Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:16]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].C(SCCCCCCCCCC([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH2:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=O)(C)C>>[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:16])([OH:14])=[O:13]
Reactant: CCOC(=O)CCCSc1ccccc1NC(=O)CCCCCCCCCSC(C)C
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Product: O=C(O)CCCCCCCCCCC(=O)Nc1ccccc1SCCCC(=O)O

Procedure:
When amine (11) is acylated with acid chloride (7) as per procedure Step (E), and the resultant diester (ethyl 4-(2-(11-carbomethoxy-undecanoylamino)phenylthio)butyrate 12 is hydrolyzed in Step I as per procedure (F), the title compound, 13 m.p. 113.5-115° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([F:10])[C:7]=1[CH:8]1[O:14][CH2:13][CH2:12][O:9]1
Reactant: OCCO
Reactant: O=Cc1c(Br)ccc(O)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1ccc(Br)c(C2OCCO2)c1F
Yield: 93.6 %

Procedure:
A solution of 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 7.35 mmol), ethylene glycol (2 mL, 36.8 mmol), para-toluenesulfonic acid (0.27 g, 0.147 mmol), and toluene (150 mL) was refluxed with a dean-stark head for 16 hours. An aqueous solution of sodium bicarbonate was added and the solution was extracted with ethyl acetate. The aqueous layer was extracted five more times with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenol (1.81 g, 94% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(O)c2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCc2c([N+](=O)[O-])ccc(O)c2N1

Procedure:
Known 8-hydroxy-3,4-dihydrocarbostyril of formula (X) is first reacted with a nitrating agent such as a mixture of concentrated nitric acid, nitric anhydride or fuming nitric acid and acetic acid, acetic anhydride or sulfuric acid to obtain 8-hydroxy-5-nitro-3,4-dihydrocarbostyril of formula (IX). The compound of formula (IX) is then reacted with a reducing agent such as a mixture of stannous chloride, tin, iron or zinc and hydrochloric acid or sulfuric acid, or hydrogenated in the presence of a catalyst such as palladium-carbon to obtain 8-hydroxy-5-amino-3,4-dihydrocarbostyril of formula (VIII). The compound of formula (VIII) is then reacted with an oxidizing agent such as ferric chloride, chromic acid, a chromate, K2CrO7 + H2SO4, KMnO4 + H2O or MnO2 + H2SO4 to obtain 5,8-dioxo-3,4,5,8-tetrahydrocarbostyril of formula (VII). The compound of formula (VII) is then reacted with a reducing agent such as sulfur dioxide or sodium bisulfite or zinc and acetic acid to obtain 5,8-dihydroxy-3,4-dihydrocarbostyril of formula (VI). Finally, the compound of formula (VI) is reacted with an alkylating agent such as methyl iodide or dimethyl sulfate or with an aralkylating agent such as benzyl chloride to alkylate or aralkylate the hydroxy group at 8-position. The alkylation or aralkylation usually occurs at 8-position only, but occurs at both 5- and 8-positions as the case may be. Thus, the 3,4-dihydrocarbostyril derivatives of formula (II) used as the starting material in the present invention are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:19]=2)[N:14]=[CH:13]1.[C:29]1(=O)[CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:32]1([CH2:29][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[N:14]=[CH:13][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]4=[O:22])[CH2:24][CH2:25]2)[CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCNCC4)cc3c2=O)c1
Reactant: O=C1CCC1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(CC5CC5)CC4)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzoate (0.5 g) and cyclobutanone (0.20 ml) in THF (42.5 ml) was added titanium (IV) isopropoxide (0.75 ml) and the solution stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.83 g) was added and the reaction stirred at room temperature for 18 hours. Water was added and the resultant solid removed by filtration. The aqueous filtrate was washed with ethyl acetate. The organic layer was washed 1N NaOH (×2), water, brine, dried (magnesium sulphate) and to yield methyl 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate as a yellow foam (0.45 g); NMR Spectrum: (DMSOd6) 1.66 (m, 2H), 1.84 (m, 2H), 2.00 m, 2H), 2.16 (s, 3H), 2.42 (m, 4H), 2.75 (m, 1H), 3.27 (m, 4H), 3.87 (s, 3H), 7.48 (s, 1H), 7.62 (m, 3H), 7.97 (s, 1H), 8.02 (d, 1H), 8.09 (s, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[CH:23]=[CH:22][C:21]=1[F:32])=[O:19].[NH4+].[Cl-]>CO.[Zn]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:18]([C:20]2[CH:25]=[C:24]([O:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[CH:23]=[CH:22][C:21]=2[F:32])=[O:19])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(c1cc(OCC(O)CO)ccc1F)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccccc1Nc1ccc(C(=O)c2cc(OCC(O)CO)ccc2F)c(Cl)c1
Temperature: 25 °C

Procedure:
Compound 520 (37 mg, 0.08 mmol) was dissolved in MeOH (2 mL), NH4Cl (29 mg, 0.55 mmol) and Zn-dust (72 mg, 1.10 mmol) were added. Reflux for 0.5 h, allowed to cool to RT and filtered. Purified by flash chromatography using DCM:MeOH (v:v=95:5) as the eluent, affording the title compound. 13C NMR (CD3OD) δ 192.4, 156.5 (d), 156.2 (d), 153.1, 144.8, 136.3, 135.1, 129.9 (d), 128.4, 128.1, 127.1, 126.8, 120.8 (d), 119.6, 118.0 (d), 117.7, 116.5 (d), 115.8, 112.5, 71.7, 71.2, 64.0
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C(#N)C>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCc2ccc(F)cc2)c1

Procedure:
To 3-hydroxybenzamide (2.0 mM) under nitrogen was added anhydrous acetonitrile (30 ml), potassium carbonate (2.0 mM), and p-fluorobenzyl bromide (2.0 mM). The mixture was refluxed for 14 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallised from hot dichloromethane (minimum amount), and petrol ether 40/60. A white crystalline solid was isolated and dried. Melting point: 161-162° C. Infrared data: KBr disc: cm-1 : 3366; 3171; 1H NMR: d6DMSO: δ=5.23 (s; 2H; CH2); 7.26-7.68 (m; 9H; NH; aromatics); 8.11 (s; 1H; H4);
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[NH2:15][C:16]([CH3:46])([CH3:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][C:20]=1[C:38]1[N:39]([CH3:44])[N:40]=[CH:41][C:42]=1[Cl:43].C(=O)C.FC(F)(F)C([O-])=O>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:43][C:42]1[CH:41]=[N:40][N:39]([CH3:44])[C:38]=1[C:20]1[CH:21]=[C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:16]([NH:15][CH2:1][CH3:2])([CH3:46])[CH3:45]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(C)(C)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
Sodium triacetoxyborohydride (34.2 mg, 161 μmol) was added to a solution of N-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (53.8 mg, 115 μmol) and acetaldehyde (5.08 mg, 115 μmol) in THF (0.5 mL), and the mixture was stirred at room temperature. After 4 hours, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The extract was evaporated to dryness, the residue was redissolved in methanol, and the product was isolated by preparative HPLC. The trifluoroacetate salt was dissolved in a mixture of ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate, and evaporated to dryness to afford the title compound (12.5 mg, 22%). LCMS m/z (%)=497.5 (M+H, 37Cl 45.4), 495.3 (M+H, 35Cl 100.0%). 1H NMR (400 MHz, MeOH-d4) δ 1.00 (t, J=7.07 Hz, 3H) 1.07 (s, 6H) 2.42-2.51 (m, 2H) 3.71 (s, 3H) 3.85-3.88 (m, J=9.35 Hz, 1H) 3.90 (d, J=9.09 Hz, 1H) 7.22 (d, J=9.09 Hz, 1H) 7.58 (s, 1H) 7.67 (d, J=2.78 Hz, 1H) 7.73 (t, J=7.83 Hz, 1H) 7.85-7.92 (m, 2H) 8.21 (d, J=7.83 Hz, 1H) 8.27 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[N-:28]=[N+:29]=[N-:30].[Na+].C(O)(C)C.Cl>[Br-].[Zn+2].[Br-].O>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[C:24]([C:26]5[NH:30][N:29]=[N:28][N:27]=5)[N:25]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: c1ccc(-c2[nH]c3cc(C4CC4)ccc3c2Cc2cccc(-c3nnn[nH]3)n2)cc1
Yield: 85.4 %

Procedure:
To a mixture of 6-(6-cyclopropyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbonitrile (93 mg), sodium azide (86.5 mg), isopropyl alcohol (3.2 mL), and water (2.1 mL) was added zinc bromide (74.9 mg), and this mixture was heated under reflux for 23 hours while stirring. The reaction mixture was left to be cooled. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (89.2 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[Cl:11][C:12]1[N:17]=[C:16](S(C)(=O)=O)[CH:15]=[CH:14][N:13]=1>CN(C=O)C.CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([O:9][CH2:8][CH2:7][OH:10])[CH:15]=[CH:14][N:13]=1
Reactant: CS(=O)(=O)c1ccnc(Cl)n1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCOc1ccnc(Cl)n1
Reaction time: 0.25 h

Procedure:
Potassium carbonate (0.89 g, 6.45 mmol) was added at room temperature to an oven-dried, nitrogen cooled flask containing a suspension of ethylene glycol (1.3 mL, 23.4 mmol) in DMF (29 mL) and the mixture was then stirred for 15 minutes. 2-Chloro-4-(methylsulfonyl)pyrimidine (1.13 g, 5.86 mmol) was then added. The solution was stirred for 1.5 h at room temperature, then diluted with EtOAc (30 mL) and washed with 1:1 water:brine (3×50 mL). The organic extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford 2-[(2-chloropyrimidin-4-yl)oxy]ethanol as a pale yellow solid. MS ESI calcd. for C6H8ClN2O2 [M+H]+ 175. found 175.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:13]1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])[C:14]=1C#N)#N.C(O)CCC.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[C:1]([O:16][CH2:15][CH2:14][CH2:13][CH3:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=CC=Cc1ccccc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C=Cc1ccccc1
Yield: 94 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), BuOH (10 mL) and toluene (15 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Butyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C4H9) is isolated in 94% yield. 1H-NMR (CDCl3, 300 MHz) δ7.48 (1H, d), 7.25 (2H, m), 7.11 (3H, m), 6.23 (1H, m), 3.98 (2H, t), 1.45 (2H, m), 1.19 (2H, m), 0.74 (3H, t); 13C-NMR (CDCl3, 75.4 MHz) δ166.5, 144.2, 134.4, 129.9, 127.9, 118.2, 64.0, 30.7, 19.1, 13.6.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.OC(C(F)(F)F)=O.[CH3:21][S:22]([CH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1)(=[O:24])=[O:23].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:21][S:22]([CH2:25][CH2:26][C@H:27]1[CH2:28][CH2:29][C@H:30]([NH:33][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:31][CH2:32]1)(=[O:23])=[O:24]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CS(=O)(=O)CC[C@H]1CC[C@H](N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.10 g, 0.46 mmol), trans-4-[2-(methylsulfonyl)ethyl]cyclohexanamine TFA salt (0.12 g, 0.60 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) in isopropyl alcohol (1.0 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified on silica gel (eluting with 0 to 45% EtOAc in dichloromethane) to give the desired product. LCMS calculated for C16H22N3O4S2 (M+H)+: m/z=384.1. Found: 384.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[F:10][C:11]([F:19])([F:18])[C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15].Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:14]([CH3:15])[CH2:13][C:12](=[O:17])[C:11]([F:19])([F:18])[F:10]
Reactant: COc1ccccc1N
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Product: COc1ccccc1N=C(C)CC(=O)C(F)(F)F
Temperature: 102.5 °C

Procedure:
A mixture of 28.4 g (0.23 mol) of o-anisidine and 43.18 g (0.28 mol) of 1,1,1-trifluoro-2,4-pentanedione is heated at 100-105° C. for one hour and then cooled and the reaction medium is taken up with ethyl ether. 10 ml of 1 N hydrochloric acid are added. The mixture is filtered to remove the insoluble product, and the filtrate is concentrated under reduced pressure to give the expected product in the form of a beige solid (yield=98%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[C:18]1([CH2:24]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[CH2:24]([O:17][C:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g (8.2 mmol) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (commercially available), 0.978 g (9.0 mmol) phenyl-methanol (commercially available), 3.16 g (9.8 mmol) O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 1.24 g (12.3 mmol) NEt3 in 10 mL DMF was stirred at room temperature for 1 h. The mixture was evaporated to dryness and extracted with DCM and Na2CO3 aq. The combined organic phases were dried with MgSO4 and evaporated. The residue was treated with 100 mL 4N HCl in dioxane at room temperature for 4 h. The mixture was evaporated to dryness to yield trans-4-amino-cyclohexanecarboxylic acid benzyl ester (MS (m/e): 360.4 (MH+)) which was used without further purification. 150 mL DCM was added, 2.95 g (14 mmol) 4-cyano-benzenesulfonyl chloride (commercially available) and 6.17 g (61 mmol) NEt3 and the mixture was stirred at room temperature for 16 h. The mixture was extracted with DCM and 1N HCl aq. and the combined organic phases were evaporated. The residue was recrystallized from methanol to yield 1.9 g (58%) of the title compound. MS (m/e): 397.0 (MH+).
Reaction SMILES: CCCCOCCOCCO[CH2:12][C:13]1[CH:14]=[C:15]2[O:24][CH2:23][O:22][C:16]2=[CH:17][C:18]=1[CH2:19][CH2:20][CH3:21].[ClH:25].O>C1C=CC=CC=1>[CH2:19]([C:18]1[C:13]([CH2:12][Cl:25])=[CH:14][C:15]2[O:24][CH2:23][O:22][C:16]=2[CH:17]=1)[CH2:20][CH3:21]
Reactant: Cl
Reactant: CCCCOCCOCCOCc1cc2c(cc1CCC)OCO2
Solvent: c1ccccc1
Solvent: O
Product: CCCc1cc2c(cc1CCl)OCO2
Temperature: 25 °C

Procedure:
15 g of piperonyl butoxide and 300 ml of concentrated hydrochloric acid were dissolved in 100 ml of benzene and the solution was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and water was added thereto. After extraction with ethyl acetate, the extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 12 g of 6-propyl-5-chloromethyl-1,3-benzodioxole in the form of a faint brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:26][CH2:25][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[N:15]=[C:16]([CH3:17])[C:3]=12
Reactant: CN1CCN(CCO)CC1
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Product: Cc1nn(CCN2CCN(C)CC2)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound Iv was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(4-methylpiperazin-1-yl)ethanol following the general procedure for the Mitsunobu reaction described above.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38]>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][N:14]([CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCCBr
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@@H](C(=O)OC)C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
To a mixture of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitrophenylsulfonamido)-propanoate iii (150 mg, 0.37 mmol) in 3 mL of DMF was added potassium carbonate (102 mg, 0.74 mmoL). This mixture was stirred at rt for 20 min followed by the addition of 5-bromo-1-pentene (65 μL, 0.55 mmoL). The reaction mixture was stirred at rt for 2 days. It was then filtered, concentrated and purified by silica gel chromatography (eluting with 25% ethyl acetate in hexane) to give 75 mg (43%) of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoate iv as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 1.42 (s, 9H), 1.54–1.64 (m, 2H), 1.97 (q, J=7.20 Hz, 2H), 3.37 (m, 2H), 3.57–3.80 (m, 2H), 3.72 (s, 3H), 4.42 (dd, J=8.60, 5.31 Hz, 1H), 4.91–5.01 (m, 2H), 5.69–5.79 (m, 1H), 7.75–7.85 (m, 3H), 8.04 (m, 1H). LC-MS (Method D, retention time: 2.68 min), MS m/z 372 (M++1-Boc).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:21]([NH2:22])[C:20]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[CH:4]2
Reactant: COc1ccccc1CCC#N
Reactant: Nc1ccc(F)cc1C=O
Product: COc1ccccc1Cc1cc2cc(F)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-fluorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[C:19]=1[CH:20]=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N:13]2[C:14](=[O:15])[C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:16][C:9]=3[NH:10][CH2:11][CH2:12]2)[C:19]=1[CH:20]=[O:21]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc2c(c1)NCCNC2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc2c(c1)NCCN(c1cccc(Br)c1C=O)C2=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
8-tert-Butyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (420 mg, 2 mmol), 2,6-Dibromo-benzaldehyde (2.03 g, 8 mmol, 3eq), Xanthphos (22 mg, 0.02eq), and cesium carbonate (1.23 g, 4 mmol, 2 eq) were taken up in dioxane (5.0 mL) and a stream of argon gas was bubbled through the mixture for 1 minute. The catalyst Pd(dba)2 (33 mg, 0.03 eq) was added and argon was bubbled through for an additional minute. The resulting mixture was sealed under argon and stirred at 100° C. for 18 hours. The reaction was cooled and filtered. The collected solid was triturated with water and filtered to give a solid. The dioxane filtrate was combined with this solid, the solvent removed under vacuum, and the residue chromatographed, eluting with 50% ethyl acetate in hexanes gave a solid, 81 mg. (M+H)+=402.