Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]3([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)[CH:7]=2)[CH:24]=[N:25][CH:26]=1
Reactant: C[C@]1(c2cc(Br)c(F)cc2F)N=C(N)OCC1(F)F
Reactant: OB(O)c1cncc(Cl)c1
Product: C[C@]1(c2cc(-c3cncc(Cl)c3)c(F)cc2F)N=C(N)OCC1(F)F

Procedure:
In a manner analogous to that described in Example 31, the cross-coupling reaction of (R)-4-(5-bromo-2,4-difluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.2) and 5-chloropyridin-3-ylboronic acid yielded the title compound as a pale yellow solid. MS (ISP): m/z=373.8 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55](=[O:59])[CH:56]([NH2:58])[CH3:57])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:41]1[C:42]2[C:37](=[N:36][C:35]3[C:44]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55]([CH:56]([NH:58][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:57])=[O:59])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:38]=[CH:39][CH:40]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 48.7 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-difluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4Br)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccccn1
Yield: 46.6 %

Procedure:
A mixture of 1.94 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-bromobenzamide, 2.95 g of 2-pyridyl tri-n-butyl tin and 400 mg of tetrakis(triphenylphosphine)palladium(O) is refluxed for 24 hours in degassed toluene for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 70% ethyl acetate:hexane to give 900 mg of the desired product as a pale yellow solid:M+1=485.
Reaction SMILES: [K].Cl.O.[NH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1>CO>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH:8]=3)=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 92.7 %

Procedure:
To a solution of potassium hydroxyde (16 g) in methanol were added at 5° C. 4-piperidone hydrate hydrochloride (30 g) and a solution of 6-methyl-1H-indole (10 g) in methanol (50 ml). The mixture was refluxed for 16 hours. After cooling precipitated inorganic salts were filtered off. Methanol was evaporated and the remaining oil was dissolved in ethyl acetate (200 ml) and subsequently washed with brine (2×100 ml). After drying (anh. MgSO4) the solvent was evaporated leaving 15 g of crude 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole, which was used without further purification. The pure tetrahydropyridyl derivative crystallized from diethyl ether. Mp: 150°-152° C. To a solution of 1-(2-chloroethyl)-3-(2-propyl)-2-imidazolidinon (32 g) in MIBK (500 ml) were added 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (15 g), potassium carbonate (16 g) and potassium iodide (5 g). The mixture was refluxed for 19 hours and finally filtered while still hot. MIBK was evaporated and the resulting oil was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml). After drying (anh. Na2SO4) ethyl acetate was evaporated. The remaining oil was stirred with diethyl ether (200 ml) and the precipitated, crystalline 3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-1,2,3,6-tetrahydro-4-pyridyl]-6-methyl-1H-indole was filtered off. Yield: 14.5 g. Mp: 170°-174° C. To a solution of the thus prepared imidazolidinon derivative (14 g) in acetic acid (300 ml) was added PtO2 (600 mg). This mixture was hydrogenated in a Parr apparatus at 3 ato. for 72 hours. The catalyst was filtered off and most of the acetic acid was evaporated in vacuo. The remaining oil was dissolved in H2O and pH was adjusted to 9-10 by addition of dil. NaOH solution. The title compound 14a was extracted with dichloromethane (2×200 ml) and isolated as above. The crude product was purified by eluting (eluent: ethyl acetate/dichloromethane/ethanol/triethyla-mine 40:40:20:5) through silica gel. Yield: 4.5 g. Mp: 185° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[S:12][C:13]2[C:14](=[C:16]([C:20](Cl)=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:15]=1.[NH2:23][CH2:24][C@@H:25]1[CH2:30][C@H:29]2[C@H:27]([CH2:28]2)[N:26]1[C:31]([C:33]1[N:34]=[C:35]([CH3:45])[S:36][C:37]=1[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)=[O:32]>C(#N)C>[CH3:45][C:35]1[S:36][C:37]([C:38]2[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=2)=[C:33]([C:31]([N:26]2[C@H:25]([CH2:24][NH:23][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:13]4[S:12][C:11]([Cl:10])=[N:15][C:14]=34)=[O:21])[CH2:30][C@H:29]3[C@@H:27]2[CH2:28]3)=[O:32])[N:34]=1
Reactant: O=C(Cl)c1cccc2sc(Cl)nc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4sc(Cl)nc34)C[C@@H]3C[C@@H]32)c1
Reaction time: 0.5 h

Procedure:
DIPEA (0.61 mmol) and 2-chloro-benzothiazole-4-carbonyl chloride (0.31 mmol) are added successively to a solution of ((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (0.31 mmol) in acetonitrile (1.0 mL). The mixture is stirred for 30 min and purified by prep. HPLC to give the desored product. LC-MS (acidic): tR=1.06 min; [M+H]+=523.0.
Reaction SMILES: FC(F)(F)C([N:5]([C:22]1[CH:41]=[CH:40][C:25]([C:26]([NH:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35]CC)=[O:34])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=O.C(O)C.[OH-].[Na+].Cl>O>[CH2:6]([NH:5][C:22]1[CH:41]=[CH:40][C:25]([C:26]([NH:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Nc2ccc(C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1

Procedure:
To a stirred solution of 3.62 g. of ethyl p-[p-(2,2,2-trifluoro-N-hexadecylacetamido)benzamido]benzoate in 72 ml. of ethanol was added a solution of 1.44 g. of sodium hydroxide in 18 ml. of water and the resulting mixture was heated under reflux for 30 min. The mixture was allowed to cool, acidified with dilute hydrochloric acid, and filtered. The white solid was recrystallized from acetonitrile.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][C@@H:14]([CH3:18])[NH:13]1.ClCCl>O>[CH3:11][C@H:12]1[NH:13][C@@H:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Temperature: 45 °C
Yield: 103.3 %

Procedure:
A suspension of 6.74 g (47.8 mmol) of 4-fluoro-nitro-benzene and 10.91 g (95.5 mmol) of cis-2,6-dimethyl-piperazine is heated at 45° C. for 1 hour. The reaction mixture is cooled and shaken with dichloromethane and water. The organic layer is dried (magnesium sulfate) and concentrated to give 11.62 g (>100%) of the product as a solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([N:26]([CH2:39][CH3:40])[CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:33]1[CH2:37][S:36][C:35](=[O:38])[N:34]=1)[CH3:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:37]2/[C:33]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:39][CH3:40])=[N:34][C:35](=[O:38])[S:36]/2)[CH2:8][CH2:7]1
Reactant: CCN(CC)CCOCCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCN(CC)CCOCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.21 g) in 2-propanol (15 mL) was added a solution of 4-({2-[2-(diethylamino)ethoxy]ethyl}amino)-1,3-thiazol-2(5H)-one (1.85 g) in 2-propanol (5 mL), and piperidinium acetate (0.52 g) was added. The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.26 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:28]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:28]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=2)[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:34][CH:35]=2)[CH2:17][NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CN(Cc2ccc(C(C)(C)C)cc2)C(Cc2ccc(OCc3ccccc3)cc2)C(=O)NCCN2CCCCC2)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(Cc2ccc(C(C)(C)C)cc2)C(CNCCN2CCCCC2)Cc2ccc(OCc3ccccc3)cc2)cc1
Yield: 72 %

Procedure:
A solution of 900 mg (1.75 mmol) 3-(4-benzyloxy-phenyl)-2-[bis-(4-tert-butyl-benzyl)-amino]-N-(2-piperidin-1-yl-ethyl)-propionamide (Example 10) in 36 mL dry THF was treated portionwise with 332 mg (8.76 mmol) lithium tetrahydriodoaluminate, and the resulting suspension was heated under reflux for 16 hours. The mixture was then carefully quenched with 0.4 mL H2O, followed by 2.0 mL 2 N NaOH solution, and finally 0.8 mL H2O. The mixture was filtered and the solids washed with chloroform. The filtrate was treated with 50 mL H2O, and after layers separated, the aqueous layer was extracted with an additional 50 mL chloroform. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate, and concentrated at reduced pressure to give 832 mg of an amber oil. The oil was purified by column chromatography on silica gel (230-400 mesh) using 2% to 5% methanol in chloroform as eluant to give 612 mg (69%) of the title compound as a viscous, pale yellow liquid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([OH:15])[C:6]=1[C:16]([O-:18])=O)=[N+]=[N-].[H][H]>CN(C)C=O.[Pd]>[OH:15][C:7]1[C:6]2[C:16](=[O:18])[NH:1][CH2:4][C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1c(C(=O)[O-])c(O)nc2ccccc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NCc2c1c(O)nc1ccccc21
Yield: 30 %

Procedure:
0.27 g (0.0010 mol) of 4-azidomethyl-2-hydroxy-quinoline-3-carboxylate was dissolved in 20 ml of hot dimethylformamide and treated with 14 mg of 10% Pd/C. A stream of hydrogen was introduced slowly during 11/2 hrs. The suspension was filtered under argon and the filtrate was partially concentrated under a high vacuum. The residue was treated with 25 ml of de-gassed ethanol, filtered off, dried in a vacuum and there were obtained ~60 mg (30%) of 4-hydroxy-2,3-dihydro-1 H-pyrrolo[3,4-c]quinolin-3-one as an air-sensitive, grey solid. The mother liquor was concentrated totally. The residue was dissolved in 75 ml of methanol and a stream of oxygen was conducted in slowly during 21/2 hrs. The mixture was filtered, concentrated, chromatographed over silica gel with ethyl acetate/methanol 9:1 as the eluent and the product was recrystallized from hot ethyl acetate. Yield: 0.033 g (15%) of 4-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-c]-quinoline-1,3-dione as yellow crystals; m.p. 340°-350° C. (dec., subl.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[C:3]=1[CH2:10][OH:11].N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].O>O1CCCC1>[Si:21]([O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:10][OH:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cccc(CO)c1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
A solution of 3-methyl-1,2-benzenedimethanol (4.16 g, 27.3 mmol) obtained from Example 22-(1) in tetrahydrofuran (50 ml) was cooled to 0° C., and imidazole (1.86 g, 27.3 mmol) and tert-butylchlorodimethylsilane (4.12 g, 27.3 mmol) were added thereto. The mixture was stirred at room temperature for 3 hours, and then after adding water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, then the solvent was distilled off under reduced pressure, and the residue was subjected to chromatography on a silica gel (120 g) column (eluent; ethyl acetate:hexane=1:4) to afford the title compound (4.93 g, 68% yield) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[N-:21]=[N+:22]=[N-:23].[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:21]=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CCCCCCCCCCCCCCCN=[N+]=[N-]

Procedure:
16-bromohexadecanoic acid methyl ester is reacted with sodium azide in acetonitrile for four days at reflux temperature to give the corresponding azide (Zinic et al., Positionally Isomeric Organic Gelators: Structure-Gelation Study, Racemic versus Enantiomeric Gelators, and Solvation Effects, Chem. Eur. J. 2010; 16:3066-82).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=3)=[C:4]2[CH:3]=[CH:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=S)=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[NH:18][C:13]3[CH:12]=[C:11]([O:10][C:9]4[CH:8]=[CH:7][N:6]=[C:5]5[NH:1][CH:2]=[CH:3][C:4]=45)[CH:16]=[CH:15][C:14]=3[N:17]=2)=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1N
Product: FC(F)(F)c1cc(Nc2nc3ccc(Oc4ccnc5[nH]ccc45)cc3[nH]2)ccc1Cl

Procedure:
The title compound was prepared by the method described in Example 1, using 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-benzene-1,2-diamine (Step D, 0.082 g, 0.34 mmol) and 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (0.081 g, 0.34 mmol). MS (MH+)=444.1, MW: 443.08 Calc'd for: C21H13ClF3N5O.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1([C:6]2[S:10][C:9]([NH2:11])=[N:8][N:7]=2)[CH2:5][CH2:4]1.CN(C)[CH:16]=[O:17]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:17]1[CH2:16][CH2:5][CH2:4][C@@H:3]1[CH2:2][N:8]1[N:7]=[C:6]([C:3]2([C:2]([F:1])([F:12])[F:13])[CH2:5][CH2:4]2)[S:10][C:9]1=[NH:11]
Reactant: Nc1nnc(C2(C(F)(F)F)CC2)s1
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: N=c1sc(C2(C(F)(F)F)CC2)nn1C[C@H]1CCCO1
Temperature: 25 °C

Procedure:
A mixture of Example 1A (0.15 g, 0.7 mmol), Example 1B (0.20 g, 0.8 mmol) and tetrabutylammonium iodide (0.13 g, 0.36 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 95° C. for 16 hr, cooled to room temperature and quenched with 1M NaHCO3 (10 mL). The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 0.2 g (crude) of the title compound. LC/MS (ESI+) m/z 294 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(S(C)(=O)=O)cc2)c1C(=O)OC
Yield: 104 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.3 g, 6.1 mmol) in acetone (25 mL) and potassium carbonate (2.5 g, 18 mmol) was added 1-bromomethyl-4-methanesulfonyl-benzene (1.6 g, 6.4 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(4-methanesulfonyl-benzyloxy)-phthalic acid dimethyl ester (2.4 g, 104% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([OH:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][O:26][C:25]([CH3:30])([CH3:29])[CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][C:25]1([CH3:30])[CH2:24][CH:23]([CH2:22][O:20][C:19]2[C:10]([C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[F:1])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:28][CH2:27][O:26]1
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(O)c1
Reactant: CC1(C)CC(CBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC2CCOC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-hydroxynicotinate (739 mg) and 4-(bromomethyl)-2,2-dimethyltetrahydro-2H-pyran (828 mg) in DMF (20 mL) was added potassium carbonate (736 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (950 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:13]([OH:14])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]>C1COCC1.O>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@H:13]1[O:14][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
(1S,2S)-trans-N-boc-2-aminocyclopentanol was dissolved in 50 ml THF and cooled to 10° C. To the reaction mixture were added 32.2 ml LiHMDS 1M in THF. After 1 hour 2.72 ml 2,4-difluoronitrobenzol were added and the mixture was stirred at rt overnight. Then the mixture was poured in water and extracted with ethylacetate. The organic layer was washed with water, dried and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:3]=1.[CH2:24]([N:27]=[C:28]=[S:29])[CH2:25][CH3:26]>N1C=CC=CC=1>[CH2:24]([NH:27][C:28](=[S:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[N:3]=1)[CH2:25][CH3:26]
Reactant: Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1
Reactant: CCCN=C=S
Solvent: c1ccncc1
Product: CCCNC(=S)Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1
Yield: 64.1 %

Procedure:
A mixture of 4-amino-2-(5-phthalimidopentyl)pyrimidine (2 g.) and propylisothiocyanate (1 g.) in pyridine (5 ml.) was heated under reflux for 16 hours then evaporated to dryness. The residual solid was triturated with acetonitrile to give 4-(3-propylthioureido)-2-(5-phthalimidopentyl)pyrimidine (1.7 g.), m.p. 146°-9°.