Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([OH:27])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[NH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>CN(C)C=O.O>[ClH:1].[N:50]1[CH:51]=[CH:52][CH:53]=[C:48]([NH:47][C:25](=[O:27])[CH2:24][C@@H:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH:49]=1
Reactant: Nc1cccnc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)Nc1cccnc1)c1nnc(C)n1-2
Yield: 52.1 %

Procedure:
(S)-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (2.64 g) is dissolved in dimethylformamide (30 ml). N-Dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (1.51 g) and triethylamine (1.08 ml) are added in order and the mixture is stirred. Five minutes later, 3-aminopyridine (0.66 g) is added to the reaction mixture and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water, and the obtained crystals are purified by column chromatography (chloroform: methanol =50: 1). The crystals are converted to hydrochloride with ethanol/hydrochloric acid in ethyl acetate, and recrystallized from ethanol/ethyl acetate to give 0.88 g of (S)-N-(3-pyridyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide hydrochloride, melting point 198°-201° C.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[CH2:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCO
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-TsOH (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf(15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:13]=3[O:12]2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1C(=Cc2c[nH]c3ccccc23)Oc2c(CN3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0305 g, 0.0664 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indol-3-yl)methylene-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0220 g, 95%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH:22]([NH2:40])[CH2:23][O:24][CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[CH2:42][C:43]([O:45][CH3:46])=[O:44].C(N(CC)CC)C>C1COCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:43]([CH2:42][NH:40][CH:22]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=2[CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=1)([O:45][CH3:46])=[O:44]
Reactant: NC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21
Reactant: COC(=O)CBr
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21

Procedure:
A mixture of the title product of Example 6, methyl bromoacetate (one equivalent) and triethylamine (one equivalent) were refluxed in THF for 22h. The reaction was partitioned between diethyl ether-water and the organic phase separated and dried (MgSO4). Solvent was removed in vacuo and the residue redissolved in ethanol. Oxalic acid was added, solvent removed in vacuo, and the residue recrystallised to give the title compound. mp 160°-165° C. (ethyl acetate-petroleum ether). 1H NMR (360MHz, DMSO-d6) 2.8-3.0 (2H, m), 3.2 (2H, s), 3.4-3.5 (6H, m), 3.6-3.65 (1H, m), 3.9-3.95 (1H, m), 4.5 (3H, s), 7.00-7.2 (8H, m), 7.9 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CNOC.[CH:26]1C=CC2N(O)N=NC=2[CH:31]=1.C([Mg]Br)=C>CN(C=O)C.C1COCC1>[F:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([F:18])[CH:14]=1)[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:19](=[O:21])[CH:26]=[CH2:31]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: C=C[Mg]Br
Agent: CNOC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-butoxycarbonyl)-3,5-difluoro-L-phenylalanine (1) is coupled to N-methyl-N-methoxylamine using the carbodimide EDC in the presence of HOBT in DMF. The “Weinreb” amide product (m.p. 48° C.) is then treated with vinylmagnesium bromide in THF at 0° C. for 2 hr. Workup provided vinyl ketone 2 (m.p. 115° C.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH3:35])([CH3:34])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[C:26](OCC)=[O:27])C>C(OC)(C)(C)C>[CH3:34][C:11]([CH3:35])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][OH:27])[CH2:10][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCCC(=O)CCCCCCC(C)(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CC(C)(CO)CCCCCCC(O)CCCCCCC(C)(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
Under N2-atmosphere, methyl tert-butyl ether (MTBE, 80 mL) was added to LiAlH4 (0.67 g, 17.65 mmol) and the suspension was stirred under cooling with an ice-water bath. A solution of 209i (3.0 g, 7.03 mmol) in MTBE (20 mL) was added dropwise, followed by additional MTBE (40 mL). After 2 h at 0° C., the reaction mixture was carefully quenched by addition of ethyl acetate (8 mL) and allowed to warm to room temperature overnight. The mixture was cooled with an ice-water bath and carefully hydrolyzed by addition of crushed ice (15 g) and water (15 mL). The pH was adjusted to 1 by addition of 2 N aqueous sulfuric acid (28 mL) and the solution was stirred at room temperature for 15 min. The layers were separated and the aqueous layer was extracted with MTBE (40 mL). The combined organic layers were washed with deionized water (50 mL), saturated NaHCO3 solution (40 mL), and brine (40 mL), dried over anhydrous MgSO4, concentrated in vacuo and dried in high vacuo. The crude product (2.65 g) was purified by recrystallization from hot CH2Cl2 (20 mL). The crystals were filtered, washed with ice-cold CH2Cl2 (20 mL) and dried in high vacuo to furnish 211i (1.59 g, 66%) as a white solid. Mp 75-77° C. 1H NMR (CDCl3): δ (ppm): 3.57 (m, 1H), 3.30 (s, 4H), 1.72 (br, 2H), 1.50-1.16 (m, 25H), 0.85 (s, 12H). 13C NMR (CDCl3): δ (ppm): 72.09, 38.79, 37.61, 35.21, 30.70, 29.85, 25.78, 24.06, 23.92. HRMS (LSIMS, gly): Calcd for C21H45O3 (MH+): 345.3369, found: 345.3364. HPLC: 95.0% pure.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[N:7]1C2[C:11](=[CH:12][CH:13]=[C:14]3C=2N=CC=C3)[CH:10]=[CH:9][CH:8]=1.C([Li])CCC.C(Cl)(=[O:31])CCCC.Cl>C1COCC1.O>[O:31]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]#[N:7]
Reactant: CCCCC(=O)Cl
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)CC#N
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a mechanically stirred solution of 14.3 g MgSO4 -dried cyanoacetic acid and ~100 mg 1,10-phenanthroline in 500 mL THF at -78° C. was added 60 mL 2.5M n-butyllithium in hexanes (~one half of the total). The indicator color persisted at this point. The solution was warmed to -5° to+5° C. after which the indicator color disappeared. Another 55 mL 2.5M n-butyllithium in hexanes was added until the indicator color again persisted. The mixture was cooled to -78° C. then 10.0 mL valeroyl chloride in 10 mL THF was added over 3 minutes. After 10 minutes the now yellow solution was allowed to warm to room temperature and stir for 1 hour. The mixture was poured into a solution of 50 mL concentrated HCl in 300 mL water. The mixture was extracted 3 times with ether. The combined organic material was washed twice with saturated NaHCO3 solution then once with brine. The washes were back extracted with ether and the back extracts were washed with brine. The back extracts were combined with the other organic material and then were dried over MgSO4. The organic material was stripped of solvent in vacuo then was distilled at ~1 Torr with the title compound distilling at 87°-91° C. The title compound was isolated as a clear oil, 6.32 g, 60% yield. To this material there was added 1% by weight BHT to prevent polymerization. The material was also kept refrigerated at 0° C. under nitrogen. Rf 0.18 in 20% EtOAc/hexane, visualized by ninhydrin stain; 1H-NMR (300 MHz, CDCl3): δ 3.46 (s, 2H), 2.62 (3 line m, 2H), 1.61 (m, 2H), 1.35 (m, 2H), 0.92 (t, J=7.3Hz, 3H); 13C-NMR (75.4 MHz, CDCl3): δ 197.6, 113.8, 41.9, 31.9, 25.3, 22.0, 13.7.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.NCC([N:61]1[CH2:66][CH2:65][N:64]([C:67](=[O:77])[C:68]2[CH:73]=[C:72]([O:74][CH3:75])[CH:71]=[CH:70][C:69]=2[Br:76])[CH:63]([CH3:78])[CH2:62]1)=O>CN(C=O)C.O>[Br:76][C:69]1[CH:70]=[CH:71][C:72]([O:74][CH3:75])=[CH:73][C:68]=1[C:67]([N:64]1[CH2:65][CH2:66][N:61]([C:20](=[O:22])[CH2:19][NH:18][C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[O:17])[CH2:62][CH:63]1[CH3:78])=[O:77]
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CN)CC2C)c1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(-c4ccccc4)cc3)CC2C)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 93.8 %

Procedure:
DIPEA (362 mg, 0.48 mL, 2.8 mmol) was added to a stirred solution of [(Biphenyl-4-carbonyl)-amino]-acetic acid (262 mg, 1.03 mmol) in DMF (3 mL). HOBT (151.6 mg, 1.12 mmol) and EDCI (214 mg, 1.12 mmol) were then added at room temperature. After 2 minutes, 2-Amino-1-[4-(2-bromo-5-methoxy-benzoyl)-3-methyl-piperazin-1-yl]-ethanone trifluoroacetic acid salt (400 mg, 0.93 mmol) (prepared by the method described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to 480 mg (93.3% yield) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-5-methoxy-benzoyl)-3-methyl-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.8%. 1H NMR (DMSO-d6): δ 8.5 (m, 1H), 8.0 (d, 2H), 7.8-7.7 (m, 4H), 7.6-7.4 (m, 4H), 7.0 (m, 2H), 4.75 (s, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.8 (d, 4H), 3.2 (m, 2H), 1.4-1.1 (m, 4H).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[H-].[Li+].[O:19]=[C:20]1[O:24][C@H:23]2[CH2:25][C@@H:26]([O:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])[C@H:27]([CH:28]=O)[C@H:22]2[CH2:21]1.O>COC(C)(C)C>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:28]/[C@@H:27]1[C@@H:22]2[C@@H:23]([O:24][C:20](=[O:19])[CH2:21]2)[CH2:25][C@H:26]1[O:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.969 g, 3.75 mmol) in anhydrous t-butyl methyl ether (15 ml), lithium hydride (28.6 mg, 3.60 mmol) was added and the mixture was stirred for two hours at room temperature. (3aR,4R,5R,6aS)-2-oxo-5-phenyl carbonyloxyhexahydrocyclopenta[b]furan-4-carbaldehyde (10) (0.686 g, 2.50 mmol) was added thereto and the mixed solution was stirred for approximately 6 hours at room temperature. Water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 28 g; ethyl acetate:hexane=1:2) to give (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan (11) (48.5 mg; 0.119 mmol; yield: 4.8%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:3]=1.[CH3:33][N:34]([CH3:46])[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)=[O:36].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:33][N:34]([CH3:46])[C:35](=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:12]=4)[CH:9]=3)[N:4]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:3]=2)[CH:38]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccc(C(=O)N4CCOCC4)c3)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)c1cccc(-c2nn(COCC[Si](C)(C)C)c3ncc(-c4cccc(C(=O)N5CCOCC5)c4)cc23)c1
Temperature: 90 °C

Procedure:
A mixture of (3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)(morpholino)methanone (50 mg, 0.089 mmol), 3-(dimethylcarbamoyl)phenylboronic acid (34 mg, 0.177 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (3.6 mg, 0.0045 mmol) and sodium carbonate (2M aqueous solution, 0.134 mL, 0.267 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford N,N-dimethyl-3-(5-(3-(morpholine-4-carbonyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide as a clear oil. MS: m/z 586.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>>[N:27]1[CH:28]=[CH:29][N:30]=[CH:31][C:26]=1[NH:25][CH2:20][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[N:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cnccn1
Reactant: O=Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNc4cnccn4)c3)n2)cc1

Procedure:
Intermediate 28 was coupled with 2-aminopyrazine following procedure B. LC-MS showed the product had the expected M+H+ of 399. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 2H), 8.1 (m, 1H), 8.0 (m, 3H), 7.7 (m, 2H), 7.5 (m, 3H), 7.1 (m, 2H), 6.7 (m, 2H), 4.6 (m, 2H), 3.6 (m, 2H), 2.8 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([C:9](=[CH:12]N(C)C)[C:10]#[N:11])=O)=[CH:5][CH:6]=1.Cl.[O:17]=[C:18]1[NH:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CO>[Br:1][C:2]1[S:3][C:4]([C:7]2[C:9]([C:10]#[N:11])=[CH:12][N:28]=[C:26]([NH:25][CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][NH:22][C:18]3=[O:17])[N:27]=2)=[CH:5][CH:6]=1
Reactant: N=C(N)NCCN1CCNC1=O
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Temperature: 100 °C

Procedure:
2-(2-Bromothiophene-5-carbonyl)-3-(dimethylamino)acrylonitrile) (3 g, 10 mmol) in N-methyl pyrrolidone (15 mL) was treated with 1-(2-(2-oxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (1 M solution in N-methyl pyrrolidone, 15 mL, 15 mmol) and cesium carbonate (3.4 g, 10 mmol). The mixture was heated at 100° C. overnight. The reaction was then allowed to cool to room temperature and poured onto crushed ice. The resulting solid that formed was suspended in hot methanol to give a yellow solid (2.3 g). The filtrate was concentrated and purified by flash chromatography using a gradient of 3 to 10% methanol in dichloromethane to obtain an additional 0.9 g of the desired product. Total yield=3.2 g. MS (M+H)+ 394.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:5][N:4]=1.[I-].[NH2:21][N+:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[K+].CO>C(Cl)Cl.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=23)[CH:6]=[CH:5][N:4]=1
Reactant: N[n+]1ccccc1
Reactant: CSc1nccc(C#Cc2cccc([N+](=O)[O-])c2)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CSc1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. solution of 2-(methylthio)-4-[(3-nitrophenyl)ethynyl]pyrimidine (4.0 g, 14.7 mmol) and N-aminopyridinium iodide (6.53 g, 29.4 mmol) in DCM (150 mL) was added potassium hydroxide (2.06 g, 36.8 mmol) in water (50 mL). The reaction was allowed to warm to rt and stirred for 16 h. The mixture was diluted with DCM and water. The organic layer was separated and the aqueous layer is extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to give a dark solid. The residue was dissolved in DCM and MeOH was added until the product formed as a precipitate. The product was collected by filtration and dried to supply the title compound (2.02 g) as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 11.36 (s, 1H), 8.62 (d, 1H, J=9.2), 8.54 (d, 1H, J=5.6), 7.94 (s, 1H), 7.82 (d, 1H, J=8.8), 7.54 (t, 1H, J=8.0), 7.46 (d, 1H, J=9.2), 7.16 (d, 1H, J=5.2), 2.59 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: CN(C)CCCN
Solvent: C1COCCO1
Product: CN(C)CCCNC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 35 μl of N,N-dimethyl-1,3-propanediamine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane/methanol/aqueous ammonia (75/23/2 by volume) to give 72 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-[3-(dimethylamino)propyl]urea, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23]O)[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S([Cl:34])(=O)=O)=CC=1.[Cl-].[Li+].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23][Cl:34])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-n2nc(CCl)cc2-c2ccc(Cl)cc2)cc1
Yield: 80.1 %

Procedure:
4-[5-(4-Chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Example 1 Step 4) (3.0 g, 8.2 mmol) was dissolved in 100 mL of dry tetrahydrofuran and treated with para-toluenesulfonyl chloride (1.56 g, 8.2 mmol), lithium chloride (350 mg, 8.2 mmol), and triethylamine (830 mg, 8.2 mmol). The solution was warmed to reflux for 16 hours and diluted with 100 mL of ethyl acetate. The solution was washed with 1 N hydrochloric acid, saturated aqueous NaHCO3, and water, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 1:1 (v:v) hexane/ethyl acetate. The appropriate fractions were combined and concentrated and the residue crystallized from ethanol/water to give pure 4-[5-(4-chlorophenyl)-3-chloromethyl-1H-pyrazol-1-yl]benzenesulfonamide as a white solid (2.51 g, 80%): mp 198-201° C. Anal. Calc'd. for C16H13N3S1O2Cl2: C, 50.27; H, 3.43; N, 10.99. Found: C, 50.34; H, 3.43; N, 10.96.