Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]=[O:33]>O1CCCC1>[Cl:26][C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1)[OH:33]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(C)Cc3ccc(Cl)cc3)nc2Cl)c2cccnc21
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was; allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde (551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to −10° C. in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (552, 0.5 g, 60%). MS (ESI) [M+H+]+=575.29.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl.C(OCN1C2N=CN=C(C3C=NN([CH:30]([O:32][CH2:33][CH3:34])[CH3:31])C=3)C=2C=C1)(=O)C(C)(C)C>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:31][CH2:30][O:32][CH2:33][CH3:34])[CH:6]=1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Reactant: Brc1cn[nH]c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a solution of 4-bromopyrazole (21, 70.0 g, 0.476 mol) in CH2Cl2 (600 mL) was added a solution of 3.1 M HCl in dioxane (4 mL) and ethyl vinyl ether (18, 41 g, 0.569 mol, 1.2 equiv). The resulting reaction mixture was stirred at room temperature for 3 hrs. The reaction was quenched with aqueous NaHCO3 and the two layers were separated. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to dryness to afford 4-bromo-1-(ethoxyethyl)-1H-pyrazole (22, 113 g, 104.3 g theoretical, 97% yield) as an oily (GC purity: 89%), which was directly used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O1CCCC1>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl(+/−)-3-(4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzamido)propanoate (74 mg, 0.16 mmol) in methanol (0.78 mL) and tetrahydrofuran (0.78 mL) was added 1 N aq sodium hydroxide (0.78 mL, 0.78 mmol). After 10 minutes, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was then acidified to pH 4 with 1 N aq hydrochloric acid and diluted with sat. aq sodium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give (+/−)-3-(4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzamido)propanoic acid. 1HNMR (400 MHz, DMSO-d6) δ 12.18 (br. s., 1H), 8.56 (d, J=2.7 Hz, 1H), 8.44 (t, J=5.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.76-7.72 (m, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.52-7.48 (m, 1H), 7.37-7.27 (m, 2H), 7.03 (d, J=7.8 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 4.73-4.61 (m, 1H), 3.46-3.37 (m, 2H), 2.47 (t, J=7.0 Hz, 2H), 2.39-2.23 (m, 1H), 2.14-1.92 (m, 2H), 1.20-1.13 (m, 1H); (M+1): 446.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)#[N:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C#N)cc1
Yield: 45.9 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)lactate (1.01 g), which is the product of Reference example 1(b), 4-cyanophenol (481 mg), triphenylphosphine (1.06 g) and solution of diethylazodicarboxylate in toluene (40%, 0.73 ml) and the reaction mixture was treated to afford the desired compound (619 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[C:13]([CH3:14])=[CH:12][S:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH2:35]([NH:39][C:16](=[O:18])[C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[C:13]([CH3:14])=[CH:12][S:11][CH:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:20])[CH3:19])[CH:36]([CH3:38])[CH3:37]
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1-c1cscc1C
Reactant: CC(C)CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(C(C)(C)C(=O)NCC(C)C)ccc1-c1cscc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)-2-methylpropanoic acid (example 35b) (630 mg, 2.2 mmol) in DMF (7 mL) were added HOBt (297 mg, 2.2 mmol), EDC (434 mg, 2.2 mmol) and isobutyl amine (214 μL, 2.2 mmol). The mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in EtOAc and successively washed with water, 10% citric acid, sat. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (30% EtOAc-hexanes) to give 190 mg (37%) of N-isobutyl-2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)-2-methylpropanamide. 1H NMR (400 MHz, dMSO): δ 0.73-0.75 (d, 6H), 1.48 (s, 6H), 1.69-1.72 (m, 1H), 2.00 (s, 3H), 2.49-2.50 (m, 2H), 3.71 (s, 3H), 6.91-6.94 (m, 2H), 7.08-7.10 (d, 1H), 7.18 (s, 1H), 7.24-7.25 (d, 1H), 7.34-7.35 (t, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:50]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:50][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CO)c2)NC(=O)OC(C)(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCl)c2)NC(=O)OC(C)(C)C)cc1

Procedure:
(S)-tert-Butyl 3-(3-(hydroxymethyl)phenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (1.0 g, 2.42 mmole) was dissolved in CH2Cl2 (5 ml). Triphenylphosphine (666 mg, 2.54 mmole) was added followed by N-chlorosuccinimide (355 mg, 2.66 mmole). After the vigorous reaction subsided, TLC showed ˜10% of unreacted starting material remained. Added 300 mg more N-chlorosuccinimide. TLC showed that the reaction was complete. The reaction mixture was purified without work-up by flash chromatography. Yield=1.0 g. MS (m/z) 433 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:11][C@H:10]([C:22]([O:24][CH3:25])=[O:23])[C@H:9]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])C1C=CC=CC=1.CO.[H][H]>[Pd]>[CH3:25][O:24][C:22]([C@H:10]1[CH2:11][C@H:12]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:16])[CH2:13][NH:8][C@@H:9]1[C:26]([OH:28])=[O:27])=[O:23]
Reactant: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2,3-dicarboxylate (144 mg, 0.000300 mol) in methanol (3.0 mL, 0.074 mol) was hydrogenated in the presence of 10% Pd/C, under balloon pressure of hydrogen, overnight. After filtered off the catalyst, the filtration was concentrated to dry to provide crude product, which was used directly in next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2CCCN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3, Step (b) from tert-butyl 2-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-(2-[(methylsulfonyl)-amino]-phenyl)-piperidyl)-2-oxoethyl]carbamoyl}(2S)pyrrolidinecarboxylate (Step a) (315 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by preparative reverse phase HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (101 mg). MS (ESI, pos. ion) m/z: 533 (M+1); (ESI, neg. ion) m/z: 531 (M−1). Calc'd for C26H33ClN4O4S: 532.19. Anal. Calcd for C26H33ClN4O4S.1.2C2HF3O2: C, 50.92; H, 5.15; N, 8.36. Found: C, 50.82; H, 5.32; N, 8.38.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.[Cl-].[NH4+]>C1COCC1>[CH:26]1([C:11]([C:10]2[S:9][C:8]([NH:17][C:18]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[O:19])=[N:7][C:6]=2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:28][CH2:27]1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
Compound 98 (127 mg, 0.355 mmol) was suspended in THF (2.5 mL), and a 0.5 mol/L solution of cyclopropylmagnesium bromide in THF (4.00 mL, 2.00 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with a mixed solvent (4:1) of chloroform and 2-propanol. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 417 (94.1 mg, 78%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[C:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[O:9][C:10](=[O:15])[C:11]=3[NH:12][C:13]=2[CH:14]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[C:26]#[N:27]>CN(C=O)C.C(OCC)(=O)C>[F:31][C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[CH2:22][N:12]1[C:11]2[C:10](=[O:15])[O:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]=2[C:5]2[CH:4]=[C:3]([CH3:20])[C:2]([F:1])=[CH:14][C:13]1=2
Reactant: Cc1cc2c(cc1F)[nH]c1c(=O)oc3ncccc3c12
Reactant: N#Cc1ccc(F)c(CBr)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c3c4cccnc4oc(=O)c3n(Cc3cc(C#N)ccc3F)c2cc1F
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 9-Fluoro-10-methyl-7H-5-oxa-4,7-diaza-benzo[c]fluoren-6-one 1G (167 mg, 0.622 mmol) in DMF (3.0 mL) was added 3-Bromomethyl-4-fluoro-benzonitrile (160.0 mg, 0.747 mmol) and CsCO3 (243 mg, 0.747 mmol) at room temperature and the reaction mixture was allowed to stir overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The concentrated crude was purified using chromatography over SiO2 using 0 to 30% ethyl acetate in hexane to provide 4-Fluoro-3-(9-fluoro-10-methyl-6-oxo-6H-5-oxa-4,7-diaza-benzo[c]fluoren-7-ylmethyl)-benzonitrile 1H (200 mg, 80%). M.S. found for C23H13F2N3O2: 402.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CC(O)C>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH:2]([CH3:3])[CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cccc2[nH]c(C(=O)OC(C)C)c(Sc3ccc(Cl)cc3)c12
Yield: 53 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with 2-propanol (2 mL) provided 40 mg (53%) of product 13 as a white solid, mp 190-192° C. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=6 Hz, 6H), 2.60 (s, 3H), 5.05-5.14 (m, 1H), 6.88 (d, J=8 Hz, 1H), 6.98 (d, J=9 Hz, 2H), 7.23 (t, J=8 Hz, 1H), 7.30 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 1H), 12.45 (s, 1H). LC-MS (CI): m/z 360.1 [(M+H)+ C19H18ClNO2S requires 359.07]. Purity (100%). Calcd for C19H18ClNO2S.0.07CH2Cl2: C, 62.61; H, 5.00; N, 3.83; S, 8.77; Cl, 11.05. Found: C, 62.32; H, 5.01; N, 3.77; S, 9.08; Cl, 10.93.
Reaction SMILES: [C:1]([C:5]1[Se:6][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S1(=O)C=CC=C[CH2:17]1.C[Mg]Br.[F:26][P-:27]([F:32])([F:31])([F:30])([F:29])[F:28].[H+]>O1CCCC1.CCOCC>[F:26][P-:27]([F:32])([F:31])([F:30])([F:29])[F:28].[C:1]([C:5]1[CH:10]=[C:9]([CH3:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[Se+:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(=O)cc(C(C)(C)C)[se]1
Reactant: O=S1C=CC=CC1
Agent: C[Mg]Br
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 76 %

Procedure:
2,6-Di-tert-butylselenopyran-4-one, compound E, (27.1 grams, 0.100 mole) was dissolved in 250 mL of dry tetrahydrofuran. To this solution was added 40 mL of a 3.0 M solution of methylmagnesium bromide (0.12 mole) in ether. After addition was complete, the reaction mixture was heated at reflux for 1 h and was cooled to ambient temperature. The reaction mixture was slowly added with stirring to 1 L of a cold solution of 10% hexafluorophosphoric acid. The solid was collected by filtration and the filter cake was washed with water (2×250 mL) and ether (3×250 mL). The crude white solid was recrystallized from acetonitrile-ether to give 28.0 g (76% of theoretical) of 2,6-di-tert-butyl-4-methylselenopyrylium hexafluorophosphate, compound F: Melting point 203-204° C.; 1H NMR (deuteriochloroform) d 8.34 (s, 2 H), 2.83 (s, 3 H), 1.66 (s, 18 H). Anal. Calculated for C14H23Se-PF6: C, 40.50; H, 5.58. Found: C, 40.51; H, 5.35.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCO
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Yield: 96.4 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and ethanolamine (1.32 g, 22 mmol) to give the title compound (5.4 g, 98%) as an off-white solid. MS (ISP) 280.0[(M+H)+].
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[S:15][C:16]([O:18]C)=[N:17][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[S:15]1[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[NH:17][C:16]1=[O:18]
Reactant: COc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2c(s1)CCNCC2

Procedure:
0.40 g (1.4 mmol) 2-methoxy-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester, 1.3 mL trifluoroacetic acid in 2.5 mL dichloromethane (DCM) were stirred at RT overnight. The reaction was concentrated to dryness. DCM and a small amount of methanol (MeOH) were added to the residue and filtrated. The precipitate were isolated and 90 mg 3,4,5,6,7,8-Hexahydro-thiazolo[4,5-d]azepin-2-one trifluoro-acetic acid was obtained. Yield: 90 mg (23% of theory). ESI-MS: m/z=171 (M+H)+; Rt(HPLC): 0.15 min (Method J).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:27]([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([N:5]([CH3:27])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(C#Cc2ccnc(Cl)c2)cn1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(C#Cc2ccnc(Cl)c2)cn1)C(C)(C)C
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
(180 mg, 574 μmol) 5-(2-Chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 2) was dissolved in DMF (3 ml) and cooled to 0-5° C. Iodomethane (54 μl, 860 μmol, 1.5 equiv.) and NaH (55%) (41 mg, 860 μmol, 1.5 equiv.) were added and the mixture was stirred for 2 hours without cooling bath. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (20 g, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide (78 mg, 42% yield) was obtained as a yellow solid, MS: m/e=328.4/330.4 (M+H+).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:2].I[C:14]1[N:18]2[C:19]3[S:25][CH:24]=[CH:23][C:20]=3[N:21]=[CH:22][C:17]2=[N:16][C:15]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CO.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>[CH3:26][C:15]1[N:16]=[C:17]2[CH:22]=[N:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[N:18]2[C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=1
Reactant: Cc1nc2cnc3ccsc3n2c1I
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc2cnc3ccsc3n2c1-c1ccc(CC#N)cc1
Temperature: 160 °C

Procedure:
A mixture of [4-(cyanomethyl)phenyl]boronic acid (from Aldrich, 9.3 mg, 0.058 mmol), 8-iodo-7-methylimidazo[1,2-a]thieno[3,2-e]pyrazine (12 mg, 0.038 mmol), and potassium carbonate (16 mg, 0.12 mmol), in acetonitrile (0.6 mL) and water (0.2 mL) was degassed. Into the mixture was added tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 0.0019 mmol). The reaction mixture was heated at 160° C. for 10 min in a microwave reactor. The reaction was diluted with methanol, filtered. The filtrate was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C17H13N4S (M+H)+: m/z=305.1. Found: 305.0. 1H NMR (CDCl3, 400 MHz) δ 9.01 (1H, s), 7.55 (4H, m), 7.49 (1H, d, J=6.0 Hz), 7.14 (1H, d, J=6.0 Hz), 3.93 (2H, s), 2.48 (3H, s) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:37])[C:24]([S:26]SC4C=CC=CC=4[N+]([O-])=O)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[BH4-].[Na+]>CCO.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:37])[C:24]([SH:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SSc4ccccc4[N+](=O)[O-])c(Cl)cc3n2COCCOC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(S)c(Cl)cc3n2COCCOC)c1
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a stirred cooled (0° C.) solution of 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(2-nitro-phenyldisulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (2.99 g, 5.29 mmol) and EtOH (24 mL) was added dropwise a solution of NaBH4 (0.729 g, 19.3 mmol), EtOH (24 mL), and water (10 mL) over 10 minutes. The reaction mixture was stirred for 15 min and additional NaBH4 (0.486 g, 12.8 mmol) in EtOH (16 mL) and water (6.7 mL) was added. The reaction mixture was stirred for an additional 30 min and then partitioned between DCM (200 mL) and water (200 mL). The aqueous layer was acidified to pH 5 with 1M HCl and the product was extracted with DCM (3×300 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-80% EtOAc/hexanes) to yield the titled compound (1.27 g, 48%) as a 2:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C17H19ClN4O4S, 410.1; m/z found, 411.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.85-8.84 (m, 2H), 8.17 (s, 2H), 7.75 (s, 0.67H), 7.72 (s, 1.33H), 7.68 (s, 1.33H), 7.64 (s, 0.67H), 6.10-6.09 (m, 4H), 4.36 (q, J=7.1 Hz, 4H), 4.02 (s, 0.67H), 3.93 (s, 1.33H), 3.66-3.62 (m, 4H), 3.47-3.44 (m, 4H), 3.31-3.30 (m, 6H), 1.38 (t, J=7.1 Hz, 6H). Large-scale synthesis of the titled compound also provided a dimer by-product, where the dimer linkage is thru the sulfur bond forming a disulfide intermediate of 1-[6-chloro-5-mercapto-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester, this by-product was isolated but not tested: MS (ESI/CI): mass calcd. for C34H36Cl2N8O8S2, 818.1; m/z found, 819.1 [M+H]+.