Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[Cl-].[NH4+].O>O1CCCC1.C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[NH2:8]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 82.1 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (22.5 g, 68.2 mmol), iron powder (19.04 g, 341 mmol), and ammonium chloride (7.30 g, 136 mmol) in tetrahydrofuran (117 mL), ethanol (117 mL), and water (39.0 mL) was heated under reflux at 100° C. for 2 hours. The reaction mixture was cooled to just below reflux temperature, filtered through Celite, and the filter cake washed with warm methanol (3×50 mL). The resulting solution was concentrated under reduced pressure and then neutralized to a pH of 8 with saturated sodium hydrogen carbonate (150 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane gradient 0-15%) to provide 3-bromo-4-(2,4-difluorophenoxy)aniline (16.8 g, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([O:15]C(C)C)[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([OH:15])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)Oc1cc(F)ccc1-n1nnn(C)c1=O
Agent: O=S(=O)(O)O
Product: Cn1nnn(-c2cc([N+](=O)[O-])c(F)cc2O)c1=O
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A solution of 1-(4-fluoro-2-isopropoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (3.50 g, 13.9 mmol, 1 equiv) in H2SO4 (35 mL) was cooled in ice/water bath. To the cooled solution, was added HNO3 (fuming >90%; 715 uL, 15.3 mmol, 1.1 equiv) dropwise, and the cooled reaction mixture was allowed to warm to RT over 2 h. The reaction mixture was quenched with ice, and extracted with EtOAc 3×. The organic layer was then extracted with saturated NaHCO3 3×. The basic aqueous layer was acidified to pH <3 with 6N HCl. Then, the acidic layer was extracted with EtOAc 3×, and the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 1-(4-fluoro-2-hydroxy-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.94 g, 83%) as brown solid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 12.5 (bs, 1H), 8.41-8.44 (d, 1H, J=8.7 Hz), 7.04-7.08 (d, 1H, J=13 Hz), 3.59 (s, 3H); 19F NMR (282 MHz; d6-DMSO) δ −111.3 (q); m/z=256 (M+H)+.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23](O)(=[O:26])[CH2:24][OH:25].N1C=CN=C1>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([O:9][C:24](=[O:25])[CH2:23][OH:26])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(O)CO
Reactant: CC(=O)SCC(C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)OC(=O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Acetylthio-2-methylpropanoic acid (6.48 g.) is taken into 40 ml. of dry tetrahydrofuran. To this 1,1'-carbonyldiimidazole (0.48 g.) is added and stirred for 30 minutes at room temperature. Glycolic acid (6.08 g.) and 11.2 ml. of triethylamine in 60 ml. of dry tetrahydrofuran are added. After several minutes, the imidazole salt of glycolic acid begins to come out of solution. The reaction is permitted to run overnight at room temperature. The crystalline salt is filtered and the filtrate concentrated to dryness in vacuo. The residue is taken up into ethyl acetate, washed with 1 N hydrochloric acid and three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo. This product is converted to its dicyclohexylamine salt by dissolving in ether/hexane and precipitating by the addition of dicyclohexylamine. The salt is recrystallized from ether, m.p. 120°-122°. This salt is then converted to the free acid, O-[3-(acetylthio)-2-methylpropanoyl]glycolic acid, by adding to ethyl acetate, adding 10% potassium bisulfate solution, then crystallizing from ethyl/hexane, yield 2.96 g., m.p. 50°-51°.
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[O:4][N:3]=1.[CH3:9][S-:10].[Na+].O>CN(C=O)C>[CH3:9][S:10][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[O:4][N:3]=1
Reactant: C[S-]
Reactant: CC1(C)CC(Cl)=NO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSC1=NOC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.8 %

Procedure:
To a solution of 193.0 g (1.07 M) of 3-chloro-5,5-dimethyl-2-isoxazoline dissolved in 500 ml of DMF was dropwise added, with ice-cooling, 1.0 kg (content=15%, 2.14 M) of an aqueous sodium methanethiolate solution. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic phase was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 115.0 g (yield: 74.1%) of 3-methylthio-5,5-dimethyl-2-isoxazoline. This residue (141.2 mmoles) was dissolved in 1 liter of chloroform. Thereto was added, with ice-cooling, 392.0 g (1.59 M) of m-chloroperbenzoic acid (purity: 70%), followed by stirring at that temperature for 1 hour and at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the precipitated m-chloroperbenzoic acid was removed by filtration. The filtrate was washed with an aqueous sodium hydrogensulfite solution, water, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with diisopropyl ether to obtain 77.6 g (yield: 59.1%) of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 82 to 84° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:28]#[C:27][CH2:26][CH2:25][OH:29])[CH:17]=3)[N:12]([CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)ccc21

Procedure:
A solution of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide [Example 1] (0.12 g), copper iodide (0.020 g), Pd(PPh3)2Cl2 (0.0067 g) and 3-butyn-1-ol (0.030 mL) in 10 mL diethylamine is stirred at room temperature for 18 h. The reaction is partitioned between ethyl acetate and H2O. The aqueous layer is extracted 3× with ethyl acetate. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L)) affords the desired product which is recrystallized with CH2Cl2/hexanes (0.059 g, 56%). Physical characteristics are as follows: m.p. 227-229° C.; 1H NMR (300 MHz, DMSO-d6) δ9.90, 8.18, 7.93, 7.40, 4.97, 4.55, 4.24, 3.62, 2.62; IR (drift) 3238, 3176, 1671, 1614, 1594, 1551, 1493, 1470, 1411, 1321, 1281, 1045, 825, 808, 733 cm−1; MS (ESI) m/z 396.0 (M+H)+; HRMS (FAB) calcd for C21H18ClN3O3+H1 396.1115, found 396.1114.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.NC(C1C=CC=CC=1)CC(O)=O>>[C:17]1([CH2:16][O:15][C:13]([NH:12][C@H:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([O:2][CH3:1])=[O:23])=[O:14])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[C:17]1([CH2:16][O:15][C:13]([NH:12][C@@H:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([O:2][CH3:1])=[O:23])=[O:14])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CC(NC(=O)OCc1ccccc1)c1ccccc1
Agent: NC(CC(=O)O)c1ccccc1
Product: COC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Product: COC(=O)C[C@H](NC(=O)OCc1ccccc1)c1ccccc1

Procedure:
Methyl-β-[[(phenylmethoxy)carbonyl]amino]-benzenepropanoate (4.87 g), prepared from 3-amino-3-phenylpropionic acid via standard methods, is separated by chiral HPLC [(R,R)-Whelk-O 1 column, elution with 40% isopropyl alcohol in hexane) to give 2.20 g of methyl (S)-β-[[(phenylmethoxy)carbonyl]amino]benzenepropanoate and 2.33 g methyl (R)-β-[[(phenylmethoxy)carbonyl]amino]benzenepropanoate. Each enantiomer is analyzed at >99% ee. Data for (S)-configuration enantiomer
Reaction SMILES: [CH3:1][B:2](OC(C)C)[O:3][CH:4]([CH3:6])[CH3:5].[C:11]1([C:17]#[C:18][Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(OCC)C>[CH3:1][B:2]([C:18]#[C:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][CH:4]([CH3:6])[CH3:5]
Reactant: [Li]C#Cc1ccccc1
Reactant: CB(OC(C)C)OC(C)C
Agent: Cl
Solvent: CCOCC
Product: CB(C#Cc1ccccc1)OC(C)C
Yield: 817.2 %

Procedure:
The reaction was run following the method of Example 14 using methyldiisopropoxyborane (6.34 g, 44 mmol) in ethyl ether (44 mL) and phenylethynyllithium (4.9 mmol) in ethyl ether (50 mL), then quenched with hydrogen chloride (14.33 mL, 49 mmol). Volatiles were removed under reduced pressure at ambient temperature to yield 7.45 g (91%) of the title product; n20D 1.5290; proton NMR (CDCl3) δ7.23 (m, 5H), 4.73 (septet, J=18 Hz, 1H), 1.23 (d, J=18 Hz, 6H), 0.53 (bs, 3); boron NMR (EE) δ+40.2 ppm(s). Mass spectrum (chemical ionization, isobutene) m/e 187 (M+H, 6%); IR (thin film) 2178, 1326 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N([CH2:15][CH3:16])CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:51])C=[C:31]([CH2:37][C:38]2[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([O:47][C:48](=[O:50])[CH3:49])[CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:51])[C:15]([CH3:16])=[C:31]([CH2:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:43])=[C:40]([O:47][C:48](=[O:50])[CH3:49])[CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: CCN(CC)CC
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=CC1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(OC)cc3)c(OC(C)=O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.5 %

Procedure:
p-Methoxyaniline (4.3 mg, 0.0349 mmol), triethylamine (5.9 mg, 0.0584 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (9.9 mg, 0.0585 mmol) were added to a methylene chloride solution (3 ml) of 4-(5,6-dimethoxy-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (11 mg, 0.0294 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:3) to obtain the titled compound (6 mg, 0.0125 mmol, 43%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].C(NC(C)C)(C)C.CN(C)C=O.[Br:20][C:21]1[CH:37]=[CH:36][C:24]2[C:25]3[N:26]=[C:27]([C:33](Cl)=[O:34])[S:28][C:29]=3[CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1>C(OCC)(=O)C>[Br:20][C:21]1[CH:37]=[CH:36][C:24]2[C:25]3[N:26]=[C:27]([C:33]([N:1]4[CH2:7][CH2:6][CH2:5][C@@H:2]4[CH2:3][OH:4])=[O:34])[S:28][C:29]=3[CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1
Reactant: O=C(Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: OC[C@H]1CCCN1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1nc2c(s1)CCOc1cc(Br)ccc1-2)N1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of D-(−)-Prolinol (0.205 g, 2.03 mmol) in N,N-Diisopropylamine (0.758 mL, 4.35 mmol) and N,N-Dimethylformamide (4.49 mL, 58.0 mmol) at room temperature was added 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl chloride (0.500 g, 1.45 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with brine, and concentrated in vacuo to give (8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone which was not further purified.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)(=[O:50])[CH:48]=[CH2:49]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([C:14]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:49]=[CH:48]/[C:47]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:50])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:24]
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Reactant: C=CC(=O)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(/C=C/C(=O)N4CCOCC4)ccc3c2n1CC1CCOCC1
Temperature: 120 °C
Yield: 51.2 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (584 mg, 1.5 mmol) in N,N-dimethylformamide (10 mL). To the solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and tri-ortho-tolylphosphine (91 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL), triethylamine (0.6 mL), and a solution of 4-acryloylmorpholine (254 mg 1.8 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness under reduced pressure. The resulting solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 345 mg of 2-ethyl-7-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp>260° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:41]([CH:38]4[CH2:40][CH2:39]4)=[O:42])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)C1CC1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1CC1)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclopropanecarbonyl chloride (34 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 162 mg, 92%. 1H NMR (rotomers seen, 400 MHz, DMSO-D6) δ ppm 8.43-8.59 (2 H, m), 7.59-7.72 (2 H, m), 7.31 (2 H, dd, J=8.46, 5.68 Hz), 7.15 (2 H, t, J=8.84 Hz), 6.52 (1 H, s), 5.10-5.36 (2 H, m), 4.22-4.60 (2 H, m), 3.95 (3 H, s), 3.03-3.26 (1 H, m), 2.53-3.01 (4 H, m), 1.42-2.10 (5 H, m), 0.62-0.79 (4 H, m); m/z (APCI+) for C27H30N5O2F 476.2 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C(N(CC)CC)C>C(O)C>[C:18]1(=[O:27])[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CCOCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCOCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[2-[2-(bromo)ethyloxy]ethyl]phthalimide (5.96 g, 20 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 12 hours and heated at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.00 g of the desired product (54.5%, light tan solid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:43])[C:9]1[S:21][C:20]2[CH2:19][C@@H:18]3[C@H:13]([CH2:14][C@@H:15]([C:23]([N:25]([CH2:38][CH2:39][CH3:40])[C:26](=O)[O:27]C4C=CC([N+]([O-])=O)=CC=4)=[O:24])[CH2:16][N:17]3[CH3:22])[CH2:12][C:11]=2[C:10]=1[C:41]#[N:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47][NH2:48]>O1CCCC1>[C:41]([C:10]1[C:11]2[CH2:12][C@@H:13]3[C@@H:18]([CH2:19][C:20]=2[S:21][C:9]=1[N:8]([CH3:43])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[N:17]([CH3:22])[CH2:16][C@H:15]([C:23]([N:25]([C:26](=[O:27])[NH:48][CH2:47][CH2:46][N:45]([CH3:49])[CH3:44])[CH2:38][CH2:39][CH3:40])=[O:24])[CH2:14]3)#[N:42]
Reactant: CN(C)CCN
Reactant: CCCN(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Solvent: C1CCOC1
Product: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Temperature: 25 °C

Procedure:
To a mixture of 4-nitrophenyl N-{[(4aR*,6R*,8aR*)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]-quinolin-6-yl]carbonyl}-N-propylcarbamate (200 mg) and tetrahydrofuran (3 mL) was added N,N-dimethyl ethylenediamine (0.071 mL) while stirring at room temperature, and the mixture was stirred at the same temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give tert-butyl N-[(4aR*,6R*,8aR*)-3-cyano-6-[({[2-(dimethylamino)ethyl]-carbamoyl}(propyl)amino)carbonyl]-8-methyl-4H,4aH,5H,6H,7H,8H,8 aH,9H-thieno-[3,2-g]quinolin-2-yl]-N-methylcarbamate (160 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccc3[nH]ccc23)cc1Cl
Temperature: 75 °C
Reaction time: 15 h
Yield: 69.6 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 3.00 g, 12.34 mmol), and 4-bromo-2-chloro-fluorobenzene (2.58 g, 12.34 mmol) in THF (42 mL)) were added Palladium catalyst Pd(PPh3)4 (0.428 g, 0.37 mmol) and the freshly prepared sodium hydroxide solution (1.50 g, 37.02 mmol in 17 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.11 g (70%) of the product 4-(3-chloro-4-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [OH-:1].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:29]([O-:31])=[O:30].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl>[N+:26]([C:21]1[CH:20]=[C:19]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=3)(=[O:39])=[O:1])=[C:5]([N+:29]([O-:31])=[O:30])[CH:6]=2)([C:15]([F:18])([F:16])[F:17])[C:11]([F:13])([F:12])[F:14])[CH:24]=[CH:23][C:22]=1[O:25][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C(c3ccc(OS(=O)(=O)c4ccc(C)cc4)c([N+](=O)[O-])c3)(C(F)(F)F)C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
11.5 g (0.205 mol) of potassium hydroxide are added to a solution of 42.6 g (0.1 mol) of 2,2-bis-(4-hydroxy-3-nitrophenyl) -hexafluoropropane and 39.1 g (0.205 mol) of p-toluenesulfonyl chloride in 300 ml of methylene chloride. The reaction mixture is then stirred at room temperature for five hours, in the course of which it turns an orange-yellow color. After precipitated potassium chloride (16 g) has been removed, the filtrate is dried over MgSO4. Removing the solvent and recrystallizing from toluene gives 43 g of 2,2-bis-(3-nitro-4-tosyloxyphenyl)-hexafluoropropane. Yield 58%; m.p. 206-208° C.