Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[S:11]1[C:15]([NH:16][C:17](=[O:32])[CH2:18][N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28]([F:31])([F:30])[F:29])=[N:20]2)=[CH:14][C:13]2[CH2:33][CH2:34][CH2:35][CH2:36][C:12]1=2.C([O-])(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH:9]([C:14]1[C:13]2[CH2:33][CH2:34][CH2:35][CH2:36][C:12]=2[S:11][C:15]=1[NH:16][C:17](=[O:32])[CH2:18][N:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]([C:28]([F:31])([F:29])[F:30])=[N:20]1)=[O:10]
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1cc2c(s1)CCCC2
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=Cc1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Temperature: 25 °C
Yield: 86.4 %

Procedure:
Phosphorus oxychloride (399 μl, 4.28 mmol) was added dropwise to a stirred solution of DMF (332 μl, 4.28 mmol) in 1,2-dichloroethane (3 mL). A suspension of N-(4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(3-trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetamide (1.64 g, 4.28 mmol) in 1,2-dichloroethane (80 mL) was added portionwise with stirring, and the mixture stirred at RT for 15 min. The resulting yellow solution was refluxed for 20 min. After cooling to RT, the mixture was added to a solution of sodium acetate (13.6 g, 166 mmol, in 130 mL of water) and the solution heated at 50° C. for 20 min. After cooling to RT, the solution was diluted with DCM (100 mL), and the phases separated. The aqueous layer was extracted with DCM (100 mL) and the combined organics washed with saturated sodium bicarbonate solution (100 mL), dried over sodium sulphate and concentrated in vacuo to afford the title compound as a yellow solid (1.52 g, 3.70 mmol, 86%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH2:12]([S:16][S:17][NH:18][C:19](F)=[O:20])[CH2:13][CH2:14][CH3:15].[OH-].[K+].[CH3:24]CCCC>>[CH3:24][N:18]([S:17][S:16][CH2:12][CH2:13][CH2:14][CH3:15])[C:19]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:20]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CCCCC
Reactant: CCCCSSNC(=O)F
Agent: [K+]
Agent: [OH-]
Product: CCCCSSN(C)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(-butylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example X by reacting 3.48 g (0.02 m) of 3,5,5-trimethyl-2-oximino thiazolidin-4-one with 3.96 g (0.02 m) of N-methyl-N-(-butylthiosulfenylcarbamoyl fluoride and 1.3 g (0.02 m) of pulverized potassium hydroxide and 0.02 g of crown ether. The residual oil was taken in pentane and chilled to yield 5.0 g of a white solid, m.p. 36°-37° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1COCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[O:20]1[CH2:21][CH2:22][N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCOCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a stirred solution of tert-butyl bromoacetate (8.47 mL, 57.4 mmol) in THF (50 mL) was added a 1:1 mixture of triethylamine (8 mL, 57.4 mmol) and morpholine (5.02 mL, 57.4 mmol), dropwise (a mild exotherm was observed) and the resulting white suspension was stirred at 60° C. for 2 h. The mixture was diluted with water (100 mL) and saturated sodium carbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated sodium carbonate (100 mL), water (3×50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated then chromatographed in 0%-100% ethyl acetate in hexanes. Product-containing fractions were concentrated in vacuo giving the title product (11.5 g, quantitative) as a pale yellow liquid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 3.78-3.71 (m, 4H), 3.10 (s, 2H), 2.59-2.54 (m, 4H), 1.46 (m, 9H).
Reaction SMILES: [Br-:1].[C:2]([C:5](=[CH2:53])[CH2:6][N+:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH2:22][S:21][C@H:20]3[N:17]([C:18](=[O:36])[C@H:19]3[NH:23][C:24](=[O:35])[CH2:25][S:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[Cl:34])[C:16]=2[C:37]([O:39]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:38])=[CH:9][CH:8]=1)([OH:4])=[O:3].N#N.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br-:1].[C:2]([C:5](=[CH2:53])[CH2:6][N+:7]1[CH:8]=[CH:9][C:10]([S:13][CH2:14][C:15]2[CH2:22][S:21][C@H:20]3[N:17]([C:18](=[O:36])[C@H:19]3[NH:23][C:24](=[O:35])[CH2:25][S:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[Cl:34])[C:16]=2[C:37]([OH:39])=[O:38])=[CH:11][CH:12]=1)([OH:4])=[O:3]
Reactant: C=C(C[n+]1ccc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)cc1)C(=O)O
Agent: N#N
Agent: [Br-]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C[n+]1ccc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A slurry of 1-[2-carboxy-2-propen-1-yl]-4-[[(6R)-trans-2-(diphenylmethyl carboxy)-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium bromide (580 mg, 0.665 mmol) in 22 mL of CH2Cl2 was cooled to 0° C. (ice bath) under an atomosphere of N2. Anisole (2.8 mL) was added followed by trifluoroacetic acid (8 mL). The cooling bath was removed, and the reaction was allowed to stir at rt for 1 h. The solution was concentrated in vacuo to remove the CH2Cl2 and most of the trifluoroacetic acid. The residue was treated with ether to precipitate a yellow solid. This solid was collected by filtration washing with ether. The solid was stirred with ethyl acetate for 30 min. stirred with acetone for 30 min., collected by filtration, and dried in vacuo to give 322 mg (66%) of 1-[2-carboxy-2-propen-1-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium bromide as a tan solid. 1H NMR (DMSO-d6) δ9.27 (d, J=8 Hz, 1H), 8.73 (d, J=6 Hz, 2H), 8.06 (d, J=6 Hz, 2H), 7.45-8.48 (m, 2H), 7.24 (dd, J=2,9 Hz, 2H), 6.41 (s, 1H), 6.08 (s, 1H), 5.63 (dd, J=5,8 Hz, 1H), 5.19 (s, 2H), 5.09 (d, J=5 Hz, 1H), 4.43 (s, 2H), 3.92 (s, 2H), 3.70 (d, J=18 Hz, 1H), 3.48 (d, J=18 Hz, 1H). IR (KBr) 1774, 1702, 1680, 1628, 1106 cm-1 ; MS (ESI) 626 (MH)+, Anal: Calcd for C25H21N3O6S3Cl2 ×HBr×0.5Me2CO; C, 42.44; H, 3.13; N, 5.94. Found: C, 43.25; H, 3.42, N, 5.71.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([CH:17]=O)[N:13]3[CH3:16])=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[NH:29]1[CH2:32][CH:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:30]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:16][N:13]1[C:12]([CH2:17][N:29]2[CH2:32][CH:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:30]2)=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:6]1[C:5]3[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=3[N:3]=[C:2]1[CH3:1])=[N:8][C:9]=2[N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CC(C)(O)C1CNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.075 g, 0.20 mmol), 2-azetidin-3-ylpropan-2-ol (0.023 g, 0.20 mmol) in DCE (2 mL), trimethoxymethane (0.215 mL, 2 mmol) and acetic acid (0.012 mL, 0.2 mmol) was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (0.042 g, 0.2 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water, and the organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90) to give 315 as an off-white solid (0.020 g, 23%). LCMS (Method G): RT=5.61 min, [M+H]+ 477.2. 1H NMR (CDCl3, 400 MHz) δ 8.11-8.07 (m, 1 H); 7.72-7.69 (m, 1 H); 7.35-7.26 (m, 2 H); 4.42-4.31 (m, 4 H); 3.89-3.82 (m, 11 H); 3.62-3.12 (m, 2 H); 2.94 (s, 3 H); 2.70-2.55 (m, 1H); 1.18 (s, 6 H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(O[N:34]1N=[N:41][C:36]2C=[CH:38][CH:39]=[CH:40][C:35]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.ClCl.[O:59]1CCCC1>ClCCl.C(O)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([CH:14]([NH:13][C:11](=[O:12])[C:9]3[CH:8]=[CH:7][C:3]([C:4]([N:34]4[CH2:38][CH2:39][CH2:40][C@H:35]4[C:36]([NH2:41])=[O:59])=[O:6])=[C:2]([Cl:1])[CH:10]=3)[CH3:15])=[N:17][C:18]=2[CH:24]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C1CCOC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: CC(NC(=O)c1ccc(C(=O)N2CCC[C@H]2C(N)=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 31 %

Procedure:
Prepared analogously to Example 1g from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and S-prolinamide in tetrahydrofuran. Yield: 31%; Rf value: 0.15 (silica gel; dichloromethane/ethanol=9:1); C22H21Cl2N5O3 (474.35); mass spectrum: (M+H)+=474/476/478 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1>[Pd].C(O)C>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:20])[NH:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:16])[CH3:19]
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Pd]
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]c1=O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 4-chloro-2-nitrobenzaldehyde (9-1, 495 mg, 2.64 mmol, 1 equiv) and 10% palladium on carbon (0.280 g, 0.264 mmol, 0.100 equiv) in ethanol (20 mL) was stirred under a hydrogen balloon for 1 h at 23° C. The catalyst was filtered onto a pad of celite and washed with ethanol (20 mL). The combined filtrate was concentrated to 20 mL, then diethyl malonate (0.801 mL, 5.28 mmol, 2.00 equiv) and piperidine (0.130 mL, 1.32 mmol, 0.500 equiv) were added. The resulting mixture was heated at reflux for 5 h. The mixture was allowed to cool to 23° C., and the precipitate was filtered and washed with cold ethanol (10 mL) to give 7-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (9-2) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C.C(O)=O>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:22]=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
(R)-1-[4-(Benzyloxy)-3-nitrophenyl]-2-bromoethanol (0.2 g, 5.7 mmol) in THF:toluene (1:1, 5 mL) was reacted with PtO2 (1% w/w) on a Parr shaker at 45 psi at rt overnight. The next morning the PtO2 was removed by filtration over celite. The filtered solution was cooled to 0° C. and a solution of acetic anhydride (0.161 mL, 0.569 mmol) and formic acid (0.043 mL, 1.140 mmol) was added dropwise to a stirred solution. After 30 min the reaction was warmed to rt and stirred for 2 h. The reaction mixture was concentrated to near dryness and water was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4 (s), and concentrated. Chromatography (1:1 Hexanes/EtOAc) gave the title compound (156 mg, 78% 2 steps). ES/MS calcd. C16H17BrNO3+ 350.0. Found m/z=350 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:10][CH3:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cncc(Cl)n1

Procedure:
2,6-Dichloropyrazine (0.067 mole) is treated with a solution of sodium methoxide (0.067 mole) in 100 ml. dry methanol for 1 hour at 25°. The solvent is removed in vacuo and the residue is extracted with boiling hexane extract. 2-Chloro-6-methoxypyrazine crystallizes from the hexane extract. Another recrystallization from isopropanol at -70° gives 2-chloro-6-methoxypyrazine as an oil at room temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>C1(C)C=CC=CC=1.C(O)C.C(Cl)Cl>[Br:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Brc1cccc(-c2cccnc2)c1
Reaction time: 0.17 h
Yield: 35 %

Procedure:
Tetrakis-(triphenylphosphine)palladium (153 mG; 0.135 mM) was added to a stirred solution of 3-bromopyridine (0.434 mL; 4.5 mM) in 9 mL of toluene. The resulting solution was stirred 10 mins. under nitrogen at R.T. 2M aqueous sodium carbonate solution (5 mL; 10 mM) followed by a solution of 3-bromophenylboronic acid (1 G; 5 mM) in 2.5 mL of absolute ethanol were added. This heterogeneous reaction mixture was vigorously stirred 20 hrs. at 80° under nitrogen, cooled, diluted with 25 mL of methylene chloride, and washed with 2×5 mL of 2M aqueous sodium carbonate solution containing 0.5 mL of conc. ammonia. The organic layer was dried over anhyd. magnesium sulfate. Solvent removal followed by purification on silica gel using ether:petroleum ether (1:1) as solvent gave 3-(3'-bromophenyl)pyridine in 35% yield as a colorless liquid boiling at 140°-2°/~2 mm.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=3[F:28])[N:12]=2)=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[Br:27][C:25]1[CH:24]=[CH:23][C:22]([F:28])=[C:21]([C:13]2[N:12]=[C:11]([NH:10][C:9]3[C:4]([C:3]([OH:29])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[N:14]=2)[CH:26]=1
Reactant: COC(=O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Yield: 82.6 %

Procedure:
A solution of 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic acid methyl ester 107 (200 mg, 0.439 mmol) and NaOH (44 mg, 1.10 mmol) in THF/MeOH/H2O (3:2:1, 5 mL), was stirred at room temperature for 3 h. The solvent was evaporated, and the residue dissolved in H2O, neutralized with AcOH, filtered off, and successively washed with H2O, MeOH and Ether to give 160 mg of the title product 16 as a yellow powder (LCMS analysis).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[I-].[K+]>CN(C=O)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[C:20](=[O:21])[CH:5]([CH2:4][CH2:3][CH2:2][N:46]3[CH2:47][CH2:48][N:43]([C:38]4[N:37]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH2:44][CH2:45]3)[CH2:6][CH2:7][C:8]=2[O:12][N:11]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2ncccn2)CC1
Temperature: 80 °C
Yield: 38.7 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (7.3 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.6 g), diisopropylethyl amine (6.2 ml), 1-(2-pyrimidyl)piperazine (5.8 g) and potassium iodide (0.4 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 16 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 4.0 g of 6,7-dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyrimidyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one as an oil which solidified upon standing. Recrystallization with ether gave the product as a solid, m.p. 115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]3[N:19]([CH3:36])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: O=c1nc(SCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1SCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]thio}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (75 mg, 0.145 mmol) and DIPEA (0.08 mL, 0.458 mmol) in DCM (2 ml) was added MeI (0.014 mL, 0.217 mmol). The solution was stirred at room temperature overnight. Purification via MDAP then afforded the title compound (13 mg, 16.88% yield). LCMS: rt=3.45 min, [M+H+]=533
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.[C:35](OCC)(=[O:41])[C:36](OCC)=[O:37]>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:7]1[CH2:8][CH2:9][N:4]2[C:1](=[O:3])[CH:2]=[C:35]([OH:41])[C:36]([OH:37])=[C:5]2[C:6]1=[O:10]
Reactant: CC(=O)N1CCNC(=O)C1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetylpiperazin-2-one (1.0 g, 7.0 mmol) in DMF (75 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)-amide in THF (7.7 mL, 7.7 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with 3-chlorobenzyl bromide (0.92 mL, 7.0 mmol), and stirred at room temperature overnight. The resultant mixture was cooled to 0° C., treated with a solution of lithium bis(trimethylsilyl)amide in THF (8.4 mL, 8.4 mmol) and stirred for 30 min, and then treated with diethyl oxalate (0.96 mL, 7.0 mmol). The resultant mixture was stirred at room temperature overnight. Additional solution of lithium bis(trimethylsilyl)amide in THF (16.8 mL, 16.8 mmol) was added and stirred for 4 hrs. The product mixture was concentrated under vacuum, and the residue was treated with a mixture of aqueous HCl and ethyl acetate. The white solid precipitated was collected by filtration and was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:47]#[N:48])/[C:10]([NH:12][CH:13]([C:17]2[CH:46]=[CH:45][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]([C:38](OC(C)(C)C)=[O:39])C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1C(=O)N(OC([CH2:66][CH2:67][CH2:68][CH2:69][C@@H:70]2[S:74][CH2:73][C@@H:72]3[NH:75][C:76]([NH:78][C@H:71]23)=[O:77])=O)C(=O)C1.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:47]#[N:48])/[C:10]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][NH:30][C:38](=[O:39])[CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]3[C@@H:71]4[C@@H:72]([NH:75][C:76](=[O:77])[NH:78]4)[CH2:73][S:74]3)=[CH:45][CH:46]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCNC(=O)CCCC[C@@H]2SC[C@@H]3NC(=O)N[C@@H]32)cc1
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of (E)-(2-(2-(2-(4-(1-(3-(6-bromopyridin-2-yl)-2-cyanoacrylamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (47; 105 mg, 0.14 mmol) and trifluoroacetic acid (0.3 mL) was stirred in dichloromethane (3 mL) for 1.5 hours. The solution was concentrated and the residue was dissolved in N,N-dimethylformamide. To this solution at ice bath temperature was added D-biotin N-hydroxysuccinimide ester (49 mg, 0.14 mmol) and DIPEA (75 μL, 0.43 mmol). The resulting mixture was stirred at this temperature for 2 hours and then partitioned between dichloromethane and water. The organic phase was washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to afford an oil. Purification by flash silica gel column chromatography, eluting with 7:93 methanol/dichloromethane, provided 48 (55 mg, 51%) as a pale yellow oil: (MS (ES+) m/z 757.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:6]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>CC#N>[N:29]1[CH:30]=[CH:31][CH:32]=[N:33][C:28]=1[O:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:2][CH2:3][O:4][C:5]2[CH:20]=[CH:19][C:8]([O:9][C:10]3[S:11][C:12]4[C:13]([N:18]=3)=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:7][CH:6]=2)[CH2:22][CH2:23]1
Reactant: c1cnc(OC2CCNCC2)nc1
Reactant: BrCCOc1ccc(Oc2nc3ncccc3s2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(OC2CCN(CCOc3ccc(Oc4nc5ncccc5s4)cc3)CC2)nc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
To a solution of 2-[4-(2-bromoethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine (131 mg, 0.37 mmol) and 2-(piperidin-4-yloxy)-pyrimidine (80 mg, 0.45 mmol, 1.2 equiv.) in CH3CN (1.9 mL) was added N,N-diisopropylethylamine (97 μL, 0.56 mmol, 1.5 equiv.). The resulting solution was allowed to stir at 70° C. for 18 h. The solution was then cooled to rt, filtered and purified using preparative reverse phase HPLC to afford the desired product as a yellow-brown solid (64 mg, 38%). 1H NMR (600 MHz, CDCl3): 8.58-8.54 (m, 1H), 8.52-8.48 (m, 2H), 8.01-7.96 (m, 1H), 7.34-7.30 (m, 2H), 7.18 (dd, J=6.7, 4.8, 1H), 6.96 (d, J=8.1, 2H), 6.92-6.87 (m, 1H), 5.14-5.04 (m, 1H), 4.14 (t, J=5.6, 2H), 2.96-2.88 (m, 2H), 2.86 (t, J=5.5, 2H), 2.56-2.46 (m, 2H), 2.16-2.04 (m, 2H), 2.01-1.90 (m, 2H). MS (ESI): mass calcd. for C23H23N5O3S, 449.15; m/z found, 450.1 [M+H]+.