Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[S:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[CH:5]=1.[CH2:13]([O:15]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:14].O.Cl>O1CCOCC1.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>[CH3:1][O:2][C:3](=[S:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:13](=[O:15])[CH3:14])[CH:5]=1
Reactant: COC(=S)c1ccc(C)c(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=S)c1ccc(C)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromo-4-methylthiobenzoic acid methyl ester (0.86 g), 1-ethoxyvinyl tributyl tin (1.39 ml) and tetrakis triphenylphosphinepalladium (IV) (0.15 g) were combined in dioxan (50 ml) and boiled for 24 h. The mixture was cooled, water (10 ml) and conc. hydrochloric acid (1 ml) added and the mixture stirred at room temperature overnight. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate and filtered through celite. The filtrate was evaporated to dryness and the residue triturated with hexane to give 3-acetyl-4-methylthiobenzoic acid methyl ester (0.45 g) as a yellow solid. m/z (API+): 225 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([S:16][CH3:17])[N:9]=2)[N:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C@@H:20]1[CH2:15][C@H:14]1[C:12]1[CH:13]=[C:8]([N:4]2[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]2)[N:9]=[C:10]([S:16][CH3:17])[N:11]=1)=[O:22])[CH3:25]
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(SC)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(SC)n1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)-6-vinylpyrimidine (1-3) (5.00 g, 20.0 mmol, 1.0 eq.) in degassed toluene (220 mL) was added ethyl diazoacetate (4.3 mL, 40.0 mmol, 2.0 eq.) and the reaction was heated to 120° C. The reaction was monitored by LC-MS and after 6 hours the mixture was cooled to room temperature and the toluene was removed by roto-evaporation. The resulting residue was purified by silica gel column chromatography (10-70% ethyl acetate in hexanes) to afford ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropanecarboxylate (1-4) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 4.17 (q, 2H, J=7.1 Hz), 2.88 (s, 3H), 2.61-2.53 (m, 1H), 2.53 (s, 3H), 2.41 (s, 3H), 2.41-2.33 (m, 1H), 1.76-1.62 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). LRMS m/z (M+H) 334 found, 334 required.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32](O)=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:41]C=2C=1.C(Cl)CCl.N>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([NH2:41])=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(=O)O)C4)c4nc[nH]c4n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4nc[nH]c4n3)cc2)CC1
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-9H-purin-6-yl)piperidine-3-carboxylic acid (40 mg, 0.086 mmol) and HOBt (30 mg, 0.196 mmol) in DMF (2 mL), EDC (35 mg, 0.183 mmol) was added. After being stirred for 90 min, NH3 (0.5 M in dioxane, 1.00 mL, 0.500 mmol) was added. The mixture was stirred for 2 h. More EDC (52 mg, 0.271 mmol) was added. It was stirred for another 20 h. The mixture was then purified by HPLC to give the titled compound (30 mg). MS 464.3 (M+H); UV 204.8, 273.8 nm.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1ccc(F)cc1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to 4-fluoro-phenylboronic acid (73 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:12]1=[O:22])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](c1ccccc1)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](c1ccccc1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a mixture of (S)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl-acetic acid methyl ester (110 mg, 0.35 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (180 mg, 0.52 mmol) in DMF (2.5 mL) is added K2CO3 (150 mg, 1.09 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, dilutes with EtOAc (50 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated. The resulting residue is purified by flash chromatography with 50% EtOAc in hexanes as the eluent to afford (S)-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-phenyl-acetic acid methyl ester (100 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=2)=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]([S:33]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:11](=[O:16])[N:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(Nc1nc(=O)[nH]cc1F)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
To a suspension of 4-chloro-N-(5-fluoro-2-oxo-1,2-dihydropyrimid-4-yl)benzamide (0.10 g, 0.37 mmol) in CH2Cl2 (4 mL) were added Et3N (0.08 g, 0.82 mmol) and 4-chlorobenzenesulfonyl chloride (0.087 g, 0.41 mmol) at 0° C., and the resulting mixture was warmed to room temperature and stirred for 3 h. The reaction was diluted with CH2Cl2 (10 mL) and washed with brine. The phases were separated and the organic phase was dried over sodium sulfate (Na2SO4), filtered, and concentrated to an amber oil (0.295 g). Purification by normal phase chromatography (12 g SiO2; gradient, 0 to 35% EtOAc/hexanes) afforded 4-chloro-N-[1-(4-chlorobenzenesulfonyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]benzamide (0.025 g, 26%) as a white solid: mp 169-172° C.; 1H NMR (300 MHz, CDCl3) δ 12.59 (s, 1H), 8.29-8.15 (m, 3H), 8.05 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H); ESIMS m/z 442 ([M+H]+), 440 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[C:11]1([CH3:20])[C:12]([N:17]=[C:18]=[O:19])=[CH:13][CH:14]=[CH:15][CH:16]=1>CC(C)=O>[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:19])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: Cc1ccccc1N=C=O
Solvent: CC(C)=O
Product: Cc1ccccc1NC(=O)Nc1nc(CC(=O)O)cs1
Yield: 65.9 %

Procedure:
To a suspension of 2-amino-4-thiazoleacetic acid (4 g, 25 mmol) in 1:1 CH2Cl:acetone (100 mL) was added o-tolylisocyanate (3.5 g, 26 mmol). The mixture was heated to reflux for 8 hr at which time a yellow precipitate had formed. the precipitate was filtered and the solid washed generously with 1:1 CH2Cl2:acetone. The solid was recrystallized with hot methanol and dried under vaccum to yield 4.8 g (66% yield) of the desired 2-(o-tolylureido)-4-thiazoleacetic acid 51.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:13][CH2:12]1.[F:14][C:15]([F:22])([F:21])[C@H:16]([OH:20])[CH2:17][CH2:18][OH:19].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH:11]1([C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=2[O:20][C@@H:16]([C:15]([F:22])([F:21])[F:14])[CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1
Reactant: OCC[C@@H](O)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2CC2)c(O[C@H](CCO)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 20 h
Yield: 7.8 %

Procedure:
6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 7.8%) and its regioisomer; MS (EI) 304.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1.Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)ccc(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 79 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 7,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 25 min, β-bromophenetole was added (0.23 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (9:1) to give 0.32 g (79%) of a white solid: mp 131.5-133.0° C.; 1H NMR (300 MHz, CDCl3) δ 6.96 (m, 3H), 6.81 (m, 2H), 4.92 (t, J=4.9 Hz, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 3.67 (m, 2H), 3.52 (m, 2H), 3.18 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance) 1686, 1498, 1474, 1404, 1366, 1350, 1318, 1295, 1248, 1227, 1221, 1167, 1116, 788, 757 cm−1; MS (EI) m/z 474 (M+), 418, 376, 374, 339, 334, 332, 77, 57, 56, 55; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.13; H, 6.00; N, 5.89.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[CH:61]=[C:60]1[CH2:68]O>C(OCC)(=O)C.O1CCCC1>[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[CH:61]=[C:60]1[CH2:68][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCc1cc2ccccc2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.23 g), tributylphosphine (1.52 mL), 1-benzothien-2-ylmethanol (0.56 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 45%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23]([CH2:26][CH2:27][OH:28])(=[O:25])=[O:24])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:29]Br)=O)(C)(C)C.[F:31][C:32]([F:44])([F:43])[S:33]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CN(C=O)C>[F:44][C:32]([F:43])([F:31])[S:33]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:29][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[S:23]([CH2:26][CH2:27][OH:28])(=[O:25])=[O:24])=[CH:16][C:11]=3[N:10]=2)=[CH:40][CH:41]=1)(=[O:34])=[O:35]
Reactant: O=S(=O)(c1ccc(O)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(CBr)nc2cc(-c3ccccc3S(=O)(=O)CCO)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(CCO)c1ccccc1-c1ccc2[nH]c(COc3ccc(S(=O)(=O)C(F)(F)F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-bromomethyl-5-[2-(2-hydroxy-ethanesulfonyl)-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.030 g, 0.0606 mmol), 4-trifluoromethanesulfonyl-phenol (0.027 g, 0.121 mmol), Na2CO3 (0.026 g, 0.242 mmol), and NaI (0.036 g, 0.242 mmol) in DMF (1 mL) was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in CH2Cl2 (1 mL) followed by an addition of TFA (0.3 mL) and the mixture was stirred at rt for 3 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica, CH2Cl2: MeOH, 5:1) to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.17 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 8.03 (d, 2H, J=8.8 Hz), 7.76-7.62 (m, 4H), 7.48-7.45 (m, 3H), 7.35 (d, 1H, J=8.4 Hz), 5.57 (s, 2H), 3.63 (t, 2H, J=6.4 Hz), 2.91 (t, 2H, J=6.6 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H23F3N3O6S2: 582.5 (M+MeCN+H), Found 582.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([N+:19]([O-])=O)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1.C(O)(=O)C>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([NH2:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1N
Reaction time: 1 h
Yield: 35.4 %

Procedure:
8-(2,4-Dichlorophenyl)-2-methyl-3-nitroimidazo[1,2-a]pyrazine (25 mg, 0.077 mmol) was dissolved in ethanol (0.36 mL), then acetic acid (0.5 mL) and iron powders (22 mg) were added thereto, and the mixture was stirred for 1 hour by heating under reflux. After the reaction mixture was allowed to cool, the solvent was evaporated and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=4:1) to give 8-(2,4-dichlorophenyl)-2-methylimidazo[1,2-a]pyrazin-3-amine (8 mg) as yellow crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[C:12]=1[CH3:19])#[N:10].CN(C)CCN(C)C.[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]I)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.O>[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:19][C:12]2[C:13]([C:17]#[N:18])=[CH:14][CH:15]=[CH:16][C:11]=2[C:9]#[N:10])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ICCCCCCCCc1ccccc1
Reactant: Cc1c(C#N)cccc1C#N
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(C#N)c1CCCCCCCCCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide 1.5M in tetrahydrofuran (6 ml, 9 mmol) was added dropwise to a stirred solution of 2,6-dicyanotoluene (0.85 g, 6 mmol) and tetramethyl ethylenediamine (1.04 g, 9 mmol) in dry tetrahydrofuran (50 ml), cooled to -70° C. under nitrogen. After one hour, 8-phenyloctyl iodide (2.15 g, 6.8 mmol) was added dropwise at -70° C. to the intense blue suspension, then allowed to warm to 0° C. over one hour. Water (100 ml) was added (cautiously at first) to the brown mixture and then extracted with diethyl ether (50 ml). The extracts were washed with 2M hydrochloric acid, dried, filtered and evaporated to a brown oil (2.67 g). Purified by chromatography on flash silica eluting with dichloromethane gave 2-(9-phenylnonyl)-1,3-benzenedicarbonitrile as an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](#[N:11])[CH:9]=[CH2:10].[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH2:17][NH:18][CH2:19][C:20]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[CH:21]=1)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][C:8]#[N:11])[CH2:19][C:20]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[CH:21]=1)[CH3:13]
Reactant: CCOC(=O)CCNCC1=Cc2ccc(OC)cc21
Reactant: C=CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(CCC#N)CC1=Cc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to 30.16 g (0.1 mol) of 3-(5-methoxybenzocyclobuten-1-ylmethylamino)-propionic acid ethyl ester in 250 ml of ethanol and the whole is stirred at room temperature for 15 hours. The reaction mixture is then concentrated under a water-jet vacuum, and the residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal solution is dried over potassium carbonate, filtered and concentrated by evaporation; 3-{N-(2-cyanoethyl)-N-[(5-methoxybenzocyclobuten-1-yl)methyl]-amino}propionic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([CH3:11])=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CCO.O>[CH:1]1([N:6]2[C:10]([CH3:11])=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cnn(C2CCCC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1C1CCCC1
Yield: 64 %

Procedure:
A solution of ethyl 1-cyclopentyl-5-methyl-1H-pyrazole-4-carboxylate (15.5 g, 70 mmol) in EtOH (200 mL) was treated with a solution of LiOH (6 g, 250 mmol) in water (100 mL) and the resultant mixture was stirred at 60° C. overnight. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was acidified with aq HCl (2 M) to pH 3 and was extracted with EtOAc. The extract was concentrated under reduced pressure to give 1-cyclopentyl-5-methyl-1H-pyrazole-4-carboxylic acid (8.7 g, 64% yield). 1H NMR (300 MHz, DMSO-d6): δ 12.05 (br s, 1 H), 8.10 (s, 1 H), 4.60 (m, 1 H), 2.28 (s, 3 H, 2.04-1.97 (m, 2 H), 1.89-1.85 (m, 2H), 1.78-1.71 (m, 2 H), 1.62-1.59 (m, 2 H); MS (ESI) m/z: 194.99 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:30]([CH3:31])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=3)[S:21][C:17]=2[C:16]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:39][N:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C(OCC)(=O)C>O>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:30]([CH3:31])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:45]4[CH:44]=[C:43]5[C:48](=[CH:47][CH:46]=4)[N:40]([CH3:39])[N:41]=[CH:42]5)[CH:27]=3)[S:21][C:17]=2[C:16]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(-c3cncc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cn1ncc2cc(B(O)O)ccc21
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 115 °C

Procedure:
(S)-2-(2-(5-bromopyridin-3-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate was telescoped into the subsequent reaction. 1-Methyl-1H-indazol-5-ylboronic acid (0.024 g, 0.14 mmol) was added to the one-half of the previous reaction mixture and reaction heated in microwave at 115° C. for 30 minutes. Reaction mixture was portioned between ethyl acetate and H2O, the organic layer removed and concentrated to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)ethyl pivalate. LCMS-ESI+: calc'd for C38H40ClN4O3S: 667.2 (M+H+); found: 667.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Sc1ccccc1
Product: COC(=O)c1ccccc1Sc1ccccc1

Procedure:
The general procedure was used to convert Methyl-2-iodobenzoate and thiophenol to the title product. Purification by flash chromatography (hexane/ethyl acetate [6:1] as the eluent) gave the analytically pure product as a clear oil (397 mg, 81% yield). 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J=6.22, 1H; Hd), 7.47 (m, 2H; Ha, Hb), 7.33 (m, 3H; He, He′, Hf′), 7.14 (td, J=5.4, 1H; Hc), 7.04 (td, J=6.02, 1H; Hf), 6.73 (dd, J=6.78, 1H; Hg), 3.85 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 166.79 (C13), 143.15 (C1), 135.47 (C6), 132.39 (C3), 132.22 (C2), 130.93 (C5), 129.65 (C7), 129.02 (C8, C12), 127.28 (C9, C11), 126.58 (C10), 124.19 (C4), 52.10 (C14). Anal. Calcd. for C14H12O2S: C, 68.83; H, 4.95; S, 13.13; Found C, 68.94; H, 5.10; S, 12.90.