Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]2)[CH2:3][NH:2]1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:2]1[CH2:1][CH:9]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CN(CCCCl)CC2C1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (1.70 g), 1-bromo-3-chloropropane (1.70 mL) and K2CO3 (3.30 g) in acetone was heated to reflux for 10 h, then cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.79 g, 35.00%), HPLC: 80.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 303.2 (M+1).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42]>>[OH:42][CH2:41][CH:40]([NH:39][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1)[CH2:43][OH:44]
Reactant: NC(CO)CO
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: O=C(NC(CO)CO)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 74.5 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 45 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 604 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=3[C:17]#[N:18])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:18][CH2:17][C:16]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=1[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][N:2]([CH3:24])[CH3:1])[N:6]=[CH:7]2
Reactant: CN(C)CCn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 113.6 %

Procedure:
To a cooled (0° C.) solution of 2-[1-(2-dimethylaminoethyl)-1H-indazol-5-yloxy]-5-fluorobenzonitrile (0.115 g, 0.303 mmol) in THF (3 mL) was added LAH (0.61 mL of 1M in THF). The mixture was warmed to room temperature and stirred for 1.5 hours. The mixture was quenched with water (23 μL), 3N NaOH (23 μL) and water (69 μL). The salts were removed by filtration and the filtrate was concentrated under reduced pressure to afford 0.113 g of product (97% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@H:16]1[C:21]([OH:23])=[O:22])=[O:14])([CH3:11])(C)C.C(Cl)(OCC1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O1CCOCC1.O>[CH:39]1[C:40]2[CH:11]([CH2:8][O:12][C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[C:21]([OH:23])=[O:22])=[O:14])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]=2[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of (S)-4-(tert-butoxycarbonyl) morpholine-3-carboxylic acid (5.00 g, 21.64 mmol) in CH2Cl2 (40 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to dryness and the crude residue (2.80 g, 21.30 mmol) was dissolved in a mixture of dioxane (30 mL) and water (10 mL). The suspension was cooled to 0° C., FMOC-Cl (6.60 g, 25.60 mmol) and K2CO3 (11.60 g, 84.2 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, diluted with water (20 mL) and acidified with 1M aqueous HCl (30 mL) to pH 2-3. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (6.41 g) as colorless oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][CH2:8]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30].CCOCC>C1COCC1>[Br:30][CH2:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Cl)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1ccc(CCBr)s1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(5-chloro-2-thienyl)-ethanol* (12.2 g) and triphenylphosphine (21.4 g) in anhydrous THF (150 ml) at 0° C. was added carbon tetrabromide (27.5 g). The reaction was stirred at 5° C. for 15 min then at room temperature for 2.5 h. Ether was added and the reaction was then filtered and the filtrate concentrated. The resultant residue was purified by flash column chromatography (silica, eluting with cyclohexane:DCM 8:1) to give the title compound (15 g) as an oil. * Schick et al., J. Amer. Chem. Soc., 70, 1948, 1646.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[O:6][C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[OH:22].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32])([CH3:25])[CH3:24].N1CCCCC1>ClCCl>[OH:22][C:3]1[CH2:4][C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7](=[O:8])[C:2]=1[S:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)CCCCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Reactant: CC(C)c1ccccc1S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)c1ccccc1SC1=C(O)CC(CCCCC(=O)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.1 mmol of 5-[5-bromo-3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl]pentanoic acid (prepared in example DDD), 1.3 mmol of 2-isopropylbenzenethiol, and 1.3 mmol of piperidine in 20 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with 5% methanol in chloroform and then with 9:1:0.5 chloroform:methanol:acetic acid, to give the title compound, (m.p. 145°-146° C.). 1H NMR (DMSO-d6) δ 1.07-1.19 (t plus m, 7 H), 1.25 (m, 1 H), 1.43 (m, 2 H), 1.91 (m, 2 H), 2.15 (t, 2 H), 3.19 (m, 1 H), 3.41 (2 H+H2O), 5.81 (d, 1 H), 6.54 (t, 1 H), 6.93 (t, 1 H), 7.12 (d, 1 H), 7.29-7.44 (m, 5 H).
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40]O)[C:5]=2[N:4]=1.C[CH2:44][N:45](CC)[CH2:46]C.CS(Cl)(=O)=O.N(C)C>C1COCC1>[F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40][N:45]([CH3:46])[CH3:44])[C:5]=2[N:4]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate from the previous step and 0.34 g (3.3 mmol) of Et3N in 20 mL of THF was cooled to 0° C. and 0.32 g (2.8 mmol) of methanesulfonyl chloride was added dropwise. After 1 hr, 6 g of 40% aqueous Me2NH was added, and the resulting mixture was stirred at room temperature for 36 hrs. The THF was removed under vacuum and the residue was diluted with water and extracted into CH2Cl2. Drying and removal of the solvent gave tert-butyl 4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.87 (dd, J=8.4. 0.6 Hz, 1H), 7.48 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.31 (t, J=6.7 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 2.51 (t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.13 (pentet, J=7.0 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[C:12]2[CH3:27])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][OH:23])=[C:12]2[CH3:27])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1c(CO)cc(-c2ccccc2)n1S(=O)(=O)c1cccc(Cl)c1
Yield: 48.1 %

Procedure:
Using ethyl 1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (0.80 g) and a 1.5 mol/L solution (4.0 mL) of diisobutylaluminum hydride in toluene, a procedure as in Reference Example 5 was performed to give the title compound as a brown oil (yield 345 mg, 48%).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:16][C:17]#[N:18]>CN(C)C=O>[C:17]([CH2:16][O:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][N:10]=1)#[N:18]
Reactant: O=C1CC(c2ccccc2)NN1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2ccccc2)[nH]n1

Procedure:
In an analogous manner to the method described in Example 1B, 40 g 5-phenylpyrazolin-3-one in 120 ml dimethyl formamide were first deprotonated by reaction with 5.6 g of an 80% oily sodium hydride preparation and subsequently reacted with 11 ml chloroacetonitrile to form 3-cyanomethoxy-5-phenylpyrazole. Melting point: 143° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:38])[N:26]([CH2:28][CH2:29][O:30]CC4C=CC=CC=4)[CH3:27])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>CO.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:38])[N:26]([CH2:28][CH2:29][OH:30])[CH3:27])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(C(=O)N(C)CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(C(=O)N(C)CCO)cc3)cc3ccccc23)CC1
Yield: 72.2 %

Procedure:
Sequentially, the resulting 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)-N-methylcarbamoyl]phenyl}isoquinoline (0.69 g) was converted into a hydrochloride in a conventional manner and then dissolved in methanol (50 ml). To the resulting solution was added 10% palladium/carbon catalyst (0.20 g), and the catalytic reduction was conducted at atmospheric pressure overnight. The catalyst was filtered off, while the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.41 g of the free compound of the title compound as a pale yellow amorphous.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.[I-].[Na+].[OH:19][C:20]1[C:21]2[C:34](=[O:35])[NH:33][CH2:32][C:22]=2[C:23]([O:30][CH3:31])=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2>FC1C=CC(CN2C(=O)C3C(OCOC)=C4C(C=CC=N4)=C(OC)C=3C2=O)=CC=1.C(O)(=O)C>[CH3:31][O:30][C:23]1[C:22]2[CH2:32][NH:33][C:34](=[O:35])[C:21]=2[C:20]([O:19][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)NC2
Reactant: COc1ccc(CCl)cc1
Agent: COCOc1c2c(c(OC)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)O
Product: COc1ccc(COc2c3c(c(OC)c4cccnc24)CNC3=O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Potassium carbonate (60.1 mg, 0.435 mmol), 4-methoxybenzylchloride (41 mg, 0.26 mmol), and sodium iodide (6.3 mg, 0.043 mmol) were added to 9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 303 (20 mg, 0.087 mmol) dissolved in dimethylformamide 8 (0.4 ml). The reaction mixture was warmed to 60° C. and stirred at 60° C. for one hour. After cooling the reaction mixture to 0° C., acetic acid (0.06 ml) was added and the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and washed once with 5% Citric Acid, twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (9/1-dichloromethane/methanol) to afford 5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 304 (16 mg, 0.046 mmol, 53%). 1H NMR (CDCl3) δ 9.0 (dd, 1H), 8.64 (dd, 1H), 7.51 (d, 2H), 7.46 (m, 1H), 6.80 (d, 2H), 6.50 (broad, 1H), 5.60 (s, 2H), 3.98 (s, 3H), 3.72 (s, 3H). MS: 351.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:29])([F:28])[C:13]2[N:18]=[CH:17][C:16]([O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1.[N-:30]=[N+:31]=[N-:32].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:30]([CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:10])[C:12]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)([F:29])[F:28])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(CN=[N+]=[N-])c3ccc(F)cc3F)nc2)cc1
Yield: 86.5 %

Procedure:
A solution of 4-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)oxy)benzonitrile (3.5 g, 8.74 mmol) and sodium azide (1.705 g, 26.2 mmol) in DMF (43.7 mL) was heated at 50° C. for 17 h. The reaction was poured into sat. aq. NaHCO3, and the mixture was extracted with Et2O (3×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated to give the title compound as a brown oil (3.353 g, 69%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]3[N:35]=[CH:36][N:37]=[C:11]23)=[CH:6][CH:5]=1.[CH3:38][C:39]1([CH3:42])[CH2:41][O:40]1.Cl>CN(C)C=O>[OH:40][C:39]([CH3:42])([CH3:41])[CH2:38][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]3[N:35]=[CH:36][N:37]=[C:11]23)=[CH:6][CH:5]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ncnn12
Reactant: CC1(C)CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(C)(C)O)cc2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a mixture of sodium hydride (0.020 g) and N,N-dimethylformamide (2 mL) was added 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.20 g) at 0° C. The mixture was stirred at 0° C. for 30 min, 2,2-dimethyloxirane (0.11 mL) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11]CC=C)=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[CH3:16][CH2:17][CH2:18]CCC.ClCCl>C1C2C(=CC=CC=2)CCC1>[CH3:1][C:2]1[CH:10]=[C:9]([CH2:18][CH:17]=[CH2:16])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]
Reactant: CCCCCC
Reactant: C=CCOc1ccc(C)c2c1C(=O)CC2
Solvent: c1ccc2c(c1)CCCC2
Solvent: ClCCl
Product: C=CCc1cc(C)c2c(c1O)C(=O)CC2

Procedure:
32 Grams of 4-methyl-7-allyloxy-1-indanone was suspended in 100 ml of tetrahydronaphthalene. The suspension was refluxed by heating for 4 hours under argon gas atmosphere. The reaction mixture was subjected to a silica gel column chromatography (eluent: n-hexane, and dichloromethane: n-hexane=1:2) to obtain 26.8 g of 4-methyl-6-allyl-7-hydroxy-1-indanone.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4]([OH:6])=O.[CH3:20][CH2:21]OCC.C([Li])C.Cl>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4](=[O:6])[CH2:20][CH3:21]
Reactant: CCOCC
Reactant: CCC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Agent: Cl
Agent: [Li]CC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)CC
Reaction time: 3 h

Procedure:
To a stirred solution of 2.5 g. of 3,7,11,11-tetramethyltrideca-2,4-dienoic acid in 30 ml. of dry ether is added slowly, at 0°, 23 ml. of a one molar solution of ethyl lithium in benzene. After about three hours at 20°, the mixture is poured into iced 1N hydrochloric acid (100 ml.) with vigorous stirring. The ether layer is separated, combined with ethereal washings of the aqueous phase, washed with water, saturated potassium bicarbonate, and then saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 5,9,13,13-tetramethylpentadeca-4,6-dien-3-one which is purified by high vacuum distillation or chromatography.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH:11]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]1=[O:13])=[O:10])[CH3:3].[C:19]1([CH3:30])[CH:24]=[CH:23][C:22]([S:25]([O:28]C)(=[O:27])=[O:26])=[CH:21][CH:20]=1.S([C:35]1C=CC(C)=CC=1)([O-])(=O)=O>C(#N)C>[C:19]1([CH3:30])[CH:20]=[CH:21][C:22]([S:25]([O-:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[CH3:1][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH:11]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]1=[O:13])=[O:10])([CH3:35])[CH3:3]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)CCCCCC(=O)C1CCCCNC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: C[N+](C)(C)CCCCCC(=O)C1CCCCNC1=O
Temperature: 25 °C

Procedure:
In a 500 mL three-necked round-bottomed flask fitted with an argon inlet, condenser, and stir bar are placed amine amide 4 (17.94 g, 0.071 mol), acetonitrile (200 mL), and methyl p-toluenesulfonate (13.13 g, 0.071 mol). While adding the tosylate, the reaction mixture mildly exotherms. The mixture is heated to reflux for 3 h and is then cooled to room temperature. While concentrating the mixture by rotary evaporation, a tan solid forms which is redissolved in a minimal amount of acetonitrile and triturated with ether until a free flowing dispersion of the solid is obtained in the solvent system. The solid is collected by vacuum filtration under a blanket of nitrogen and transferred to a round-bottomed flask. The solid product is a suitable cationic bleach activator. It is dried at room temperature under vacuum (0.1 mmHg) for 24 h to give 5 (Cationic Bleach Activator A) (27.84 g, 90%) as an off-white solid, mp 128°-131° C. (softens at 118° C.).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:26][N:27]([CH2:41][CH:42]([NH2:53])C(OCC1C=CC=CC=1)=O)[CH2:28][CH:29]([NH2:40])C(OCC1C=CC=CC=1)=O)[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=O)C1C=CC=CC=1.O>C(O)(C)C.[Pd]>[NH2:11][CH:12]([CH2:26][N:27]([CH2:28][CH2:29][NH2:40])[CH2:41][CH2:42][NH2:53])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: NC(CN(CC(CCCC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC(N)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CC(C)O
Product: NCCN(CCN)CC(N)CCCC(=O)O
Reaction time: 8 h

Procedure:
14.2 g (20 mmol) of benzyl 4-benzyloxycarbonylamino-5-[bis(2-benzyloxycarbonyl-aminoethyl)amino]pentanecarboxylate are dissolved in 300 ml of isopropanol, treated with 30 ml of water and 3 g of palladium catalyst (10% Pd/C) are added. The mixture is hydrogenated at 50° C. for 8 hours. It is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:1]2[CH2:6][CH2:5][N:4]([C:14](=[N:13][C:10]3[CH:11]=[CH:12][C:7]([CH3:23])=[CH:8][CH:9]=3)[NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[CH2:3][CH2:2]2)=[N:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(N=C(Nc2ccc(C)cc2)N2CCN(C(=Nc3ccc(C)cc3)Nc3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
0.5 mmol of piperazine was dissolved in 10 ml of DMF and 1.05 mmol of 1,3 di-p-tolylcarbodiimide was added. After 0.5 h. of stirring at room temperature, a small precipitation was filtered off and washed twice with 1 ml of DMF. The filtrates were collected and kept at room temperature overnight. To the DMF solution, 50 ml of water was added. The precipitated solid was filtered and washed with water. The solid was dissolved in ethyl acetate (20 ml) and 0.2 ml of conc. HCl conc. was added. The product began to precipitate within 15 min. After 1 hour, the precipitate was filtered and washed with ethyl ether. Yield=76%.
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21](C(OCC5C=CC=CC=5)=O)[CH2:20]4)=[CH:15][C:14]=3[F:35])[NH:9][C:8]=2[CH:7]=[C:6]([F:36])[CH:5]=1)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O>[F:36][C:6]1[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:15][C:14]=3[F:35])[NH:9][C:8]=2[CH:7]=1
Reactant: NC(=O)c1cc(F)cc2[nH]c(-c3ccc(C4CCCN(C(=O)OCc5ccccc5)C4)cc3F)nc12
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(F)cc2[nH]c(-c3ccc(C4CCCNC4)cc3F)nc12

Procedure:
A solution of EXAMPLE 59D (150 mg) in TFA (10 mL) at 40° C. was stirred for 2.5 days and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 1.83-1.96 (m, 2H), 2.07-2.15 (m, 2H), 3.02-3.21 (m, 3H), 3.44-3.54 (m, 2H), 7.32 (dd, J=4.14, 1.69 Hz, 1H), 7.35 (s, 1H), 7.50 (dd, J=8.29, 2.45 Hz, 1H), 7.69 (dd, J=10.43, 2.45 Hz, 1H), 8.30 (t, J=7.98 Hz, 1H).