Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[C:17]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([Cl:37])[CH:28]=4)[O:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Li+]>CS(C)=O.O1CCCC1.O.CO>[Cl:37][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][N:13]=[C:12]4[N:1]3[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: O=C(O)C1CCNC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCC(C(=O)O)C5)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
A mixture of 3-pyrrolidinecarboxylic acid (ABCR Product List; 36.0 mg, 0.312 mmol), and sodium hydride (60%; 9.99 mg, 0.250 mmol) in dimethyl sulfoxide (DMSO) (2 ml) were stirred at room temperature for 30 min. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was left to stir at 120° C. under nitrogen for 3 hours. The cooled reaction mixture was loaded onto an SCX column. The column was flushed with methanol and then the desired product was eluted with 2M ammonia in methanol. The solvent was removed in vacuo from the appropriate fractions to give a yellow solid. Lithium hydroxide (2.99 mg, 0.125 mmol), methanol (2.00 ml), water (1 ml) and tetrahydrofuran (THF) (2.00 ml) were added and the mixture stirred at 80° C. for 1 hour. The solvent was removed in vacuo to give an orange solid which was triturated under ether and filtered. The solid was dissolved in water and then extracted with ether. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a yellow solid (9 mg).
Reaction SMILES: C[CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Al](Cl)(C)C.[Al](Cl)(CC)CC.[C:18](OC)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C(Cl)Cl>[C:18]([N:3]1[CH2:2][CH2:7][NH:6][CH2:5][CH2:4]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC1CNCCN1
Agent: CC[Al](Cl)CC
Agent: C[Al](C)Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCNCC1
Yield: 105129.4 %

Procedure:
To a stirred solution of 2-methylpiperazine (10.0 g, 0.1 mol) in dry CH2Cl2 (500 ml) under argon was added a solution of 1.0 M Me2AlCl or Et2AlCl in hexanes (100 ml, 0.1 mmol) and methyl benzoate (12.4 ml, 0.1 mmol) at room temperature. The reaction mixture was then stirred for 2 days before 2N NaOH (200 ml) was added. Aqueous layer was extracted with EtOAc (3×100 ml). The combined organic layer was dried over MgSO4 and concentration of solution provided 20.0 g of crude product (98%), with was pure enough for the further reactions.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[N+]([O:9][CH2:10][C:11]([CH2:22][O:23][N+]([O-])=O)([CH2:17][O:18][N+]([O-])=O)[CH2:12][O:13][N+]([O-])=O)([O-])=O>O>[OH:9][CH2:10][C:11]([CH2:22][OH:23])([CH2:17][OH:18])[CH2:12][OH:13]
Reactant: O=[N+]([O-])OCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OCC(CO)(CO)CO

Procedure:
Sodium nitrate (400 grams) which had been ground in a ball mill and screened through a 35-mesh (Tyler) screen was incorporated into the emulsion at 23° C. by gentle stirring. Pentaerythritol tetranitrate (PETN) (1200 grams), wet with 63 grams of water at 23° C., was incorporated in the same manner, stirring having been accomplished with a wooden spatula. The PETN was a crude grade obtained by nitrating pentaerythritol, washing to neutralize the surface, and drying. The temperature of the emulsion then was 30° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:40]([C:47]2[CH:52]=[CH:51][C:50]([S:53]([CH3:56])(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:42]1([CH:41]=[C:40]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][OH:22])[CH:18]=[C:13]3[CH:12]=2)[C:47]2[CH:52]=[CH:51][C:50]([S:53]([CH3:56])(=[O:55])=[O:54])=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)[Si](OCCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(OCCO)cnc3[nH]2)cc1
Yield: 99.9 %

Procedure:
A solution of 1-benzenesulfonyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (870 mg, 1.08 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 10 mL, 10 mmol) was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethanol (460 mg, quant.) as a white solid: LC/MS m/e calcd for C23H26N2O4S [M+H]+ 427.54, observed 427.4.
Reaction SMILES: C(OC1C=C(C=CC=1O)CN1CCC(NC2C=C(C(F)(F)F)C(C(O)=O)=CN=2)CC1)C.Cl.Cl.C[O:35][C:36](=[O:54])[C:37]1[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:40]([NH:47][CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[N:39][CH:38]=1.[CH2:55]([O:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[CH:63]=O)[CH:56]([CH3:58])[CH3:57]>>[CH2:55]([O:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[CH2:63][N:51]1[CH2:50][CH2:49][CH:48]([NH:47][C:40]2[CH:41]=[C:42]([C:43]([F:44])([F:45])[F:46])[C:37]([C:36]([OH:35])=[O:54])=[CH:38][N:39]=2)[CH2:53][CH2:52]1)[CH:56]([CH3:57])[CH3:58]
Reactant: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Reactant: COc1ccc(C=O)cc1OCC(C)C
Agent: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1O
Agent: Cl
Product: COc1ccc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)cc1OCC(C)C

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acid (example 201) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 3-isobutoxy-4-methoxy-benzaldehyde (intermediate E12) in a yield of 9.0 mg (12%). MS (ISP): 482.3 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]1[SH:22])([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.Cl.[CH2:24](O)[CH2:25][CH3:26]>>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH2:24][CH2:25][CH3:26])=[O:20])=[CH:17][N:16]=[C:15]1[SH:22])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCO
Reactant: O=C(O)c1cnc(S)n1C(c1ccccc1)c1ccccc1
Agent: Cl
Product: CCCOC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccc1

Procedure:
3.1 g (0.01 mol) of 1-benzhydryl-2-mercapto-5-imidazole carboxylic acid (Example 2a) and 100 cc of 1-propanol were heated to 97° C. while introducing gaseous hydrogen chloride until esterification was completed. Working up in a basic medium yielded 3.3 g (94% of the theory) of 1-benzhydryl-2-mercapto-5-propoxycarbonyl-imidazole, m.p. 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18](F)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.[OH:26][C:27]1[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][NH:31][C:32]2=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:26][C:27]3[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]4[C:28]=3[CH:29]=[CH:30][NH:31][C:32]4=[O:38])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc2c(=O)[nH]ccc2c1O
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4F)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(=O)[nH]ccc45)ncnc32)cc1
Temperature: 130 °C
Yield: 51 %

Procedure:
A mixture of 9-(4-methoxybenzyl)-6-(2-fluoropyridin-3-yl)-9H-purine (0.48 g, 1.4 mmol), 5-hydroxy-6-methylisoquinolin-1(2H)-one (0.25 g, 1.4 mmol) and cesium carbonate (1.1 g, 3.3 mmol) in NMP (5 mL) was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 130° C. for 60 min (100 watts, Powermax feature on, ramp time 1 min) The crude reaction mixture was partitioned between 3:1 CHCl3:IPA (100 mL) and water (150 mL). The aqueous phase was extracted with 3:1 CHCl3:IPA (50 mL). The combined organic extracts were washed with 1 N NaOH (2×75 mL), water (2×75 mL), satd NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a viscous brown oil which was chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 1% to 7% MeOH in CH2Cl2, to provide 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-6-methylisoquinolin-1(2H)-one (0.35 g, 51% yield) as a white solid. MS (ESI, pos. ion) m/z: 491.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](O)([CH3:17])[CH3:16])=[CH:4][CH:3]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1
Reactant: CC(C)(O)c1ccccc1Nc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
30.3 g (116 mmol) of 2-[2-(4-chlorophenylamino)phenyl]propan-2-ol are dissolved in 700 ml of degassed toluene, a suspension of 93 g of polyphosphoric acid and 61.7 g of methanesulfonic acid is added, and the mixture is stirred at room temperature for 1 h and heated at 50° C. for 1 h. The batch is cooled and poured onto ice and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Filtration of the crude product through silica gel with heptane/ethyl acetate (20:1) gives 25.1 g (89%) of 2-chloro-9,9-dimethyl-9,10-dihydroacridine as pale-yellow crystals.
Reaction SMILES: [N:1]1([C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate (11.7 g) obtained in Reference Example 81(1) is dissolved in methanol (50 ml), and thereto is added a solution of sodium hydroxide (3.95 g) in water (20 ml). The mixture is then stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure. The residue is diluted with ice-water and washed with diethyl ether. The resulting aqueous layer is acidified with 10% hydrochloric acid and extracted twice chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and collected by filtration to give the title compound (10.1 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30]([CH:27]5[CH2:29][CH2:28]5)=[O:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CC1

Procedure:
The title compound, off-white solid (72 mg, 73%), MS (ISP) m/z=397.4 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and cyclopropanecarboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14]([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][O:39]3)[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=COCCC1
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of N-{4-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (65 mg, 0.18 mmol) produced in Example 1-B (vi) in tetrahydrofuran (3.0 mL) were added p-toluenesulfonic acid monohydrate (41 mg, 0.22 mmol) and 3,4-dihydro-2H-pyran (140 mg, 1.7 mmol), and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with ethyl acetate (40 mL), the combined organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0) to give the title compound (71.0 mg, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1.I[CH3:35].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:35])[C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1
Reactant: COc1cn(-c2ccc(N3CCNC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc(N3CCN(C)C3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 1-[2-fluoro-4-(2-oxoimidazolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (40 mg, 0.09 mmol), iodomethane (0.02 mL, 0.36 mmol), and sodium hydride (60% in oil) (7.0 mg, 0.18 mmol) in DMF (4.0 mL) was stirred at 0° C. for 2 h. The reaction mixture was quenched with H2O, and extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (24 mg, 59% yield) as a white solid: mp 208-209° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 2.79 (3H, s), 3.42-3.58 (2H, m), 3.77 (3H, s), 3.78-3.86 (2H, m), 6.95 (1H, d, J=1.9 Hz), 7.01 (1H, t, J=9.0 Hz), 7.22-7.51 (6H, m), 7.73 (1H, dd, J=14.1, 2.4 Hz), 7.78 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 461 [M+H]+. Anal. Calcd for C24H21FN6O3.0.75H2O: C, 60.06; H, 4.49; N, 18.27. Found: C, 60.05; H, 4.26; N, 18.16.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1Br
Product: CC(=O)Nc1ccc(Cl)cc1Br

Procedure:
A solution of 2-bromo-4-chloroaniline (1 g, 4.84 mmol) in acetic anhydride (5 ml, 4.84 mmol) was stirred at RT for 1.5 hrs. The resulting suspension was collected by filtration and dried on a vacuum line to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1Br.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C1(OP(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(OC2C=CC=CC=2)(OC2C=CC=CC=2)=O)(OC2C=CC=CC=2)=O)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[N:23]1[CH2:22][CH2:21][N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:26])([F:27])[F:12])[CH:15]=2)[CH2:25][CH2:24]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1cc(Cl)c(Br)c(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(Cl)c1
Temperature: 100 °C
Yield: 54 %

Procedure:
A stirred mixture of 2.5 grams (0.0096 mole) of 1,3-dichloro-5-methoxy-2-bromobenzene (known compound), 0.18 mL (0.0096 mole) of 1-(α,α,α-trifluoro-meta-tolyl)piperazine (known compound), 0.18 gram (0.0002 mole) of tris(dibenzylideneacetone)dipalladium(0), 0.36 gram (0.0006 mole) of racemic-2,2′-bis(diphenylphosphono)-1,1′-binaphthyl, and 1.66 grams (0.017 mole) of sodium tert-butoxide in 100 mL of toluene was heated at 100° C. for about 60 hours. After this time, the reaction mixture was cooled and washed with two 10 mL portions of water. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:3 and 1:1 mixtures of methylene chloride:hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.1 grams of the subject compound, mp 87-89° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][N:3]=1.C([Li])CCC.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>O1CCCC1.CCOCC>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[S:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: ClCCCCCBr
Reactant: Cc1ccsn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCl)sn1
Reaction time: 0.25 h
Yield: 49.4 %

Procedure:
To a solution of 6.4 g 3-methylisothiazole in 100 ml dry tetrahydrofuran at -78° C. under nitrogen was slowly added 7.6 ml n-butyllithium (9.5 m). After 15 min. at -78° C., a solution of 12.0 g 1-bromo-5-chloropentane in 10 ml dry ether was added. The reaction mixture was allowed to reach room temperature where it was stirred for 90 min., then diluted with ether, washed with water and sodium chloride solution, and dried over sodium sulfate. Concentration and flash filtration (silica gel, 4:1 hexane/ethyl acetate) gave 6.5 g of 5-(5-chloropentyl)-3-methylisothiazole as a red oil, sufficiently pure (NMR) for use in the subsequent reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:22]2[C:23]3[C:10]([CH2:11][C@@H:12]4[C@@H:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]([CH2:24][OH:25])[CH2:14][N:13]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.CC1(C)N([O])C(C)(C)CCC1.C(O)(=[O:47])C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:22]2[C:23]3[C:10]([CH2:11][C@@H:12]4[C@@H:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]([C:24]([OH:47])=[O:25])[CH2:14][N:13]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]21
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.7 %

Procedure:
To a solution of 1,6-di-(tert-butoxycarbonyl)-8β-hydroxymethyl-ergoline (328 g) in dichloromethane (1.97 L) and water (13.5 g) is added TEMPO (22.2 g). The solution is cooled using a ice-bath and iodobenzene diacetate (597 g) is added in portions. The mixture is stirred at room temperature for 12-16 h and the reaction is monitored by TLC. The reaction is quenched with the addition of sodium thiosulfate solution (184 g in 1315 mL of water), and the organic layer is separated. The aqueous is extracted with dichloromethane (656 mL) and the combined dichloromethane layers are washed with water and then evaporated to remove the solvent. The product is crystallized from cold methanol to furnish 1,6-di-(tert-butoxycarbonyl)-ergoline-8β-carboxylic acid (334 g) in 88.5% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc2ncccc2c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
A mixture of 3-quinolin-6-yl-acrylic acid ethyl ester (200 mg, 0.881 mmol) and 10% wt Pd/C (93 mg, 0.088 mmol) in methanol (3 mL) was stirred at room temperature under hydrogen atmosphere for 3 h. Mixture was filtered through celite and the filtrate was absorbed on silica gel. Purification on silica gel with 0-65% gradient of ethyl acetate in hexane provided 100 mg of product as a clear oil. 1H NMR 500 MHz (DMSO) δ 1.13 (t, 3H), 2.74 (t, 2H), 3.05 (t, 2H), 4.04 (q, 2H), 7.50 (dd, 1H), 7.67 (dd, 1H), 7.78 (d, 1H), 7.94 (d, 1H), 8.29 (dd, 1H), 8.84 (dd, 1H); MS (m/z) 230 [M+H+]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][CH:15]1[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])ccc(OCC2CC2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A flask with stirbar was charged with 2-bromo-3-methyl-4-nitrophenol (Parkway Scientific, 1.15 g, 4.96 mmol), (bromomethyl)cyclopropane (0.60 mL, 6.19 mmol) and cesium carbonate (2.65 g, 8.13 mmol) in dimethylformamide (16 mL). The mixture was stirred overnight at ambient temperature. The mixture was then heated to 50° C. in an oil bath. After 3 hours, the mixture was cooled and shaken in a separatory funnel with 100 mL each of ethyl acetate and saturated aqueous sodium chloride. The organics were washed twice with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 0-30% ethyl acetate in hexanes) to provide 1.24 g (87%) of the title compound