Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[N:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[ClH:25].[ClH:25].[N:26]1([CH2:32][CH2:33][CH2:34][NH:35][C:1]([CH2:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:2])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NCCCN1CCCCC1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC(=O)NCCCN1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 64 h
Yield: 263 %

Procedure:
To a stirring solution of 1-[3-carboxypropyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (0.540 g, 1.5 mmol) in N,N-dimethylformamide (60 ml) were added sequentially 3-(piperidin-1-yl)propylamine (235 mg, 1.1 eq), 1-hydroxybenzotriazole (223 mg, 1.1 eq), and dicyclohexylcarbodiimide (340 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 0.731 grams of the title compound as an orange solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[O:22])[CH2:15]2.CO>O1CCCC1>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[O:22])[CH2:15][CH2:1]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CN2CCC1CC2
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An ice-cooled solution (5° C.) of (trimethylsilyl)diazomethane/hexane (2 N, 30 mL, 60 mmol; Aldrich) under nitrogen was treated dropwise with a solution of quinuclidin-3-one (7500 mg, 60 mmol) in dry tetrahydrofuran (40 mL). Methanol (20 mL) was added, and the yellow solution was warmed to room temperature, stirred for 24 hours, and quenched to colorless by addition of acetic acid. After a few minutes, saturated aqueous sodium carbonate (15 mL) was added. The organic layer was separated, and the aqueous solution was extracted with methylene chloride (3×50 mL). The combined organic layer and extracts were dried over magnesium sulfate, and concentrated in vacuo to give the titled compound. The material was used directly for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][C:25](O)=[O:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)COC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) in acetonitrile (10 ml) were successively added methoxyacetic acid (0.08 ml), triethylamine (0.17 ml), HOBt (0.18 g) and WSC (0.23 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was recrystallized from ethanol-water to give the title compound as colorless needle crystals (0.16 g, 44%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:4][CH2:3]1.[C:17]([O-:22])(=[O:21])[C:18]([O-:20])=[O:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:17]([OH:22])(=[O:21])[C:18]([OH:20])=[O:19].[O:19]=[C:18]([C:5]1([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH3:17]
Reactant: CN1CCC(OCc2ccccc2F)CC1
Reactant: O=C([O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)C1(OCc2ccccc2F)CCN(C)CC1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a suspension of 1-methyl-4-(2-fluorophenylmethoxy)piperidine (liberated from 30.6 g, 90.7 mmole, of the oxalate, and 165 ml of water was added a solution of 22 ml of conc. sulfuric acid in 53 ml of water. To the solution was added 4.0 g (13.4 mmole) of mercuric sulfate. The mixture was heated at reflux for 1.5 hr. under nitrogen and allowed to cool to room temperature. The mixture was poured into cold saturated sodium carbonate, extracted twice with ether and washed with saturated sodium chloride. The ether solution was dried over anhydrous potassium carbonate, filtered and the solvent evaporated to provide an oil. The oxalate salt was precipitated, and recrystallization from methanol/ethanol provided 21.1 g (59.4%) of 4-(1-oxoethyl)-4-(2-fluorophenylmethoxy)-1-methyl piperidine oxalate. The material appeared pure by TLC on silica gel in methanol:methylene chloride (9:1), Rf =0.4 and on alumina in ether, Rf =0.3. IR (Nujol), NMR-DMSO-d6 and MS (ci MH+ =266) are consistent with the structure, m.p.=180°-181° C.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14](OCC)=[O:15])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.CN1CCCC1>O>[CH2:8]([C:5]1[N:4]=[N:3][C:2]([N:10]2[CH2:20][CH2:19][CH:13]([CH2:14][OH:15])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH3:9]
Reactant: CCc1ccc(Br)nn1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1ccc(N2CCC(CO)CC2)nn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1.67 g (0.011 mol) of 3-bromo-6-ethylpyridazine was added to 1.5 mL (10 mmol) ethyl isonipecotate and 3.5 mL (20 mmol) diisopropylethylamine and 5 mL N methylpyrrolidine (NMP). This mixture was heated to 140° C. for 4 hours. Upon cooling 100 mL of water was added to the mixture and the contents were extracted with methylene chloride then washed twice with water and once with brine and the solvent evaporated in vacuo. The resulting oil was eluted through a short silica gel plug with 80% ethyl acetate and 20% hexanes and dried in vacuo. This intermediate was taken up in 25 mL THF and was exposed to 3-fold excess lithium aluminum hydride with stirring under nitrogen for 1 hour. The reaction was chilled on ice and quenched by dropwise addition of water. The slurry was dried, treated with charcoal and filtered yielding 6-ethyl-3-(4-hydroxymethyl-1-piperidinyl)pyridazine (Formula IV: R1 =C2H5 ; Y=CH2 ).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:10][C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:27]>C(O)(=O)C>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([C:11]2[NH:27][C:3](=[O:2])[C:5]3[N:6]([CH:7]=[CH:8][CH:9]=3)[CH:10]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2cccc12
Temperature: 25 °C

Procedure:
A solution of 106 mg (0.34 mmol) 1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester and 789 mg (10.2 mmol) ammonium acetate in 2 ml acetic acid is heated to 80° C. under stirring. The mixture is stirred at this temperature for 5 hours and then cooled to room temperature. The mixture is partitioned between THF and saturated sodium chloride solution. The organic phase is washed two times with 25% aqueous ammonia and two times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as colourless crystals; HPLC/MS 2.11 (A), [M+H] 279;
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6](=[O:18])[NH:7][CH:8]=2)[CH2:3]1.[H-].[Na+].Cl[CH2:22][CH2:23][CH2:24]I>CN(C=O)C.C1COCC1>[NH3:2].[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:22][CH2:23][CH2:24][N:2]3[CH2:11][CH2:10][CH2:9][CH2:4][CH2:3]3)=[N:7][CH:8]=2)[CH2:3]1
Reactant: ClCCCI
Reactant: CN1Cc2cc(=O)[nH]cc2C(c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1Cc2cc(OCCCN3CCCCC3)ncc2C(c2ccccc2)C1
Product: N
Reaction time: 0.5 h
Yield: 10 %
Yield: 2 %

Procedure:
A solution of 6-methyl-8-phenyl-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-3-one (82.8 mg, 0.326 mmol) in DMF (3 mL) and THF (2 mL) was treated with NaH (60% in oil; 62 mg). After 30 min, 1-chloro-3-iodopropane (0.075 mL) was added. After 1 h at 0° C., the mixture was diluted with satd. aq. NaHCO3 and extracted with DCM. The organic layer was washed with H2O (2×), dried, and concentrated. The residue was diluted with n-butanol (5 mL) and treated with piperidine (1.5 mL), Na2CO3 (150 mg), and KI (˜10 mg). After 18 h at 55° C., the mixture was cooled, concentrated, neutralized with satd. aq. NaHCO3, and extracted with DCM. The organic layer was dried and concentrated. Preparative TLC (SiO2; 10% 2 M NH3 in MeOH/DCM) gave the title compound (2.5 mg, 2%). 1H NMR (CDCl3): 7.34-7.19 (m, 5H), 6.84 (s, 1H), 6.31 (s, 1H), 4.05-4.00 (m, 1H), 3.88-3.82 (m, 2H), 3.66 (d, J=15.9, 1H), 3.40 (d, J=16.0, 1H), 2.99-2.93 (m, 1H), 2.46-2.40 (m, 1H), 2.39 (s, 3H), 2.55-2.06 (m, 6H), 1.87-1.74 (m, 2H), 1.46-1.33 (m, 6H). 6-Methyl-8-phenyl-2-(3-piperidin-1-yl-propyl)-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-3-one (22.6 mg, 19%) was also obtained. 1H NMR (CDCl3): 7.65 (s, 1H), 7.32-7.17 (m, 5H), 6.45 (s, 1H), 4.27-4.18 (m, 3H), 3.65 (d, J=15.7, 1H), 3.53 (d, J=15.6, 1H), 3.04-2.99 (m, 1H), 2.58-2.37 (m, 9H), 2.00-1.91 (m, 2H), 1.70-1.54 (m, 5H), 1.47-1.40 (m, 2H).
Reaction SMILES: C(O[C@@:5]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([O:30][CH3:31])[C:24]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)=[C:23]2[Cl:43])([C:12]1[C:13]([CH3:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[C:6]1[N:10]([CH3:11])[N:9]=[N:8][CH:7]=1)(=O)C.[NH3:44].CO>>[Cl:43][C:23]1[C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:5]([C:12]3[C:13]([CH3:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=3)([C:6]3[N:10]([CH3:11])[N:9]=[N:8][CH:7]=3)[NH2:44])[CH:21]=2)[N:26]=[C:25]([O:30][CH3:31])[C:24]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:37][CH:38]=1
Reactant: N
Reactant: COc1nc2ccc([C@](OC(C)=O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: COc1nc2ccc(C(N)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 65 °C

Procedure:
A mixture of (S)-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methyl acetate (646 mg, 1.06 mmol, Intermediate 55) and ammonia in MeOH (3.3 mL, 23 mmol, 7.0 M) in a sealed pressure tube was heated at 65° C. for 18 h, and concentrated in vacuo. The residue was purified by flash column chromatography (40 g silica gel column, 50-100% EtOAc in heptanes, and 5-10% MeOH in CH2Cl2) to give the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=2.02 Hz, 1H), 7.82 (d, J=9.09 Hz, 1H), 7.51 (d, J=8.08 Hz, 2H), 7.37-7.44 (m, 3H), 7.08 (d, J=8.08 Hz, 1H), 7.02 (s, 1H), 6.98 (d, J=8.08 Hz, 1H), 4.34 (s, 2H), 4.09 (s, 3H), 3.94 (s, 3H), 2.56 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.CCOCC.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccc(F)cc3)c3ccccc23)CC1
Yield: 53 %

Procedure:
A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 15 ml of 4-fluorobenzoyl chloride was heated at 200° for 2 hrs. The reaction mixture was poured into ether and the precipitate was collected. The precipitate was treated with dilute aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield 2.5 g (53%) of product, mp 132°-133° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25](=O)([O-])[O-:26].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([CH:25]=[O:26])[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](N1CCN(C=O)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 120 °C
Yield: 36.5 %

Procedure:
A mixture of compound 2 (200 mg, 0.6 mmol) and potassium carbonate (248 mg, 1.8 mmol) in DMF (5 ml) was heated at 120° C. for 24 h. The contents were poured into cold water and extracted with ethyl acetate (3×20 ml). The combined organic extract was washed with water, brine and dried over sodium suphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/MeOH; 98:2) to give the title compound as colorless solid (80 mg, 36%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]3[NH:21][C:20]([CH:22]=[C:23]4[N:46]=[C:26]([C:27]([CH:39]([CH2:43][CH2:44]Br)[CH2:40][CH2:41]Br)=[C:28]5[NH:38][C:31](=[CH:32][C:33]6[CH:34]=[CH:35][C:36]=2[N:37]=6)[CH:30]=[CH:29]5)[CH:25]=[CH:24]4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:48][P:49]([O:52][CH3:53])[O:50][CH3:51]>>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]3[NH:21][C:20]([CH:22]=[C:23]4[N:46]=[C:26]([C:27]([CH:39]([CH2:43][CH2:44][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:48])[CH2:40][CH2:41][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:48])=[C:28]5[NH:38][C:31](=[CH:32][C:33]6[CH:34]=[CH:35][C:36]=2[N:37]=6)[CH:30]=[CH:29]5)[CH:25]=[CH:24]4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(OC)OC
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c3nc(cc4ccc([nH]4)c(C(CCBr)CCBr)c4nc(cc5ccc2[nH]5)C=C4)C=C3)cc1
Product: COP(=O)(CCC(CCP(=O)(OC)OC)c1c2nc(cc3ccc([nH]3)c(-c3ccc(OCC(=O)OC(C)(C)C)cc3)c3nc(cc4ccc1[nH]4)C=C3)C=C2)OC
Yield: 65 %

Procedure:
A sample of 15a (38.7 mg, 0.048 mmol) was dissolved in trimethylphosphite (5.0 mL). The solution was refluxed under argon for 1.5 days. The P(OMe)3 was evaporated at reduced pressure. The residue was chromatographed (silica, CH2Cl2/MeOH, 0→5%) to yield a dark purple solid (24.6 mg, 65%): 1H NMR δ 1.64 (s, 9H), 3.15 (m, 2H), 3.32-3.36 (m, 2H), 3.43 (s, 3H), 3.47 (s, 6H), 3.50 (s, 3H), 3.81-3.87 (m, 4H), 4.84 (s, 2H), 5.44 (m, 1H), 7.35 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.1 Hz, 2H), 9.10 (s, 2H), 9.40 (s, 2H), 9.50-9.51 (m, 1H), 9.73-9.74 (m, 2H), 10.30-10.31 (m, 2H); LD-MS obsd 803.7, calcd 800.3104 (C41H48N4O9P2); λabs (log ε) 407 (4.90), 504 nm; λem (λexc 407 nm) 636 nm, 702 nm. Varying amounts of a less polar purple solid (16a-Br) were isolated along with small amounts of the starting material 15a (limited characterization). Data for 16a-Br: 1H NMR δ 0.86-0.95 (m, 1H), 1.65 (s, 9H), 1.91-2.00 (m, 1H), 3.13-3.40 (m, 6H), 3.44 (s, 3H), 3.48 (s, 3H), 3.55-3.85 (m, 2H), 4.83 (s, 2H), 5.51-5.61 (m, 1H), 7.34 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.1 Hz, 2H), 9.08-9.10 (m, 2H), 9.37-9.41 (m, 2H), 9.49-9.51 (m, 2H), 9.67-9.68 (m, 1H), 9.84-9.85 (m, 1H), 10.30 (s, 2H); LD-MS obsd 773.6, calcd 773.2 [(M+H)+, M=C39H42BrN4O6P2]; λabs 407, 502 nm; λem (λexc 407 nm) 634, 702 nm.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]([NH2:17])=O.[N+:18]([C:21]1[CH:58]=[CH:57][C:24]([C:25]([O:27][C@@:28]([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41]3[CH:50]=[C:49]4[C:44]([C:45]([C:53](=O)[CH2:54]Br)=[CH:46][C:47]([C:51]#[N:52])=[N:48]4)=[CH:43][CH:42]=3)[CH:39]=2)([C:31]([F:34])([F:33])[F:32])[CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>O1CCOCC1.C(OCC)(=O)C>[N+:18]([C:21]1[CH:58]=[CH:57][C:24]([C:25]([O:27][C@@:28]([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41]3[CH:50]=[C:49]4[C:44]([C:45]([C:53]5[N:17]=[CH:15][S:2][CH:54]=5)=[CH:46][C:47]([C:51]#[N:52])=[N:48]4)=[CH:43][CH:42]=3)[CH:39]=2)([C:31]([F:34])([F:33])[F:32])[CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC=O
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4cscn4)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of P4S10 (34 mg, 0.08 mmol) in dioxane (1 mL) at 0° C. was added formamide (57 mg, 1.26 mmol). The reaction mixture was warmed to room temperature for 1 h. A solution of 1-(1-{[4-(bromoacetyl)-2-cyanoquinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (see Example 52, Step 2) (160 mg, 0.25 mmol) in dioxane (1 mL) was then added and the mixture stirred at room temperature overnight. The reaction mixture was diluted in ethyl acetate, washed with water, brine and dried over MgSO4. The crude compound was purified on silica gel (eluting solvent: 5% acetone in dichloromethane) to give the desired product. 1H NMR (acetone-d6): δ 9.35 (s, 1H), 8.80 (d, 1H), 8.55 (s, 1H), 8.40 (m, 3H), 8.30 (d, 2H), 8.22 (s, 1H), 8.05 (s, 1H), 7.75 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14](N)[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].C[N:39](C=O)C>>[NH2:39][C:15]1[N:16]=[CH:17][N:18]=[C:19]2[C:14]=1[N:13]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:20]2[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)NCCCBr
Reactant: Nc1nc(Sc2cc3c(cc2I)OCO3)nc2[nH]cnc12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)C(=O)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio-9H-purin-6-amine (50 mg, 0.12 mmol) in DMF (2 mL) was added N-(3-bromopropyl)isobutyramide (50 mg, 0.24 mmol) and Cs2CO3 (78 mg, 0.24 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS46 as a white solid (22 mg, 34%). 1H NMR (500 MHz, CDCl3/MeOH-d4): δ 8.22 (s, 1H), 7.61 (br s, 1H), 7.41 (s, 1H), 7.08 (s, 1H), 6.07 (s, 2H), 4.27 (m, 2H), 3.21 (m, 2H), 2.45 (s, 1H), 2.02 (m, 2H), 1.19 (d, J=6.9 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C19H22IN6O3S, 541.0519. found 541.0508.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.C(Br)(Br)(Br)[Br:26].[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60]O)=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCOC(C)=O>[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60][Br:26])=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(OC)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(OC)c2)c1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a flamed dried flask was added triphenylphosphine (98 mg, 0.373 mmol) and 1.5 mL anhydrous THF. This was stirred until all the triphenylphosphine had dissolved. Then CBr4 (123 mg, 0.373 mmol) was added. The reaction mixture was stirred for one-half hour at room temperature then it was cooled to ° C. before N-dodecyl-3-bromo-4-(2-hydroxyethoxy)-5-(3-methoxyphenyl)benzamide (200 mg, 0.373 mmol) was added. The cooling bath was removed after the addition was complete. After the reaction mixture had warmed up to room temperature, 0.2 eq each of triphenylphosphine (19.6 mg, 0.075 mmol) and CBr4 (24.8 mg, 0.075 mmol) were added. The reaction was stirred for one-half hour then the solvent was removed under vacuum to give a yellow semisolid. This material was subjected to flash chromatography (25% EtOAc:75;% Hexanes) to yield 150 mg, 67% of a yellow oil. 1H NMR (CDCl3) δ1.25 (t, J=8.13 Hz, 3H); 1.22-1.40 (m, 18H); 1.52-1.63 (m, 2H); 3.35 (t, J=8.18 Hz, 2H); 3.40 (q, J=6.54 Hz, 2H); 3.84-3.90 (m, 5H); 6.00 (m, 1H); 6.93 (dd, J=8.18 Hz, 2.45 Hz, 1H); 7.07-7.11 (m, 2H); 7.35 (t, J=8.18 Hz, 1H); 7.65 (d, J=2.45 Hz, 1H); 7.9 (d, J=2.45 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70 mg, 0.309 mmol) in DCM (3 mL) were added acetyl chloride (32 μL, 0.450 mmol) and triethylamine (54 μL, 0.526 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, and washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (3 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (41 mg, 79%).