Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[Br-:11].C(OC([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P+:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)(C)(C)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C(Cl)Cl>>[Br-:11].[NH3+:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P+:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Br-:11].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: CC(C)(C)OC(=O)NCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [NH3+]CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of TFA/CH2Cl2 (1:1, 50 ml) containing triisoproylsilane (0.2 ml) was added to (6-((tert-butoxycarbonyl)amino)hexyl)triphenylphosphonium bromide (8.0 g). The mixture was stirred for 2 hours. After removal of the solvent, the compound was dried over a vacuum and directly used in next step.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[C:4]([F:17])[CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][CH2:31][C:25]=3[N:24]([CH3:39])[C:23]=2[N:40]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]5[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][C:25]=5[N:24]([CH3:39])[C:23]=4[N:40]=3)[C:10](=[O:14])[CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5F)cc4=O)nc31)CNCCC2
Temperature: 135 °C
Reaction time: 21 h
Yield: 88.5 %

Procedure:
A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (46 mg, 0.18 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (76 mg, 0.20 mmol), CuI (41 mg, 0.22 mmol), 8-hydroxyquinoline (5 mg, 0.04 mmol) and Cs2CO3 (65 mg, 0.20 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 21 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a clear solid. 2 N HCl in Et2O (100 mL) was added to a solution of the clear solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 22 h. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et2O was added, and the resulting suspension was filtered. The solid was washed with Et2O and put in a vacuum oven at 40° C. for 1 h to afford 39 mg (44%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.92 (br s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz, 1H), 7.55 (dd, J=10.0, 2.0 Hz, 1H), 7.41-7.35 (m, 2H), 6.15 (dd, J=8.0, 2.5 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 4.52-4.45 (m, 2H), 3.76 (s, 3H), 3.60-3.31 (m, 2H), 3.17-3.11 (m, 2H), 2.13-2.04 (m, 2H); ESI MS m/z 453 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([CH3:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=5)=[CH:3][C:4]=4[CH3:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(F)cc2)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Temperature: 150 °C
Yield: 58.1 %

Procedure:
A microwave vial was charged with 4-(4-bromo-2-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (60.0 mg, 0.148 mmol), (4-fluorophenyl)boronic acid (20.71 mg, 0.148 mmol), PdCl2(dppf) (5.42 mg, 7.40 μmol), K2CO3 (51.2 mg, 0.370 mmol), 1,4-dioxane (3 mL) and water (1 mL). The reaction was purged with nitrogen, sealed and heated in a microwave reactor at 150° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO, filtered through a syringe filter and purified by reverse phase HPLC (Gilson, YMC-Pack ODS-A C18 5 μm 75×30 mm column, 10-90% MeCN/water+0.1% TFA, 2×1 mL injections). The appropriate fractions were concentrated to remove a majority of the MeCN. The remaining aqueous mixture (product had oiled out) was extracted with two portions of dichloromethane. The combined dichloromethane layers were dried over Na2SO4, filtered, concentrated under reduced pressure and dried to constant weight under vacuum to provide the title product (36 mg, 0.086 mmol, 57.8% yield) as a yellow solid. MS(ES)+ m/e 421.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (d, J=4.04 Hz, 1H), 7.75-7.86 (m, 2H), 7.73 (br. s., 1H), 7.58-7.66 (m, 1H), 7.42 (td, J=8.34, 4.29 Hz, 1H), 7.33 (t, J=8.84 Hz, 2H), 3.59-3.88 (m, 1H), 3.46-3.59 (m, 1H), 2.82-3.38 (m, 2H), 2.28-2.49 (m, 3H), 2.12-2.20 (m, 3H), 1.87-2.07 (m, 1H), 1.39-1.76 (m, 2H), 0.59-0.76 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1.Cl.C(=O)([O-])[O-].[NH4+:36].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[NH:36])[NH2:30])[CH:24]=1
Reactant: [NH4+]
Reactant: Cn1c(COc2cccc(C#N)c2)nc2cc(NS(=O)(=O)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(COc2cccc(C(=N)N)c2)nc2cc(NS(=O)(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(3-cyanophenyl)-oxymethyl]-5-(benzenesulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5].FC(F)(F)S(O)(=O)=O.[CH3:29][C:30]([CH3:32])=[CH2:31].[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][C:30]([CH3:32])([CH3:31])[CH3:29])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5]
Reactant: C=C(C)C
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC(C)(C)C

Procedure:
A solution of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methyl-benzophenone (3.0 g; 9.6 mmol) in 50 ml of methylenechloride is cooled down to -70° C., trifluoromethanesulfonic acid (0.3 ml) is added, then a stream of 2-methylpropene (5.5 g; 100 mmol) is introduced within 4 hours. Triethylamine (1.2 ml) is added, the temperature goes up to 20° C. The solution is shaken twice with diluted sodium hydroxide and the solvent is evaporated. The residue is purified chromatographically (flash column with 30 g of silicagel, elution with toluene/acetone 20:1 (v/v)). The residue is treated with petrolether to give 0.7 g of white crystalls (20% y); mp. 102° C.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]1([C@@H:38]([CH3:42])[C:39]([O-:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:41][C:39](=[O:40])[C@@H:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42])=[O:31])(=[O:30])[CH3:29]
Reactant: C[C@@H](C(=O)[O-])c1ccccc1
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium 2(R)-phenyl-propionate (0.37 g, 1.31 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 81%. 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.38 (m, 1H), 7.33 (t, 1H), 7.27-7.15 (m, 6H), 5.78-5.72 (m, 2H), 4.63-4.57 (m, 1H), 4.04-3.95 (m, 2H), 3.84 (q, 1H), 3.76-3.69 (m, 2H), 3.36-3.26 (m, partially obscured by water, 2H), 3.17-3.12 (m, 1H), 3.07-3.04 (m, 2H), 2.31 (d, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H), 1.35 (d, 3H); MS-APCI (m/z+): 341, 385, 517, 591.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.B(Br)(Br)Br>ClCCl>[N:19]1([S:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][OH:2])[N:9]=3)[CH2:15][CH2:14]2)(=[O:18])=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COCc1nccc(N2CCN(S(=O)(=O)N3CCCC3)CC2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(N1CCCC1)N1CCN(c2ccnc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxymethyl-4-[4-(pyrrolidine-1-sulfonyl)-piperazin-1-yl]-pyrimidine (prepared according to the method of Example 121, Step A, 3.1 g, 9.4 mmol) in dichloromethane (47 mL) was added boron tribromide (1 M in dichloromethane, 19 mL, 18.7 mmol) at 0° C. then stirred at ambient temperature for 2 h. The mixture was washed twice with saturated aqueous sodium bicarbonate, and the organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil which was crystallized from isopropyl ether to give the title compound as a white solid, 2.43 g (77%). 1H NMR (CDCl3, 300 MHz) δ1.82 (m, 4H), 3.15 (m, 8H), 3.81 (m, 4H), 4.35 (d, 2H), 4.83 (t, 1H), 6.71 (d, 1H), 8.18 (d, 1H); mp: 128-131° C.; MS (CI) 328 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.C(Cl)(Cl)Cl.P(Br)(Br)[Br:19].CCCCCC>C(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:19])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: -5 °C
Yield: 42.5 %

Procedure:
A 500-mL three-necked round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol 103h (37.0 g, 148 mmol) and chloroform (160 mL). The reaction was cooled to −5° C. using an ice/acetone bath and phosphorous tribromide (40.0 g, 148 mmol) was added portionwise. The cooling bath was removed and the reaction stirred at reflux for 2 h. After this time, the reaction was cooled to −5° C. and saturated aqueous sodium bicarbonate (250 mL) was added until a pH of 8.5 was reached. The mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were washed with saturated aqueous sodium carbonate (2×50 mL), brine (75 mL), dried over sodium sulfate and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford a yellow residue that was dissolved with gentle heating in methylene chloride (60 mL). Hexane (approximately 20 mL) was added and the solution became cloudy. The mixture was heated until a solid precipitate formed, methylene chloride (9 mL) was added and the solution became clear. The solution was left to cool to room temperature and after 4 h the resulting crystals were collected by vacuum filtration. The filter cake was washed with a ice cold 1:2 mixture of methylene chloride:hexanes (2×20 mL) to afford 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 103i (19.7 g). The combined filtrates were evaporated and the procedure was performed again to afford an additional 9.70 g of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 103i. The solids were combined and dried under high vacuum for 18 h to afford a 57% yield (26.0 g) of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 103i as white crystals: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 1H), 4.63 (t, 2H, J=6.0 Hz), 4.54 (s, 2H), 3.86 (t, 2H, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[F:15])[CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:20][C:21]([F:35])([F:34])[C:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)=[CH:23]Cl.[Cl-].[Na+]>CN(C)C=O.O>[F:20][C:21]([F:34])([F:35])[C:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)=[CH:23][O:11][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([F:15])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CCOc1ccc(C(=CCl)C(F)(F)F)cc1
Reactant: OCc1ccc(F)c(Oc2ccc(Cl)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=COCc2ccc(F)c(Oc3ccc(Cl)cc3)c2)C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A solution of 3-(4-chlorophenoxy)-4-fluorobenzyl alcohol (6.3 g) in N,N-dimethylformamide (20 cm3) was added to a stirred suspension of sodium hydride (1.2 g of a 50% dispersion in oil) in N,N-dimethylformamide. After 30 minutes, this mixture was added to a stirred solution of EZ-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-chloroprop-2-ene (5 g) in N,N-dimethylformamide (25 cm3) at a temperature maintained at -10° C. during the addition. After 45 minutes the reaction mixture was poured into water (150cm3) and sodium chloride added. The products were extracted into diethyl ether (4×100 cm3), and the combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. The crude residue was purified by column chromatography on a silica gel support, eluted with n-hexane containing 6% by volume diethyl ether, to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-[3-(4-chlorophenoxy)-4-fluorobenzyloxy]prop-2-ene (6 g).
Reaction SMILES: [H-].[Na+].[H][H].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.CS(C)=O>[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=[CH:5][CH2:6][CH2:7][CH3:8])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Solvent: CS(C)=O
Product: CCCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 449 %

Procedure:
A 500 mL 3-necked flask fitted with a stirrer, was charged with sodium hydride (1.61 g, 67 mmol) and DMSO (40 mL). The resulting suspension was heated to 90° C. for 30 min, until the evolution of hydrogen ceased. The suspension was cooled on an ice-bath for 20 min followed by addition of a slurry of butyltriphenylphosphonium bromide (26.6 g, 67 mmol) in DMSO (70 mL). The red mixture was stirred for 15 min at rt. 1-Benzyl4-piperidone 1 (14.0 g, 74 mmol) was slowly added over 30 min, and the mixture was stirred at room temperature over night. H2O (200 mL) was added to the reaction mixture followed by extraction with heptane (4×100 mL) and ethyl acetate (2×100 mL). The combined organic phases were dried and evaporated to dryness, producing 38.1 g of a yellow oil. The oil was distilled to give 14.9 g (88%) of 2, bp 101-105° C. (0.1 mm Hg). 1H NMR (CDCl3) δ0.90-0.95 (t, 3H), 1.25 1.41 (m, 2H), 1.90-2.20 (m, 2H), 2.18-2.30 (m, 4H), 2.40-2.45 (m, 4H), 2.50 (s, 2H), 5.17 (t, 1H), 7.20-7.42 (m, 5H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:47]1[C:51](=[O:52])[C:50]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:49]2[C:48]1=[O:57].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][N:47]3[C:48](=[O:57])[C:49]4=[CH:56][CH:55]=[CH:54][CH:53]=[C:50]4[C:51]3=[O:52])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propanol (560 mg, 1.5 mmol), as prepared in the preceding step, triphenylphosphine (520 mg, 2.0 mmol), and N-hydroxyphthalimide (245 mg, 1.5 mmol) in tetrahydrofuran (15 mL) at 0° C. was added diethyl azodicarboxylate (350 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added, and the reaction mixture was extracted into ethyl acetate (3×50 mL). The ethyl acetate solution was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (4:1 dichloromethane/ethyl acetate) to give the title compound as a colorless foam (580 mg, 75%). 1H-NMR (300 MHz, CDCl3) δ9.42 (s, 1H), 8.81 (d, J=6.1 Hz, 1H), 8.56 (d, J=6.1 Hz, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.31 (d, J=7.2 Hz, 1H), 7.84 (m, 2H), 7.77 (m, 2H), 7.68 (t, J=7.7 Hz, 1H), 6.59 (s, 1H), 6.33 (s, 1H), 6.21 (s, 1H), 4.31 (t, J=6.1 Hz, 2H), 4.00 (t, J=6.1 Hz, 2H), 2.17 (s, 3H), 2.11 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][NH:5][C:4](=[O:7])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Li+].[I-].[CH2:17](Br)[C:18]#[CH:19]>C(#N)C>[CH3:1][C:2]1([CH3:8])[N:6]([CH2:19][C:18]#[CH:17])[NH:5][C:4](=[O:7])[CH2:3]1
Reactant: CC1(C)CC(=O)NN1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1NC(=O)CC1(C)C
Yield: 44.2 %

Procedure:
To a solution of 102 (10.0 g, 87.7 mmol) in acetonitrile (100 mL) was added K2CO3 (12.7 g, 92 mmol), LiI (0.59 g, 4.4 mmol) and propargyl bromide (11.0 g, 92 mmol). The resulting reaction mixture was refluxed for 24 h. Progress of the reaction was monitored using TLC. Upon completion of the starting material, the crude reaction mixture was filtered in a small pad of Celite and the solvent was evaporated under vacuum at room temperature. The crude material was passed through column eluting with EtOAc/hexane (3:7) to afford 103 (5.9 g) in 45% yield as a crystalline, pale yellow solid. 1H NMR (CDCl3) δ 7.45 (bs, 1H), 3.53 (d, J=2.2 Hz, 2H), 2.46 (s, 2H), 2.29 (t, J=2.6 Hz, 1H), 1.35 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[CH:7][C:8](=[O:12])[S:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][N:26]=[C:27]=[O:28])[CH3:22].Cl>ClCCl>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][NH:26][C:27]([C:7]1[C:8](=[O:12])[S:9][C:10]2[C:5]([C:6]=1[OH:13])=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)=[O:28])[CH3:22]
Reactant: CCOC(=O)CN=C=O
Reactant: O=c1cc(O)c2ccc(F)cc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1c(O)c2ccc(F)cc2sc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
7-Fluoro-4-hydroxy-thiochromen-2-one (2.0 g, 10.2 mmol) was dissolved in a mixture of triethylamine (1.7 mL, 12.23 mmol) and dichloromethane (50 mL). Isocyanato-acetic acid ethyl ester (1.4 mL, 12.23 mmol) was added to the solution and the reaction stirred overnight (18 h) at ambient temperature. The reaction mixture was acidified to pH 3 using 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and the crude residue purified by silica gel chromatography (10%-40% ethyl acetate in hexanes) to provide [(7-fluoro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (900 mg, 30%). MS ESI(−) m/e: 324.117 (M−1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].[Na+].[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[C:10]1([S:16]([C:2]2[N:3]=[CH:4][S:5][C:6]=2[CH:7]=[O:8])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1scnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1scnc1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of 4-chlorothiazole-5-carbaldehyde (0.15 g), benzenesulfinic acid sodium salt (0.25 g) and dimethyl sulfoxide (7.0 mL) was stirred at 100° C. for 30 minutes. The mixture was cooled to room temperature, poured onto ice/water (50 mL) and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a tan oil (0.23 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.CCOC(C)=O.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.O>[CH3:11][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(Br)cc(C(=O)O)c1C
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ccccc2)cc(C(=O)O)c1C
Temperature: 100 °C
Yield: 46.4 %

Procedure:
To a solution of 5-bromo-2,3-dimethyl-benzoic acid (690 mg, 3.0 mmol, 1.0 eq), phenylboronic acid (404 mg, 3.3 mmol, 1.1 eq) and Na2CO3 (958 mg, 9.0 mmol, 3.0 eq) in a mixture of EtOH (5 mL), DMF (20 mL) and water (5 mL) was added Pd(PPh3)4 (0.17 g, 0.15 mmol, 0.05 eq). The reaction was heated at 100° C. overnight then diluted with EtOAc and filtered through celite. The aqueous layer was acidified to pH 4-5 with diluted HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 10:1 then CH2Cl2:MeOH, 400:0 to 20:1) to give the title compound as a white solid (315 mg, 46%).