Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[I:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([I:13])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Reactant: CCOC(=O)Cc1ccsc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.6 %

Procedure:
To a solution of ethyl 2-(2-bromothiophen-3-yl)acetate (24.00 g, 96.32 mmol) and 4-iodo-3-nitrobenzoyl chloride (30.00 g, 96.32 mmol) in anhydrous CH2Cl2 (100 mL) was added AlCl3 (38.53 g, 288.96 mmol) over a period of 4 hours at room temperature. The resulting mixture was stirred for 2 days. The reaction mixture was slowly poured onto 200 g of ice and allowed to warm to room temperature. The aqueous phase was extracted with Et2O (4×30 mL), and the combined organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 2 as a light yellow solid (20.00 g, 40%). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=2.0 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.69 (dd, J=2.0, 8.2 Hz, 1H), 7.48 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), and 1.28 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 183.84, 169.61, 153.25, 142.83, 141.87, 138.32, 136.49, 135.94, 133.07, 125.69, 124.50, 91.79, 61.76, 35.20, and 14.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:11]2[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ncc(N2CCC3(CC2)OCCO3)nc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ncc(N2CCC(=O)CC2)nc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
As shown in step 9-iv of Scheme 9, A suspension of Compound 1030 (2.46 g, 8.745 mmol) in 6N aq. HCl (43 mL) was stirred at room temperature for 2 hours. The crude reaction mixture was neutralizes at ˜4° C. by the slow addition of 6N NaOH followed by the addition of 1N aq. K2CO3). The reaction was extracted with EtOAc (3×) and the combined organics dried (MgSO4), followed by concentration under reduced pressure to give 1-(5,6-dimethoxypyrazin-2-yl)piperidin-4-one as an off white semi solid (Compound 1031, 1.51 g, 73%), which was used in the next step without further purification: 1H NMR (CDCl3, 300 MHz) δ 7.33 (s, 1H), 4.07 (s, 3H), 4.04 (s, 3H), 3.86 (m, 4H), 2.62 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[O:12][N:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[O:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OC)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2noc(CCC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-[3-(4-methoxyphenyl)methyl-1,2,4-oxadiazol-5-yl]propionate (2.4 g) was dissolved in a mixed solvent of ethanol (20 ml) and water (10 ml). Sodium hydroxide (3 g) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was concentrated. 2N hydrochloric acid was added to the residue to become acidic, which was extracted with ethyl acetate. The extract was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[N:18][CH2:19][C@H:20]([OH:37])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.B>O1CCCC1>[CH:1]([N:14]1[CH2:15][CH:16]([NH:18][CH2:19][C@H:20]([OH:37])[CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:28]=2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@@H](CN=C1CN(C(c2ccccc2)c2ccccc2)C1)COc1ccc(OCc2ccccc2)cc1
Agent: B
Solvent: C1CCOC1
Product: O[C@@H](CNC1CN(C(c2ccccc2)c2ccccc2)C1)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of (2S)-1-(1-Benzhydryl-azetidin-3-ylideneamino)-3-(4-benzyloxy-phenoxy)-propan-2-ol (0.49 g, 1 mmol) in tetrahydrofuran (4 ml) was added 1.2 ml of borane- tetrahydrofuran (1.0 M in THF), and the mixture was stirred at room temperature for 20 h. It was then quenched with 1.5 ml of 2 N NaOH, and the volatiles were evaporated. The aqueous solution was removed, and the residue was washed with water, and treated with 3 ml of 2 N HCl and 3 ml of methanol for 20 h. The mixture was then made alkaline with 1 N NaOH, and the methanol was evaporated. The resulting suspension was filtered, and the precipitate washed with water, and dried in vacuo to give 0.46 g of a white solid; m.p. 109-110° C.; MS (ES) m/z 495.7 (MH+); HRMS (EI) Calcd. for C32H34N2O3 (M+): 494.2570, Found: 494.2561.
Reaction SMILES: I[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:35][O:34][CH2:33]4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:3]=1.[C:36]([O:39][CH2:40][C:41]1[C:46]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[CH:45][C:44]([F:62])=[CH:43][C:42]=1B1OC(C)(C)C(C)(C)O1)(=[O:38])[CH3:37].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:36]([O:39][CH2:40][C:41]1[C:42]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:35][O:34][CH2:33]5)[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:3]=2)=[CH:43][C:44]([F:62])=[CH:45][C:46]=1[N:47]1[CH2:58][CH2:57][N:56]2[C:49](=[CH:50][C:51]3[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=32)[C:48]1=[O:61])(=[O:38])[CH3:37]
Reactant: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)nc(I)nc21
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3ncn(COCC[Si](C)(C)C)c3n2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 39.2 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-iodo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-amine 117f (360 mg, 0.60 mmol), {2-[(acetyloxy)methyl]-3-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-5-fluorophenyl}boronic acid 110g (360 mg, 0.90 mmol), Pd(dppf)Cl2 (30 mg, 0.030 mmol), K3PO4 (270 mg, 1.2 mmol), sodium acetate (180 mg, 1.2 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 123a as a yellow solid (200 mg, 35%). MS-ESI: [M+H]+ 850.4
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][N:9]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:10][CH:5]1[C:3]([OH:2])=[O:4])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mmol of Piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester were dissolved in 20 ml methylenchloride. 1.05 eq of DIPEA and mesylchloride were added. The reaction mixture was stirred at room temperature for 30 min. The product was extracted from etylacetate/water. The crude material was redissolved in methanol and treated with 2N NaOH. The reaction mixture was stirred at room temperature for 2 h. The mixture was neutralized with HCl and the product isolated via extraction from ethylacetate/water.
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:11])([CH3:10])[C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[CH2:12]([O:14][C:15]([C:17]1[C@@H:18]2[N:44](C)[C@H:22]([CH2:23][C:24]=1[C:25]1[CH:26]=[N:27][C:28]([O:31][CH2:32][CH2:33][O:34][C:35]3[C:40]([Cl:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=3[Cl:43])=[CH:29][CH:30]=1)[CH2:21][N:20]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19]2)=[O:16])[CH3:13]>>[Cl:7][C:6]([Cl:9])([Cl:8])[C:5]([O:4][C:2]([N:44]1[C@H:18]2[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:24]([C:25]3[CH:26]=[N:27][C:28]([O:31][CH2:32][CH2:33][O:34][C:35]4[C:40]([Cl:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=4[Cl:43])=[CH:29][CH:30]=3)[CH2:23][C@@H:22]1[CH2:21][N:20]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[CH2:19]2)=[O:3])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Reactant: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 44.3 %

Procedure:
2,2,2-Trichloro-1,1-dimethylethyl chloroformate (2.77 g, 11.6 mmol) was added to a sol. of compound C4 (1.40 g, 2.31 mmol) in CH2ClCH2Cl (30 mL), and the mixture was heated to reflux for 2 h. 2,2,2-Trichloro-1,1-dimethylethyl chloroformate (1.40 g, 5.5 mmol) was added again, and the mixture was heated to reflux for 2 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was diluted with EtOAc, and washed with aq. 1M NaOH (2×). The combined aq. layers were extracted back with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4) yielded the title compound (815 mg, 44%). LC-MS: tR=1.25 min; ES+: 796.32.
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:35]Cl)[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:35][C@H:22]([NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)CCC(=O)OCc1ccccc1
Reactant: Nc1nccc2ccc(O)cc12
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COc1ccc2ccnc(N)c2c1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
8.81 g (27 mmol) of 1-amino-7-hydroxyisoquinoline monohydrobromide was dissolved in 120 ml of DMF. 14.0 g (41 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-chloropentanoate, 11.2 g (81.0 mmol) of potassium carbonate and 9.96 g (27 mmol) of tetrabutylammonium iodide were added to the obtained solution, and they were stirred at 70° C. for 3 days. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:34])[NH:10][C@@H:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]2[O:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:34])[CH2:30][CH:31]([CH3:32])[CH3:33])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCCCNS(=O)(=O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)NCCCCNS(=O)(=O)c1ccc(F)cc1
Yield: 55.3 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 17f (213 mg, 0.42 mmol); LiOH (21 mg, 0.85 mmol); after extraction afforded the desired product as a white solid (110 mg, 54.7%). 1H NMR (DMSO-d6, 400 MHz): δ 8.15 (s, 1H); 7.89-7.85 (m, 2H); 7.38 (s, 1H); 7.21-7.17 (t, 2H); 6.14 (s, 1H); 3.68-3.60 (d, 2H); 3.38-3.37 (d, 1H, J=1.60 Hz); 3.10-3.09 (d, 1H, J=1.60 Hz); 2.97 (s, 1H); 2.85 (s, 1H); 1.65-1.56 (m, 7H); 0.91-0.88 (m, 6H). 13C NMR (DMSO-d6, 100 MHz): 173.41, 170.47, 166.90, 166.52, 163.99, 135.75, 135.72, 130.03, 129.93, 116.71, 116.48, 53.83, 52.32, 43.08, 41.34, 39.65, 26.76, 26.22, 24.95, 22.94, 22.06. ESI-HRMS (m/z): [M+H+] calcd. for C20H28FN3O7S: 474.5705, observed: 474.5707. HPLC Method 1: Rt=20.9 min, purity=99.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9][C:16]([C:13]3[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1cc(Cl)ccc1S
Product: Clc1ccc2sc(-c3ccncc3)nc2c1
Yield: 18.2 %

Procedure:
2-Amino-4-chlorothiophenol (6.5 g, 0.04 mol) and 4-pyridine carboxaldehyde (4.4. g, 0.04 mol) were reacted as exemplified in Example 7 step 1, to afford the title compound as a brown solid (1.8 g, 20%). δH (CDCl3), 7.44 (1H, m, ArH), 7.86 (1H, m, ArH), 7.92 (2H, m, ArH), 8.08 (1H, s, ArH), 8.78 (2H, m, ArH). m/z (ES+) 247 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.C1C[O:24][CH2:23]C1.C([Li])CCC.[Cl-].[NH4+]>C(=O)=O.CC(C)=O.CN(C=O)C>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: C1CCOC1
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCSc1ccccc1-c1nc2cc(C=O)cnc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (2 g) and THF (60 ml), n-butyllithium (1.6 M in hexane) (4.3 ml) was added dropwise with cooling in dry-ice-acetone bath. The mixture was stirred for 30 minutes, and then DMF (2.2 ml) was poured. The mixture was heated to room temperature, and then saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 189 mg of 2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-carbaldehyde (hereinafter referred to as Present Compound 51).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.Cl.[F:16][C:17]1[CH:18]=[C:19]([NH:28][C:29]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[O:30])[CH:20]=[CH:21][C:22]=1[CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>C(Cl)(Cl)Cl>[C:1]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[C:22]1[CH:21]=[CH:20][C:19]([NH:28][C:29]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[O:30])=[CH:18][C:17]=1[F:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(C2CCCN2)c(F)c1)c1cnccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 ml of acetic anhydride was added to a pyridine (50 ml) solution of 4.3 g of N-(3-fluoro-4-pyrrolidin-2-ylphenyl)pyrazine-2-carboxamide dihydrochloride, and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:8][C@@H:9]([OH:20])[C@H:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:11]=[CH2:12])[O:7][CH2:6][CH2:5][O:4]1.N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(=O)(O)[O-].[Na+]>ClCCl>[Si:30]([O:1][CH2:2][C:3]1([CH2:8][C@@H:9]([OH:20])[C@H:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:11]=[CH2:12])[O:4][CH2:5][CH2:6][O:7]1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](OCOCCOC)[C@H](O)CC1(CO)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@@H](OCOCCOC)[C@H](O)CC1(CO[Si](C)(C)C(C)(C)C)OCCO1
Yield: 97.5 %

Procedure:
A solution of Compound 10 (6.55 g, 22.4 mmol) in dichloromethane (40 mL) at zero degrees C was treated with imidazole (3.21 g, 47.2 mmol), and then TBSCl (3.47 g, 23.1 mmol) in dichloromethane (20 mL) and stirred for two hours. The mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL), extracted with dichloromethane (3×50 mL), concentrated, and the residue purified by flash chromatography (ether) to give Compound 10-1 (8.88 g, 98 percent) as a colorless oil; Rf =0.51 (Et2O); [a]D25 =-33.3° (c 5.3, CH2Cl2); IR (thin film) νmax 3490 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 5.77 (m, 1 H, CH=CH2), 5.30-5.26 (m, 2 H, CH=CH2), 4.73 (ABq, J =6.5 Hz, Dn =40 Hz, 2 H, OCH2O), 4.03-3.95 (m, 5 H, CH--OH, ethylene ketal), 3.93 (dd, J =5.4, 10.0 Hz, 1 H, CH--OMEM), 3.82 (m, 1 H, OCHH--CH2 --OMe), 3.61 (m, 1 H, OCHH--CH2 --OMe), 3.55 (ABq, J =10.4 Hz, Dn =23 Hz, 2 H, CH2 --OTBS), 3.53 (m, 2 H, OCH2CH2 -13 OMe), 3.48 (bs, 1 H, OH), 3.37 (s, 3 H, OMe), 1.94 (dd, J =1.4, 14.9 Hz, 1 H, CHH), 1.83 (dd, J =10.0, 14.9 Hz, 1 H, CHH), 0.88 (s, 9 H, tBu), 0.04 (s, 6 H, SiMe2); 13C NMR (125 MHz, CDCl3) δ 134.7, 119.3, 110.4, 92.9, 80.2, 71.7, 69.5, 67.0, 66.2, 65.5, 65.1, 65.1, 58.9, 37.2, 25.8, 18.2, -5.5; FAB HRMS (NBA/CsI) m/e 539.1430, M+Cs+ calcd for C19H38O7Si 539.1441.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]#[N:40])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:45])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])=[CH:30][CH:31]=[C:26]4[C:25]([C:39]([NH2:40])=[O:45])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(-c6ccccc6Cl)nc54)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(-c6ccccc6Cl)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (4 mg, 6.92 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (29.7 μg, 0.0692 μmol, Eq: 0.01) were combined with Ethanol (853 μl) and Water (853 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h, then concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate is lyophalized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(2-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (3.9 mg, 95%, [M+H]+ 596).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11](Cl)[C:10]=12)=[O:5])[CH3:2].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[NH:21][NH2:22].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([NH:22][NH:21][C:20]([O:24][CH2:25][CH3:26])=[O:23])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Reactant: CCOC(=O)NN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)NNc1nc2ccccc2n2cnc(C(=O)OCC)c12
Yield: 58.4 %

Procedure:
To a solution of 4-chloroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (5.5 g) in acetonitrile (120 ml) was added ethyl carbazate (9 g) and triethylamine (20 ml) with stirring. The mixture was refluxed for 18 hours, then evaporated under water aspirator vacuum to dryness. The residue was taken up in chloroform, washed with water, dried by magnesium sulfate, concentrated to a small volume, then put through a silica gel dry column (2% methanol in chloroform as eluant). From column the product was isolated as an off-white solid (4 g, 58% yield). Recrystallized from a mixture of chloroform and hexane, m.p. 126°-128° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]2[N:34]=[C:35]([CH:37]=O)[N:36]=[C:29]2[N:28]=1>CC(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[C:16]([CH2:37][C:35]3[N:36]=[C:29]4[N:28]=[C:27]([CH3:26])[CH:32]=[C:31]([CH3:33])[N:30]4[N:34]=3)=[C:15]([OH:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CC(C)(C)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4cccc(C(C)(C)C)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling the 6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): d 1.29 (s, 9H), 1.46–1.76 (br m, 8H), 2.19 (m, 2H), 2.47 (s, 3 Hz), 2.56–2.70 (m, 7H), 2.87 (d, 1H, J=17.5 Hz), 3.80 (d, 1H, J=16.2 Hz), 3.90 (d, 1H, J=16.2 Hz), 7.12 (m, 2H), 7.28 (m, 3H), 10.92 (s, 1H). Anal. Calcd. For C30H38N4O3.0.4 AcOH: C, 70.24; H, 7.58; N, 10.64. Found: C, 70.27; H, 7.42; N, 10.59.