Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]=[N:12]O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)([Cl:16])=O.[CH2:18]([Cl:20])[Cl:19]>>[Cl:19][C:18]([Cl:16])([Cl:20])[C:4]1[NH:5][CH:10]=[CH:9][N:8]=1.[Cl:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Reactant: ON=Cc1c[nH]c2ncnc(Cl)c12
Product: ClC(Cl)(Cl)c1ncc[nH]1
Product: N#Cc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (E-4) (865 mg, 4.40 mmol, 1.0 eq) in DCM (20 mL), thionyl chloride (3.1 mL, 43.7 mmol, 10.0 eq) is added and the resulting mixture is stirred at RT overnight. The reaction mixture is concentrated in vacuo. The residue is suspended in water (60 mL) and saturated aqueous NaHCO3 is added to adjust the pH to 4. The solid is collected by filtration, rinsed with water followed by ethyl acetate to afford a first portion of product. The filtrate is then extracted with ethyl acetate (50 mL×3). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is combined with the first portion of product. The product is then re-crystallized in ethyl acetate/hexanes (1:1) and dried in vacuo to afford the final product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (E-5) as a pale solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[S:8].Br[CH:12]([CH3:20])[C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:9]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])[S:8][C:12]=1[CH3:20]
Reactant: CN(C)CCCNC(N)=S
Reactant: COC(=O)CC(=O)C(C)Br
Product: COC(=O)Cc1nc(NCCCN(C)C)sc1C
Yield: 50.8 %

Procedure:
The title compound (854 mg) was prepared from 1.0 g (6.20 mmol) of 3-dimethylaminopropyl thiourea and 1.30 g (6.20 mmol) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 45: low resolution MS (FAB)m/e 272 (M+).
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+].C(OCC)(=O)C>ClCCl.C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)Nc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 0.5 g (1.4 mMol) [6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-carbamic acid methyl ester in 3.0 ml dichloromethane was added over 10 minutes to a solution of 1.98 ml (6.9 mMol ) Red-Al® (70% in toluene) and 2.5 ml toluene (exothermic, cool with a water bath to avoid temperature to go >50° C.). The reaction mixture was stirred 2 hours at 50° C., cooled to 0° C., and 4 ml aqueous NaOH 1N were carefully (exothermic) added over 15 minutes, followed by 20 ml ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with deionized water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.37 g (89%) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine as an orange resin.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-:13])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][NH-:24])[CH:18]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:24])=[O:13])[CH:18]=2)=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(O)cc1F
Reactant: CC(C)(C)[O-]
Reactant: [NH-]Cc1cc(Cl)ccn1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
4-Amino-3-fluorophenol (5.7 g) was dissolved in dimethyl sulfoxide (57 ml) under a nitrogen atmosphere, and potassium tert-butoxide (5.6 g) was added at room temperature, followed by stirring for 15 min. To the reaction mixture was added 4-chloropicolylamide (5.0 g), followed by stirring in an oil bath at an external temperature of 80° C. under a nitrogen atmosphere for 50 min. The reaction mixture was allowed to cool down to room temperature. To the reaction mixture was added a 1N aqueous solution of sodium hydroxide (85.5 ml), followed by stirring. The precipitated solid was collected by filtration, and washed with water. The solid was dried under aeration, then hot air-dried at 100° C. to provide the titled compound as pale brown powder (5.88 g, 74.3%).
Reaction SMILES: CS[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:22][NH2:23]>CO>[CH3:22][NH:23][C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: COC(=O)C/C=C/c1ccc(NC(=C[N+](=O)[O-])SC)cc1
Reactant: CN
Solvent: CO
Product: CNC(=C[N+](=O)[O-])Nc1ccc(/C=C/CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
1.00 g of methyl (E)-4-{4-((1-methylthio-2-nitroethen-1-yl)amino)phenyl}-3-butenoate was suspended in 5 ml of methanol, followed by the addition of 1.25 ml of a 40% solution of methylamine in methanol. The obtained mixture was stirred at a room temperature for 4 hours and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1)] to obtain 0.5 g of the title compound as a pale yellow solid (yield: 54%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@H:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@H:30]([OH:31])[CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCc1ccc(OC[C@H]2CO2)cc1
Product: CCc1ccc(OC[C@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 228 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedure Z. M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=7.6 Hz, 1H), 7.81-7.76 (m, 2H), 7.59-7.54 (m, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.87-6.82 (m, 2H), 4.85 (d, J=4.8 Hz, 1H), 3.99-3.92 (m, 2H), 3.86-3.81 (m, 1H), 3.07 (s, 2H), 2.85-2.75 (m, 2H), 2.55-2.41 (m, 6H), 1.98 (d, J=14.4 Hz, 2H), 1.85-1.77 (m, 2H), 1.14 (t, J=8.0 Hz, 3H); LCMS: 480 [M+H].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1ccc(N2CCCCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCCCC5)cc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-1-yl-phenyl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 1-(4-bromo-phenyl)-piperidine (110.0 mg, 0.4581 mmol) in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.039 g, 25%). MP=229-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm):
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>CN(C=O)C>[CH2:18]([NH:21][C:22]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])[CH2:19][CH3:20]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCCN=C=O
Solvent: CN(C)C=O
Product: CCCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C

Procedure:
The title compound was prepared in DMF using 3,5-di-tert-butyl-4-hydroxybenzaldehyde and n-propyl isocyanate according to the procedure described in Example H. The title compound was isolated in 100.0% yield as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=O)[CH:12]=[O:13]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: O=CC(=O)O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Yield: 90.4 %

Procedure:
4,5-Dichloro-1,2-phenylenediamine (25 g, 141.2 mmol) was suspended in 780 ml EtOH, and 13 g (142.0 mmol) of glyoxylic acid (HO2CCOH/H2O) was added. The mixture was heated at reflux for 3 hours, and then cooled and filtered, yielding 27.45 g of 6,7-dichloroquinoxalin-2-one as a solid. The product (25 g, 116.3 mmol) and 230 ml (911.7 mmol) of phosphorous oxychloride (POCl3) were stirred at reflux (100° C.) for 3 hours. The mixture was cooled and ice/H2O added. The resulting brown/grey solid was filtered, and dried in an oven, yielding approximately 25 g of 2,6,7-trichloroquinoxaline.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].C(O[C:12]([N:14]1[C:18]2O[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22][C:17]=2[C:16]([NH2:30])=[N:15]1)=[O:13])(C)(C)C.ClC[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=2[CH3:49])[CH2:38][CH2:37]1)=O>C(#N)C>[NH2:30][C:16]1[C:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:1](=[O:4])[C:18]=2[N:14]([C:12](=[O:13])[CH2:33][CH2:34][N:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=3[CH3:49])[CH2:38][CH2:37]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2c1ON(Cc1ccccc1)CC2
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCN(C(=O)CCCl)CC2)c(C)c1
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(N2CCN(CCC(=O)n3nc(N)c4c3C(=O)N(Cc3ccccc3)CC4)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
Potassium carbonate (68.2 mg, 0.494 mmol) was added to a solution of t-butyl-3-amino-6-benzyl-4,5,6,7-tetrahydro-7-oxapyrazolo[3,4-c]pyridin-1-carboxylate (154 mg, 0.449 mmol) dissolved in anhydrous acetonitrile (1.9 mL) and then stirred at room temperature for 30 minutes. After adding 3-chloro-1-{4-(2,4-dimethylphenyl)piperazin-1-yl}propan-1-one (132.2 mg, 0.471 mmol), reaction was carried out overnight. A target compound (25.4 mg, 0.052 mmol, 11.6%) was yielded as white solid.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:49])[C@H:8]([N:30]([S:38]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:16])[CH2:11][CH2:10]1)(C)(C)C.C(O)C.C(Cl)[Cl:54]>>[ClH:54].[OH:5][NH:6][C:7](=[O:49])[C@H:8]([N:30]([S:38]([C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=1)(=[O:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: ClCCl
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NOC(C)(C)C)C2CCN(C(=O)OCCc3cccc4ccccc34)CC2)cc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NO)C2CCN(C(=O)OCCc3cccc4ccccc34)CC2)cc1
Product: Cl
Temperature: -10 °C
Reaction time: 144 h

Procedure:
N-(t-Butyloxy)-2-(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-[(N-(2-(1-naphthyl)-ethoxycarbonyl))-4-piperidinyl]acetamide (3 g, 4.65 mmol) is dissolved in methylene chloride (100 ml) containing ethanol (0.27 ml, 4.6 mmol) and the reaction mixture is cooled to -10° C. Hydrochloric acid gas (from a lecture bottle) is bubbled trough the solution for 15 minutes. The flask is sealed, the reaction mixture is allowed to slowly warm to room temperature and stirred at room temperature for 6 days. The reaction mixture is concentrated in vacuo to provide N-hydroxy-2-(R)-[(4-methoxy-benzenesulfonyl) (4-picolyl)amino]-2- [(N-(2-(1-naphthyl)-ethoxycarbonyl))-4-piperidinyl]acetamide hydrochloride as a white solid, m.p. >137° C. (dec).
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:16][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCC(=O)OCCN(C)C
Yield: 62.6 %

Procedure:
A solution of 91.35 g (0.40 mol) of myristic acid, 35.7 g (0.40 mol) of 2-dimethylaminoethanol, 0.5 g of p-toluenesulfonic acid and a suitable volume of toluene was heated at reflux for approximately 48 hours in a 1-neck 3 liter flask equipped with Dean-Stark trap and condenser. At the end of this time, 7.0 ml of water had collected in the trap. The solution was cooled, stirred with K2CO3, filtered and concentrated. The residue was distilled to give 75.0 g of product; bp=145°-50° C/0.050 mm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.N1C=CC=CC=1.[C:59](OC(=O)C)(=[O:61])[CH3:60]>ClCCl>[C:59]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:26][CH:27]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1)(=[O:61])[CH3:60]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCNC(C)=O)c3c2Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 0.185 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.1 ml of dichloromethane is admixed successively with 0.50 ml of pyridine and 0.21 ml of acetic anhydride and stirred at room temperature for 2 hours. The reaction mixture is poured onto water (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed successively with 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (EtOAc-heptane=4:1); Rt=5.89.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:77]=[CH:76][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([C:51]4[CH:56]=[CH:55][C:54]([O:57][C:58]5[CH:63]=[CH:62][C:61]([N:64]=[N:65][C:66]6[CH:71]=[CH:70][C:69]([NH:72]C(=O)C)=[CH:68][CH:67]=6)=[CH:60][CH:59]=5)=[CH:53][CH:52]=4)([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]5[CH:38]=[CH:37][C:36]([N:39]=[N:40][C:41]6[CH:46]=[CH:45][C:44]([NH:47]C(=O)C)=[CH:43][CH:42]=6)=[CH:35][CH:34]=5)=[CH:28][CH:27]=4)[CH3:25])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=O)C.Cl.C(O)C>O>[NH2:47][C:44]1[CH:43]=[CH:42][C:41]([N:40]=[N:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][C:29]3[CH:30]=[CH:31][C:26]([C:24]([C:21]4[CH:22]=[CH:23][C:18]([O:17][C:16]5[CH:76]=[CH:77][C:13]([N:12]=[N:11][C:8]6[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=6)=[CH:14][CH:15]=5)=[CH:19][CH:20]=4)([C:51]4[CH:52]=[CH:53][C:54]([O:57][C:58]5[CH:63]=[CH:62][C:61]([N:64]=[N:65][C:66]6[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=6)=[CH:60][CH:59]=5)=[CH:55][CH:56]=4)[CH3:25])=[CH:27][CH:28]=3)=[CH:34][CH:35]=2)=[CH:46][CH:45]=1
Reactant: CC(=O)Nc1ccc(N=Nc2ccc(Oc3ccc(C(C)(c4ccc(Oc5ccc(N=Nc6ccc(NC(C)=O)cc6)cc5)cc4)c4ccc(Oc5ccc(N=Nc6ccc(NC(C)=O)cc6)cc5)cc4)cc3)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 52.6 %

Procedure:
To a 100 mL round-bottomed flask with a stir-bar and a condenser, 1,1,1-tris[4-(4-(4-acetamidophenyldiazenyl)phenoxy)phenyl]ethane (Example 4; 0.50 g, 0.49 mmol), 6 M HCl (20 mL) and 95% ethanol (20 mL) were charged and heated to 80° C. The mixture was stirred at 80° C. for 3 days. After the mixture was allowed to cool to room temperature, water (60 mL) added. The resulting red solid was collected by filtration and washed with dilute sodium bicarbonate solution, followed by deionized water (300 mL). After being air dried, the crude product was purified by column chromatography (silica gel, ethyl acetate as eluent). The solvent was removed by a rotary evaporator to afford 0.23 g (52.5%) of orange red solid, mp >300° C. MS (m/e): 892 (M+). Anal. Calcd. for C56H45N9O3: C, 75.40%; H, 5.08%; N, 14.13%. Found: C, 75.44%; H, 5.08%; N, 13.98%. 1H-NMR (d6-DMSO, δ in ppm): 2.12 (s, 3H, CCH3), 6.03 (s, 6H, NH2), 6.67-6.70 (d, 6H, J=8.7 Hz), 6.99-7.02 (d, 6H, J=8.7 Hz), 7.09-7.13 (m, 12H), 7.62-7.66 (d, 6H, J=8.7 Hz), 7.75-7.78 (d, 6H, J=8.7 Hz). 13C-NMR (d6-DMSO, δ in ppm): 30.34, 51.91, 113.41, 118.44, 118.69, 123.52, 124.96, 129.93, 142.92, 144.25, 148.41, 152.56, 154.21, 157.75.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([Cl:10])[N:7]([C@@H:11]3[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]3[O:13]C(=O)C)[C:6]=2[CH:29]=1>N.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([Cl:10])[N:7]([C@@H:11]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]3[OH:13])[C:6]=2[CH:29]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(N)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: Nc1ccc2nc(Cl)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2c1

Procedure:
A solution of 0.283 g (0.665 mmole) of 77 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature<40° C.). The residue was recrystallized from MeOH to give 0.170 g (2 crops, 85%) of 79 as beige crystals. MP ~170° C. (dec.). MS (EI) m/e 299.0862 (16%, M+ =299.0673). 1H NMR (DMSO-d6): d 7.25 (d, 1, 4-H, J4-5 =8.5 Hz), 6.87 (d, 1, 7-H, J7-5 =2.0 Hz), 6.57 (dd, 1, 5-H), 5.75 (d, 1, 1'-H, J1'-2' =7 5 Hz), 5.43 (d, 1, 2'-OH, J2'-2'OH =6-5 Hz), 5.18 (d, 1, 3'-OH, J3'-3'OH =5.0 Hz), 5.04 (s, 2, 6-NH2), 5.03 (t, 1, 5'-OH, J5'-5'OH =5.5 Hz), 4.48 (m, 1, 2'-H, J2'-3' =6.0 Hz), 4.07 (m, 1, 3'-H, J3'-4' =3.0 Hz), 3.90 (m, 1, 4'-H, J4'-5' =4.0 Hz, J4'-5" =5.0 Hz), 3.66 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): d 145.34 (C6), 135.63 (C2), 134.34 (C7a), 133.18 (C3a), 118.83 (C4), 111.71 (C5), 95.79 (C7), 88.79 (C1'), 85.24 (C4'), 70.17 (C2'), 69.70 (C3'), 61.55 (C5').
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([CH2:16][NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:17]([CH2:16][CH:13]2[CH2:15][CH2:14]2)[CH2:18][CH2:19][CH3:20])[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CCCNCC1CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)c1cc(C(=O)OC)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, 10.00 g; 48.3 mmol) in dry THF (200 ml) was treated dropwise over 1 hour with a solution of N-(cyclopropylmethyl)propane-1-amine (6.92 ml; 48.3 mmol) and triethylamine (7.37 ml; 53.1 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 18 hours. Water (200 mL) was poured into the reaction mixture, which was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under vacuum to afford the crude product, which was precipitated from MTBE (50 mL) to give the title compound as a beige solid.
Reaction SMILES: C[O-].[Na+].CO.[C:6]([O:12][CH3:13])(=[O:11])[C:7]([O:9]C)=O.[CH3:14][C:15]([CH3:17])=[O:16]>O>[O:9]=[C:7]([CH2:14][C:15](=[O:16])[CH3:17])[C:6]([O:12][CH3:13])=[O:11]
Reactant: CC(C)=O
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=O)CC(C)=O
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a 500 mL flask, 25% sodium methoxide of methanol solution (43.20 g, 0.200 mol), methanol (200 mL) were added, the mixture of dimethyl oxalate (23.60 g, 0.200 mol) and acetone (11.60 g, 0.200 mol) were added dropwise at ice-salt bath. The reaction mixture was stirred for 8 hours at 0˜5° C. The reaction mixture was poured into 200 mL water and extracted with ethyl acetate (150 mL) to remove organic impurity. The aqueous solution was acidified with concentrated hydrochloric acid to pH of 2˜3 and extracted with ethyl acetate (3×200 mL). The organic layer was washed with water (150 mL), and saturated brine (150 mL), dried over anhydrous magnesium sulfate and concentrated to give the product (25.9 g) as yellow oil in 90% yield. 1H NMR (300 MHz, CDCl3): 6.396 (s, 1H, enol isomer), 3.906 (s, 3H), 2.279 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH3:16].C(N(C(C)C)CC)(C)C>CCO>[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH3:16])[C:7]1[CH:6]=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CNCCOC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ccc([N+](=O)[O-])nc1
Temperature: 90 °C
Yield: 41 %

Procedure:
A solution of 2-nitro-5-bromopyridine (500 mg, 3.15 mmol) in EtOH (15 mL) was treated with methoxyethyl-N-methylamine (1.12 g, 12.6 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol). The resulting mixture was then heated in a sealed tube at 90° C. for 4 days then cooled and partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient to afford the product as a thick yellow oil that crystallized slowly upon standing (270 mg, 41% yield). HRMS m/z calcd for C9H13N3O3 [M+Na]+: 234.0849; Found: 234.0850.