Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH:33]([CH3:35])[CH3:34]>>[CH3:34][CH:33]([CH3:35])[CH2:32][C:31]1[N:27]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:28][CH:30]=1
Reactant: CC(C)CC(=O)CBr
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)Cc1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (about 0.182 mmol) of the compound from Example 115A and 49 mg (0.273 mmol) of 1-bromo-4-methylpentan-2-one (J. Org. Chem., 19, 2005, 4141-4153) were reacted according to the General Method 3. Yield: 50 mg (55% of theory).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](I)([CH3:9])[CH3:8].[OH:11][C:12]1[CH:21]=[CH:20][C:15]2[S:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1.O>CN(C)C=O>[CH:7]([O:11][C:12]1[CH:21]=[CH:20][C:15]2[S:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)([CH3:9])[CH3:8]
Reactant: CC(C)I
Reactant: O=c1oc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2sc(=O)oc2c1
Reaction time: 4 h

Procedure:
Potassium carbonate (829 mg) and isopropyl iodide (300 μL) were added to a solution of 6-hydroxy-1,3-benzoxathiol-2-one (504 mg) in N,N-dimethylformamide (15 mL) to form a reaction solution. This reaction solution was stirred for 4 hours at normal temperature, and then for 8 hours at 40° C. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the target product (300 mg) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[N:12]1([C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1oc(N2CCCC2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N2CCCC2)oc1C(=O)O
Reaction time: 8 h

Procedure:
The 5-pyrrolidine-1-yl-methyl-furan-2-carboxylic acid ethyl ester (770 mg, 3.45 mmol) obtained in Example 55 (1) was dissolved in ethanol (4 ml). A 1 N sodium hydroxide aqueous solution (5.17 ml) was added dropwise to the solution, and the mixture was stirred overnight. The reaction mixture was neutralized with a 1 N hydrochloric acid solution (5.17 ml), and then ethanol was evaporated. The residue was dried to afford 5-pyrrolidine-1-yl-methyl-furan-2-carboxylic acid containing sodium chloride (1.08 g, sodium chloride content: 38% wt., quant.) as a white solid, which was used directly for the following reaction.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8](=[O:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[O:18]=[C:8]([CH2:1][CH3:2])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Ethyl magnesium bromide (1M solution in tetrahydrofuran, 13.7 ml, 13.7 mmol)) was added to a stirred solution of tert-butyl 2-[methoxy(methyl)amino]-2-oxoethylcarbamate (Synth. Commun. 1988, 18, 2273) (1 g, 4.58 mmol) in tetrahydrofuran (25 ml) at 0° C. then stirred at 0° C. for 15 minutes. The solution was allowed to warm to room temperature and was stirred for 45 minutes. Ethyl acetate (5 ml) was added, followed by saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine. The organic phase was then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of hexane:ethyl acetate (85:15 to 70:30), to afford the title compound as a colorless oil, 730 mg, 84% yield.
Reaction SMILES: I[N:2]1[C:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:9][NH:10][C:5]=2[CH:4]=[CH:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:24][C:25]=1[O:26]CC1C=CC(OC)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl.C(#N)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:2]2[C:6]3[N:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=4)[CH2:9][NH:10][C:5]=3[CH:4]=[CH:3]2)[CH:23]=[CH:24][C:25]=1[OH:26]
Reactant: Oc1ccc(C2=Nc3c(ccn3I)NC2)cc1
Reactant: COc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2OC)cc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(-n2ccc3c2N=C(c2ccc(O)cc2)CN3)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
84 mg (0.25 mmol) of 4-(5-iodo-1H-pyrrolo[2,3-b]pyrazin-3-yl)-phenol, 120 mg (0.33 mmol) of 2-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 15 mg (8 mol %) of dichlorobis(triphenylphosphino)palladium(II) were placed in a vial and 1.5 ml of acetonitrile and 1.5 ml of a 2 M aqueous solution of sodium carbonate were added. The mixture was irradiated in a Personal Chemistry® microwave reactor to 165° C. for 1200 sec. The resulting mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes. The resulting intermediate was dissolved in 120 ml of dichloromethane and 1.5 g (2.12 mmol) of PS-thiophenol (Argonaut Technologies) was added. To this was added 2 ml of trifluoroacetic acid and the mixture stirred at room temperature for 1 hour. The resin was filtered off and washed with dichloromethane. The filtrate was washed with a saturated aqueous solution of sodium bicarbonate. The phases were separated and the aqueous layer extracted twice with ethyl acetate. All organic phases were combined, dried over sodium sulfate and evaporated. The residue was heated up with acetonitrile, cooled down to room temperature and the supernatant was removed. The residue was dried in vacuo to afford 15 mg (45 μmol, 18% yield) of 4-{5-[3-methoxy-4hydroxyphenyl]-1H-pyrrolo[2,3-b]pyrazin-3-yl}-phenol as a beige powder. 1H-NMR (d6-DMSO) δ: 12.06 [1H] d, 9.35 [1H] s, 9.30 [1H] s, 8.83 [1H] s, 8.20 [1H] d, 8.12 [2H] d (m), 7.75 [1H] d, 7.65 [1H] dd, 6.93 [1H] d, 6.85 [2H] d (m), 3.91 [3H] s. MS, m/z: 334 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.I[C:17]1[N:18]=[CH:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:10]=[C:9]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=3)[S:8][C:7]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CCOC(=O)Cn1cnc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
To a solution of 7-chlorothienopyridine (2.23 g, 13.1 mmol) in dry THF (50 mL) at −78° C. under N2 was added n-butyllithium (2.5 M in hexanes, 5.6 mL, 14 mmol), dropwise, with stirring. The resulting suspension was stirred for 30 min at −78° C., then ZnCl2 (0.5M in THF, 30 mL, 15 mmol) was added and the mixture was allowed to warm to 0° C. Imidazole 372 (3.20 g, 11.4 mmol) and tetrakis(triphenylphosphine)palladium (0.40 g, 0.35 mmol) in THF (50 mL) were then added to the aryllithium suspension, and the mixture was heated under reflux for 2 h, then cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was collected, filtered, dried (anhydrous MgSO4), filtered again and concentrated. The resulting solid was triturated (1:1 ethyl acetate/hexanes) to afford 373 (1.62 g, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.55 (d, J=5.1, 1H); 7.91 (d, J=1.2, 1H); 7.78 (d, J=1.2, 1H); 7.77 (s, 1H); 7.45 (d, J=5.2, 1H); 5.05 (s, 2H); 4.17 (q, J=7.2, 2H); 1.23 (t, J=7.0, 3H). LRMS (M+H): 322.0
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]1[O:10][N:9]=[C:8](Cl)[CH2:7]1)[C:3]([OH:5])=[O:4].[OH-:12].[Na+].Cl>>[CH2:7]1[C:8]([OH:12])=[N:9][O:10][CH:6]1[CH:2]([NH2:1])[C:3]([OH:5])=[O:4]
Reactant: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(C(=O)O)C1CC(O)=NO1
Yield: 80 %

Procedure:
To 1.20 g. (6.75 mmole) of (αS,5S)-α-amino-3-chloro- 4,5-dihydro-5-isoxazol-acetic acid (AT-125), is added 20 ml. of 2 N sodium hydroxide and stirred at 25° for 36 hours. The solution is brought to ~3.5 pH with 6 N hydrochloric acid (dropwise addition) and then stored at -10° (freezer) overnight. The crystals are collected by filtration, washed twice with cold water, and then dried giving 720 mg. of trichloromic acid. The initial filtrate is lyophilized and the resulting powder is taken up in 4 ml. of water, filtered, and washed with two 4 ml. portions of cold water, and dried yielding an extra 160 mg. of tricholomic acid (total 80% yield)
Reaction SMILES: [S:1]([C:5]1[CH:23]=[CH:22][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:22]=[CH:23][C:5]([S:1]([NH2:2])(=[O:3])=[O:4])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCOc1ccc(S(N)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCOc1ccc(S(N)(=O)=O)cc1
Yield: 177.4 %

Procedure:
A solution of tert-butyl (4-(4-sulfamoylphenoxy)butyl)carbamate (0.72 g, 2.09 mmol) in TFA (5.0 mL) and DCM (5.0 mL) was stirred at rt for overnight. After the solvent was evaporated under a steam of N2, the reaction mixture was dissolved in water (20.0 mL) and acetonitrile (5.0 mL) and lyophilized to afford 4-(4-aminobutoxy)benzenesulfonamide as a yellow solid (0.906 g) containing TFA. 1H NMR (400 MHz, DMSO) 7.74-7.72 (m, 4H), 7.20 (s, 2H), 7.06 (d, 2H), 4.06 (t, 2H), 2.89-2.82 (m, 2H), 1.80-1.75 (m, 2H), 1.71-1.65 (m, 2H); MS (ESI), 245.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Yield: 87.4 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-6-fluorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (3.0 g, 6.06 mmol), DCM (30 mL) and trifluoro acetic acid (2.0 mL) to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.81 (s, 3H), 3.85 (s, 3H), 7.34-7.73 (m, 6H), 12.80 (s, 1H); MS (m/z): 376.16 (M−H)−.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[C:17]4[O:71][C:67]5=[C:68]([Cl:70])[CH:69]=[C:64]([CH:65]=[CH:66]5)[C@@H:63]([OH:72])[C@@H:62]5[NH:73][C:74](=[O:75])[C@@H:43]([C:44]6[CH:45]=[CH:46][C:47]([OH:79])=[C:48]([C:50]7[C:55]([OH:56])=[CH:54][C:53]([OH:57])=[CH:52][C:51]=7[C@@H:58]([C:76]([OH:78])=[O:77])[NH:59][C:60]5=[O:61])[CH:49]=6)[NH:42][C:40](=[O:41])[C@H:39]5[C:19](=[CH:20][C:21]=3[O:22][C:23]3[CH:24]=[CH:25][C:26]([C@@H:30]([OH:94])[C@@H:31]([NH:84][C:85]([C@H:87]([NH:92][CH3:93])[CH2:88][CH:89]([CH3:91])[CH3:90])=[O:86])[C:32]([NH:34][C@@H:35]([CH2:80][C:81]([NH2:83])=[O:82])[C:36]([NH:38]5)=[O:37])=[O:33])=[CH:27][C:28]=3[Cl:29])[CH:18]=4)[O:13][C@H:12]([CH2:95][OH:96])[C@@H:11]([OH:97])[C@@H:10]2[OH:98])[CH2:5][C@@:4]([NH2:100])([CH3:99])[C@@H:3]1[OH:101].Cl.Cl.[CH3:104][O:105]C(=O)CN.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O.O.CO.C(Cl)(Cl)Cl.CN(C=O)C>[CH3:104][O:105][NH:59][CH2:58][C:76]([OH:78])=[O:77].[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([O:15][C:16]3[C:17]4[O:71][C:67]5=[C:68]([Cl:70])[CH:69]=[C:64]([CH:65]=[CH:66]5)[C@@H:63]([OH:72])[C@@H:62]5[NH:73][C:74](=[O:75])[C@@H:43]([C:44]6[CH:45]=[CH:46][C:47]([OH:79])=[C:48]([C:50]7[C:55]([OH:56])=[CH:54][C:53]([OH:57])=[CH:52][C:51]=7[C@@H:58]([C:76]([OH:78])=[O:77])[NH:59][C:60]5=[O:61])[CH:49]=6)[NH:42][C:40](=[O:41])[C@H:39]5[C:19](=[CH:20][C:21]=3[O:22][C:23]3[CH:24]=[CH:25][C:26]([C@@H:30]([OH:94])[C@@H:31]([NH:84][C:85]([C@H:87]([NH:92][CH3:93])[CH2:88][CH:89]([CH3:90])[CH3:91])=[O:86])[C:32]([NH:34][C@@H:35]([CH2:80][C:81]([NH2:83])=[O:82])[C:36]([NH:38]5)=[O:37])=[O:33])=[CH:27][C:28]=3[Cl:29])[CH:18]=4)[O:13][C@H:12]([CH2:95][OH:96])[C@@H:11]([OH:97])[C@@H:10]2[OH:98])[CH2:5][C@@:4]([NH2:100])([CH3:99])[C@@H:3]1[OH:101]
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN[C@H](CC(C)C)C(=O)N[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H]2C(=O)N[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)O)c4cc(O)cc(O)c4-c4cc3ccc4O)[C@H](O)c3ccc(c(Cl)c3)Oc3cc2cc(c3O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O[C@H]2C[C@](C)(N)[C@H](O)[C@H](C)O2)Oc2ccc(cc2Cl)[C@H]1O
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CONCC(=O)O
Reaction time: 0.17 h

Procedure:
Vancomycin hydrochloride (317 mg, 0.213 mmol) and glycine methyl ester hydrochloride (54 mg, 0.426 mmol) are dissolved in 2 mL DMSO and 2 mL DMF and stirred at 0° C. Diisopropylethylamine (186 μL, 0.3195 mmol) is added to the reaction vessel via syringe followed by HOBt/HBTU (710 μL 0.45M DMF solution, 0.319 mmol). The ice bath is removed after addition. After 10 minutes, the reaction is completed and the reaction solution is directly loaded to a poly(divinylbenzene) column (30 mm×8 cm, 50-100 micron particle size) and eluted with methanol/water (0, 10%, 20%, 30%, 40%, 50% of 100 mL each). The fractions containing the pure products are combined and evaporated to give 249 mg of (CXXIX) as a white powder, 77%. Rf=0.15 (CHCl3:MeOH:H2O=3:2:0.5). Mass Spec. [M+H]+, 1521; [M−V]+, 1377.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>CN(C=O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
11 g of hydroquinone (100 mmol) in 100 ml of DMF is placed at 80° C. for 2 h. This mixture is cooled at ambient temperature then a solution of ethyl bromoisobutyrate (14.7 ml, 100 mmol) in 30 ml of DMF is added dropwise. The mixture is stirred for 3 h then the reaction medium is dry concentrated. The residue obtained is taken up in a 1 N HCl solution then extracted with AcOEt. The organic phases are washed with water, dried on MgSO4, then dry concentrated. The residue obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 80:20). 9 g of oil corresponding to intermediate 10c are thus isolated (40% yield). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 70:30, Rf=0.50.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21](C4CCCCO4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([C:31](=O)[CH3:32])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)C1C=CC=CC=1.[CH3:35][C@H:36]1[CH2:41][NH:40][CH2:39][C@@H:38]([CH3:42])[N:37]1C(OC(C)(C)C)=O>>[CH3:35][C@@H:36]1[NH:37][C@H:38]([CH3:42])[CH2:39][N:40]([CH:31]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=3[F:34])[N:20]=[C:19]3[NH:21][N:22]=[C:23]([CH3:24])[C:18]=23)[CH3:32])[CH2:41]1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(C(C)N3C[C@@H](C)N[C@@H](C)C3)c12

Procedure:
The title compound was prepared in analogy to Example 97 starting from 1-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethanone and (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][OH:8])[N:6]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][O:8][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N)nc1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 2.0 g (9.8 mmol) of ethyl 2-amino-4-(hydroxymethyl) -1,3-thiazole-5-carboxylate (Intermediate 209) and 1.3 g (19.4 mmol) of imidazole in 20 ml DMF was added 1.6 g (10.6 mmol) of t-butyldimethylsilyl chloride. After stirring for 2 h, solvent was removed and the residue was taken up in water. Insoluble solids were collected, ground up, washed with water and dried in vacuo to afford 2.95 g of product. MS (ES) (MH+): 317 for C13H24N2O3SSi; NMR (d6-DMSO): 0.03 (s, 6H), 0.86 (s, 9H), 1.2 (t, 3H), 4.1 (q, 2H), 4.8 (s, 2H), 7.8 (s, 2H).
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(N(C(C)C)CC)(C)C.Br[C:29]1[CH:30]=[N:31][C:32]([NH:35][CH3:36])=[N:33][CH:34]=1.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>CCOC(C)=O.[Cu]I.O1CCOCC1>[CH3:36][NH:35][C:32]1[N:31]=[CH:30][C:29]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:34][N:33]=1
Reactant: CNc1ncc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNc1ncc(C#C[Si](C)(C)C)cn1
Reaction time: 8 h

Procedure:
A 100 mL round bottom flask was charged with palladium(bisbenzonitrile)dichloride (0.23 g, 0.61 mmol), trit-butylphosphonium tetrafluoroborate (0.35 g, 1.2 mmol) and copper (I) iodide (0.11 g, 0.61 mmol) under argon. 20 mL dioxane was added, followed by diisopropylethylamine (2.6 mL, 18 mmol), 5-bromo-N-methylpyrimidin-2-amine (2.3 g, 12 mmol), and trimethylsilyl acetylene (3.4 mL, 24 mmol). The reaction was allowed to stir overnight. The cloudy brown mixture was diluted with EtOAc and filtered through a pad of silica gel and concentrated in vacuo to give a brown solid. This was further purified by silica gel chromatography, eluting with 0-50% EtOAc/dichloromethane to give N-methyl-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine as a yellow solid. MS m/z=206 [M+H]+. Calc'd for C10H15N3Si: 205.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][C:11]=2[C:10]([NH2:25])=[N:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][N:42]3[CH2:47][CH2:46][N:45]([C:48](=O)[CH2:49]CCl)[CH2:44][CH2:43]3)=[CH:40][C:35]=2[O:34][CH2:33]1>>[NH2:25][C:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13](=[O:24])[C:12]=2[N:8]([C:6](=[O:5])[CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][N:42]([CH2:41][C:39]3[CH:38]=[CH:37][C:36]4[O:32][CH2:33][O:34][C:35]=4[CH:40]=3)[CH2:43][CH2:44]2)[N:9]=1
Reactant: Cc1ccc(N2CCc3c(N)nn(C(=O)OC(C)(C)C)c3C2=O)cc1
Reactant: O=C(CCCl)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(Cc5ccc6c(c5)OCO6)CC4)c3C2=O)cc1

Procedure:
A target compound (101.7 mg, 0.196 mmol, 51.9%) was yielded as white solid in the same manner as Example 1 by reacting 1-N-t-butoxycarbonyl-3-amino-4,5,6,7-tetrahydro-6-N-(p-tolyl)pyrazolo[3,4-c]pyridin-7-one (130 mg, 0.379 mmol) with potassium carbonate (57.6 mg, 0.417 mmol) and 1-[4-{(benzo[d][1,3]dioxol-5-yl)methyl}piperazin-1-yl]-3-chloropropan-1-one (123.7 mg, 0.398 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:17]3[CH:26]=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cnc4ccccc4n3)C2C1
Temperature: 80 °C
Yield: 107 %

Procedure:
To a mixture of 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (Intermediate 1, 1.07 g, 5.05 mmol) and 2-chloro-quinoxaline (1.02 g, 6.06 mmol) in DMF (20.0 mL) was added Cs2CO3 (3.95 g, 12.1 mmol). The reaction mixture was heated at 80° C. for 16 h then cooled to ambient temperature. The reaction mixture was partitioned between water (400 mL) and ethyl acetate (50 mL) twice. The organic layers were combined and washed with water. The organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield crude title compound (1.84 g) which was used in the next step without purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([NH:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]([NH:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: CC(C)(NC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)O

Procedure:
A solution of 2{(E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acryloylamino}-2-methylpropionic acid (40 mg) in EtOAc (4 mL) is hydrogenated at 1 atm over 20 mg of 10% Pd/C for 24 h. The catalyst is filtered through Celite and the solvent removed under reduced pressure to give the title compound as a yellow solid: (M−1)−=384, HPLC retention time=0.71 min. (Method A).