 18 h, followed by chromatography of the product on silica gel, eluting with petroleum ether and pentane (foreruns) and then with 5-25% Et2O/pentane, gave 2-bromo-5-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(iodomethyl)propoxy]pyridine (188) (97%) as a colourless oil; 1H NMR (CDCl3) δ 8.07 (d, J=3.0 Hz, 1H), 7.37 (dd, J=8.7, 0.3 Hz, 1H), 7.11 (dd, J=8.7, 3.2 Hz, 1H), 4.06 (dd, J=9.2, 5.7 Hz, 1H), 3.99 (dd, J=9.2, 6.1 Hz, 1H), 3.74 (dd, J=10.1, 5.6 Hz, 1H), 3.70 (dd, J=10.1, 5.5 Hz, 1H), 3.36 (d, J=6.0 Hz, 2H), 2.12 (sept, J=5.8 Hz, 1H), 0.89 (s, 9H), 0.06 (2 s, 6H); HRESIMS calcd for C15H26BrINO2Si m/z [M+H]+ 487.9935, 485.9955. found 487.9931, 485.9952.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:46]([CH2:49]C)CC)C.[OH2:51]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:26][C:49](=[O:51])[NH:46][CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: O
Reactant: CCN(CC)CC
Reactant: O=C(O)C(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2cccc(OCC(F)(F)F)c2)C(c2ccc(F)cc2)O1
Yield: 87 %

Procedure:
To a solution of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionic acid (2.68 g, 7.20 mmol) in tetrahydrofuran (60 ml) were added diphenylphosphoryl azide (1.71 ml,7.92 mmol) and triethylamine (1.51 ml, 10.8 mmol) and the mixture was heated under reflux for 3 hrs. The reaction solution was allowed to stand at room temperature, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS,5SR)-5-(4-fluorophenyl)-4-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one (2.31 g, 87%).
Reaction SMILES: C[O-].[Na+].[P:4]([O-:10])([O:8][CH3:9])([O:6][CH3:7])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:16]=[O:17].FC(F)(F)C(O)=O>CO>[CH3:9][O:8][P:4]([CH:16]([OH:17])[C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=1)(=[O:10])[O:6][CH3:7]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COP(=O)([O-])OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(O)P(=O)(OC)OC)cc(OC)c1OC
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A round-bottom flask equipped with thermometer, condenser and gas inlet was charged with methanol (150 mL) and sodium methoxide (1.074 g, 20 mmol) and cooled to 0° C. under nitrogen protection. To a stirred solution were added subsequently dimethyl phosphate (19.52 g, 0.177 mol) and 3,4,5-trimethoxybenzaldehyde (30 g, 0.153 mol). A resulted solution was heated at 50° C. for 1 hour, cooled down to r.t. and treated with trifluoroacetic acid (4.6 ml). The mixture was concentrated under reduced pressure, the residue dissolved in EtOAc (300 mL), washed once with 18% brine, then once with saturated brine, dried over sodium sulfate. The filtered solution was concentrated until precipitation started. To the resulted suspension 1:1 mixture of t-butylmethyl ether and heptane was added (50 mL). Solid was filtered out, washed with two portions (20 mL) of the same solvent mixture and vacuum-dried to give 41.2 g (88%) of 1, LC purity 99.4% (AUC), m.p. 103-104° C.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.O>C(O)(=O)C>[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:1])=[CH:14][CH:15]=1
Reactant: CSc1ccc(C(=O)c2sc(=O)[nH]c2C)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(S(C)=O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Hydrogen peroxide (1 equivalent, 30%) is added to a solution of 4-methyl-5-[4-(methylthio)benzoyl]-2(3H)-thiazolone (2.7 g) in glacial acetic acid (80 ml). The mixture is stirred for 3 hours at 50° C. The precipitate obtained on addition of water is recrystallized from ethanol to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].ClCCl.CC(N(C)C)=O.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[S:30][CH:31]=[C:32]([C:34](Cl)=[O:35])[N:33]=3)=[CH:28][C:23]=2[CH2:22][CH2:21]1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[NH2:10][C:8]([C:3]1[N:4]([CH3:7])[N:5]=[CH:6][C:2]=1[NH:1][C:34]([C:32]1[N:33]=[C:29]([C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][CH2:22][C:23]=3[CH:28]=2)[S:30][CH:31]=1)=[O:35])=[O:9]
Reactant: O=C(Cl)c1csc(-c2ccc3c(c2)CCO3)n1
Reactant: Cn1ncc(N)c1C(N)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2csc(-c3ccc4c(c3)CCO4)n2)c1C(N)=O
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
4-Amino-2-methyl-2H-pyrazole-3-carboxamide (35 mg) is introduced into dichloromethane (1 ml) and dimethylacetamide (0.5 ml), and triethylamine (50 microlitres) and 4-dimethylaminopyridine (DMAP) (spatula tip) and 2-(2,3-dihydro-1-benzofuran-5-yl)-1,3-thiazole-4-carbonyl chloride CAS 306936-10-7 (66 mg) are added, and the mixture is left to stir at room temperature for 18.5 h. The solvent is then removed in vacuo, and preparative HPLC results in Example 2.1 as a white solid (35 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.[CH:35]([S:37]([CH:40]=C)(=[O:39])=[O:38])=[CH2:36].Cl.C(OCC)C>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][CH2:35][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: C=CS(=O)(=O)C=C
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)CCN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 152, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with vinyl sulfone. The crude product was dissolved in DCM and treated with 4N HCl. After stirring for 10 min diethyl ether was added and the solid precipitate collected by filtration to give 175 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 10.63 (s, 1H); 8.45 (s, 1H); 8.30 (s, 1H); 7.85 (td, J=8.75, 5.90 Hz, 1H); 7.72 (t, J=9.62 Hz, 1H); 7.42 (t, J=8.57 Hz, 1H); 7.22 (d, J=2.33 Hz, 1H); 7.11 (dd, J=8.45, 2.37 Hz, 1H); 6.97 (d, J=8.34 Hz, 1H); 4.22 (t, J=5.02 Hz, 2H); 3.82 (t, J=7.50 Hz, 2H); 3.76-3.63 (m, 2H); 3.59 (d, J=9.30 Hz, 2H); 3.16 (s, 3H); 3.14 (m, 2H); 3.06 (t, J=5.04 Hz, 2H); 2.66 (s, 1H); 1.96-1.76 (m, 4H). LCMS: RT=7.54 min, M+H+=555
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].[OH2:18].Cl>N1C=CC=CC=1>[C:1]([O:11][C:2]([CH3:10])([CH3:3])[CH3:1])(=[O:18])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O
Reactant: CC(C)(C)O
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
Terephthaloyl dichloride (5.0 g: 24.6 mmol) was dissolved in 50 ml of dehydrated pyridine, and tert-butanol (4.0 g: 54.1 mmol) was added to the mixture. The reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, dried, and recrystallized from methanol to provide 6.1 g (21.9 mmol) of 1,4-di(tert-butyl) terephthalate.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOCC)C.P(Cl)(Cl)(Cl)=O.[CH3:18][C@:19]12[CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH2:26][C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][C:29](=[O:37])[CH:28]=4)[C@@H:23]1[CH2:22][CH2:21][C:20]2=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]=[C:26]1[C:27]2[C@:32]([CH3:33])([CH2:31][CH2:30][C:29](=[O:37])[CH:28]=2)[C@@H:34]2[C@H:24]([C@H:23]3[C@@:19]([CH2:36][CH2:35]2)([CH3:18])[C:20](=[O:38])[CH2:21][CH2:22]3)[CH2:25]1
Reactant: CC(=O)[O-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), anhydrous chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and androst-4-ene-3,17-dione (0.78 g, 2.7 mmol) was stirred at reflux for about 7 hours, i.e. until the starting material had disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alkaline. The organic layer was separated, neutralized with water washings, and dried with sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluant. Thus almost pure 6-methylenandrost-4-ene-3,17-dione was obtained in 60% yield (0.843 g).
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[C:6](=[O:12])[NH:7]2)C.S(=O)(=O)(O)O.[OH:19]O.[C:21](O)(=O)[CH3:22]>>[CH2:21]([C:11]1[CH:3]=[C:4]2[C:5]([O:13][C:6](=[O:12])[NH:7][C:8]2=[CH:9][CH:10]=1)=[O:19])[CH3:22]
Reactant: CC(=O)O
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Reactant: OO
Agent: O=S(=O)(O)O
Product: CCc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 30 °C
Yield: 48 %

Procedure:
4-Ethyl isatin (3.1 g, 0.018 mol) was added to a mixture of conc. sulphuric acid (45 l) in acetic acid (14 ml). The suspension was warmed to 30° C., hydrogen peroxide 35% (2.2 ml) was added and after the addition the temperature was raised to 65° C. After being heated for 3 hours, the mixture was cooled and the precipitate filtered off, washed with water and dried to give the title compound (1.7 g), yield 48%.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccc5)c(C)c4)c23)CC1
Yield: 61 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and N-ethylpiperazine to give the title compound in 61% yield; NMR Spectrum: 0.95 (t, 3H), 2.22 (s, 3H), 2.24 (q, 2H), 2.22-2.55 (m, 8H), 2.77 (t, 2H), 4.41 (t, 2H), 5.13 (s, 2H), 7.01 (d, 1H), 7.31-7.48 (m, 7H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 488 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[C:32](=O)([O:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[O:33]C1C=CC([N+]([O-])=O)=CC=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[O:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(OCc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1cccnc1
Temperature: 100 °C
Yield: 33.8 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (25 mg, 0.074 mmol) was dissolved in dichloromethane (0.7 mL). Pyridine (0.7 mL) was added followed by 4-nitrophenyl (3-pyridylmethyl) carbonate (30 mg, 0.110 mmol). After heating at 100° C. overnight, the solvent was removed and the residue was purified by preparative LC/MS to give 3-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (12 mg, 0.025 mmol). 1H NMR (CDCl3-d) δ 2.08 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H), 4.15 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 5.54 (bs, 2H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.35 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 8.15 (m, 1H), 8.29 (s, 1H), 8.61 (s, 1H), 8.71 (s, 1H). LC/MS MH+=475.