Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl.[Br:18][C:19]1[CH:20]=[C:21]2[S:27][C:26](Cl)=[N:25][C:22]2=[N:23][CH:24]=1.[Na]>CN(C=O)C>[Br:18][C:19]1[CH:20]=[C:21]2[S:27][C:26]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[N:25][C:22]2=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nc2ncc(Br)cc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc3ncc(Br)cc3s2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.88 g, 4.37 mmol) in DMF (8.7 mL) was added NaH (0.121 g, 4.81 mmol) at 0° C. Upon completion of addition, the mixture was warmed to rt until the mixture became a clear solution. In a separate flask, 6-bromo-2-chlorothiazolo[4,5-b]pyridine hydrochloride (0.5 g, 1.748 mmol) was suspended in DMF (8.74 mL) and the above sodium salt solution was transferred into the thiazolepyridine suspension via cannulation. The resulting mixture was then heated in a 50° C. oil bath. After 4 h, the reaction mixture was analyzed by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to rt, and then quenched with NaHCO3 (saturated aq, 10 mL). The resulting mixture was extracted with EtOAc (3×5 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to give Compound 21B as a white solid (150 mg, 21% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.54 (d, J=2.2 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 5.43-5.52 (m, J=8.0, 8.0, 4.0, 3.9 Hz, 1H), 3.70-3.84 (m, 2H), 3.24-3.34 (m, 2H), 2.07-2.17 (m, 2H), 1.80-1.92 (m, J=12.7, 8.5, 8.5, 4.1 Hz, 2H), 1.46 (s, 9H). LC/MS (m/z)=415 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:15]=[C:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)c(OC(=O)C(C)(C)C)c1

Procedure:
2,4-dihydroxybenzophenone 1 g (0.005 mole) was warmed to 50° C. with 1.25 g (0.015 mole) of pivaloyl chloride and 30 mls of dry pyridine solvent removed by rotary evaporation H2O+EtOAc+Et2O added and stirred. Layers were separated and the organic layer was washed with 5% K2CO3, then H2O, then dried over Na2SO4. Solvent was removed after filtration via rotary evaporator. The resulting oily residue was placed on top of a 15 g florisil column and eluted with toluene. Product isolated by removal of solvent. Oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](Cl)=[O:22].[H-].[Na+]>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Yield: 39.6 %

Procedure:
Using 2-amino-4-nitrophenol (10 g, 65 mmol), triethylamine (11.7 mL, 84 mmol) and chloroacetyl chloride (5.4 mL, 68 mmol) in THF (150 mL) followed by sodium hydride (5.2 g of a 60% suspension in oil, 130 mmol) to yield the title compound as a grey solid (5 g, 33%). δH (DMSO-d6) 4.78 (2H, s), 7.15 (1H, d, J 8.9 Hz), 7.74 (1H, d, J 2.4 Hz), 7.84 (1H, dd, J 8.9, 2.6 Hz), 11.09 (1H, s).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]([C:20]([CH:22]=[CH2:23])=[O:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:23][CH2:22][C:20](=[O:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)C(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (4.76 g, 0.02 mole) was reacted with isopropylvinyl ketone (3.6 g) and triethylamine (3 ml) in methanol (50 ml) by the method of Example 3 to give the title compound, m.p. ca. 50°-53° C. Analysis calc. for C20H32O2S(336.52):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[O:16][CH:15]([O:17]CC)[CH2:14][C@H:13]([OH:20])[CH2:12]1>C(O)(=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[O:16][CH:15]([OH:17])[CH2:14][C@H:13]([OH:20])[CH2:12]1
Reactant: CCOC1C[C@H](O)C[C@H](CCc2ccc(Cl)cc2Cl)O1
Solvent: CC(=O)O
Solvent: CCOCC
Product: OC1C[C@H](O)C[C@H](CCc2ccc(Cl)cc2Cl)O1
Reaction time: 2 h

Procedure:
6(S)-[2-(2,4-dichlorophenyl)-ethyl]-2-ethoxy-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran (0.305 g, 1 mmole) is dissolved in 80% aqueous acetic acid (5 ml) and heated at 70° to 80° for 2 hours. When tlc shows that, the reaction is complete, (if necessary the reaction may be heated at 90° bath temp. for 2 hours). The reaction solution is dissolved in ether and extracted with water, then dilute sodium hydroxide, until washings are basic, and then with water. The ether layer is dried (MgSO4), filtered, and the solvent is evaporated in vacuo to leave 6(S)-[2-(2,4-dichlorophenyl)ethyl]-2-hydroxy-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:18]([NH2:20])=[O:19].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31](OC)=O)=[CH:24][C:23]=2[O:22]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31]3[NH:20][C:18](=[O:19])[C:3]4[CH:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:2]=4[N:1]=3)=[CH:24][C:23]=2[O:22]1
Reactant: CC(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CC(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 65.5 %

Procedure:
18 mg (0.066 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-pyrazole-4-carboxamide and 41 mg (0.21 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 1 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 18 mg (64%) of a solid, Rf=0.34 (dichloromethane/methanol=15:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][Br:19])=[N:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2cc(Br)cnc21
Temperature: 80 °C
Yield: 6.6 %

Procedure:
A mixture of tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x154 (10.8 mmol, 1 eq, 3.37 g), N-bromosuccinimide (1.92 g, 1 eq, 10.8 mmol) and azo-bisiso-butyronitrile (AIBN) (10.8 mmol, 1 eq, 1.77 g) in CCl4 (50 ml) is heated for 2 hours at 80° C. The solvent is removed under reduce pressure, water is added and the resulting mixture is extracted with dichloromethane. The combined organic phases are dried over MgSO4, filtered and volatiles removed under reduced pressure. The product is purified by chromatography on silicagel (hexane/AcOEt 8/2) and recristallized in AcOEt to afford 0.28 g of pure tert-butyl 5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)([Cl:11])=[O:10]>>[Cl:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)Cl
Reactant: OCc1ccccc1
Product: O=C(Cl)OCc1ccccc1

Procedure:
324.4 Parts of benzyl alcohol are reacted with phosgene to give 505 parts of benzyl chloroformate as a colourless liquid b.p. 78° C/2.0 mm.
Reaction SMILES: C([O:4][CH:5]1[CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[O:19][C:20](=O)[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7][CH2:6]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=O)C.C[N:36](C)C=O>N>[OH:4][CH:5]1[CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:33])[NH:36][C:20](=[O:19])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7][CH2:6]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CN(C)C=O
Reactant: CC(=O)OC1CCc2c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc3n2C1
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(O)CC4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 150 mg of 3-[7-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 6 ml of dimethylformamide and 6 ml of 33% aqueous ammonia was heated to 150° C. for 6 hours. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate gave 120 mg of 3-[6,7,8,9-tetrahydro-7-hydroxypyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 252°-255° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCc1ccc(O)cc1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 4 from above was coupled with 4-aminomethyl-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 442.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([F:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N+:21]([C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:5]2[C:10]([F:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(F)c2c(Cl)nc(Cl)nc21
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(F)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a vial containing 2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (389.5 mg, 1.2 mmol) was added m-nitrophenol (161 mg, 1.2 mmol), DMF (5 mL) and K2CO3 (320 mg, 2.3 mmol). The reaction mixture was heated at 60° C. for 1 hr. The reaction was diluted with EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated to give an oil. The oil was purified via flash chromatography eluting with 100% heptanes. The solvent was removed to afford the title compound (505 mg, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (t, J=2.27 Hz, 1H) 8.22-8.28 (m, 1H) 7.90-7.96 (m, 1H) 7.86 (d, J=8.31 Hz, 1H) 7.78-7.84 (m, 1H) 5.59 (s, 2H) 3.54-3.66 (m, 2H) 0.84-0.99 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C18H20ClFN4O4Si 439.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([CH3:28])[CH:16]=1.C(N(CC)CC)C.[CH:36]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O>[CH:36]1([NH:41][C:42]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=5)[N:10]=[CH:9][N:8]=4)=[CH:16][C:17]=3[CH3:28])[CH2:23][CH2:24]2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2c1
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(Nc3ccc(OC4CCN(C(=O)NC5CCCC5)CC4)c(C)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a suspension of (6-Methoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (150 mg, 0.251 mmol) in N,N-dimethylformamide (1.5mL) was added triethylamine (143 μL, 1.03 mmol) and cyclopentyl isocyanate (0.343 mmol). The reaction was stirred at room temperature overnight The reaction was then filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 36.3 mg of 4-[4-(6-Methoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-piperidine-1-carboxylic acid cyclopentylamide was isolated. 1H NMR (300 MHz, DMSO d6) δ 9.505 (s, 1H), 8.436 (s, 1H), 7.904 (d, J=0.9 Hz, 1H), 7.707 (d, J=3.0 Hz, 1H), 7.498-7.458 (dd, J=9.0, 3.0 Hz, 1H), 7.571-7.513 (m, 2H), 7.045 (d, J=3.0 Hz, 1H), 6.28 (d, J=2.3 Hz, 1H), 4.564-4.514 (m, 1H), 3.962-3.894 (m, 1H), 3.950 (s, 3H), 3.677-3.599 (m, 2H), 3.246-3.163 (m, 2H), 2.216 (s, 3H), 1.928-1.863 (m, 2H), 1.862-1.751 (m, 2H) 1.671-1.518 (m, 4H), 1.517-1.365 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([Sn](=O)CCCC)CCC.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[S:8][C:7]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]3[NH:35][N:34]=[N:33][N:16]=3)=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(C#Cc2ccc([N+](=O)[O-])s2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C#Cc2ccc(-c3nnn[nH]3)cc2)s1
Temperature: 25 °C

Procedure:
To a solution of 4-[(5-nitro-2-thienyl)ethynyl]benzonitrile (0.6 g) and dibutyltin oxide (59 mg) in anhydrous toluene (30 ml) was added trimethylsilyl azide (0.5 ml). The reaction mixture was heated to reflux in the dark for 12 hours, then allowed to cool to room temperature. The reaction mixture was washed with saturated sodium bicarbonate (2×300 ml) and the combined aqueous layer was acidified to pH 1 with concentrated hydrochloric acid (30 ml). The acidified solution was washed with 1:1 ethyl acetate/tetrahydrofuran (500 ml) and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 5-[4-[(5-nitro-2-thienyl)ethynyl]-phenyl]-1H-tetrazole as a yellow solid.
Reaction SMILES: [CH2:1]=[O:2].[OH-].[Na+].[CH:5](=[O:12])[CH:6]1[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]1>>[C:6]1([CH2:1][OH:2])([CH2:5][OH:12])[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]1
Reactant: O=CC1CC=CCC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCC1(CO)CC=CCC1
Temperature: 25 °C
Yield: 70 %

Procedure:
One hundred (100) parts by weight of a formaldehyde aqueous solution (37 wt. % formaldehyde) was charged to a reactor. To this solution, cooled externally with an ice-water bath, was added 118 parts of an aqueous sodium hydroxide solution (25 wt. % sodium hydroxide) by several portions and the temperature of the reaction content was maintained at 20 to 30° C. This was followed by a slow addition of 54 parts of 1,2,5,6-tetrahydrobenzaldehyde at such a rate that the reaction content temperature did not exceed 55° C. After the exotherm dissipated, it was heated at 55° C. for two hours with an external heating. The product precipitated out of the solution upon cooling and was collected by suction filtration. The wet-cake was washed thoroughly in the funnel with copious amount of water (5×100 parts). The crude product was allowed to dry in air overnight and purified by a recrystallization from toluene. The final product was an off-white colored crystalline material (yield 70%. m.p.: 92-93° C.).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@H]2[C@H]3C[C@H](C=C3)[C@H]2C(N)=O)C(Cl)=CN=1.[N:62]1(C2C=C(C=CC=2)C=O)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>>[Cl:8][C:9]1[C:10]([NH:31][C@H:32]2[C@H:37]3[CH2:38][C@H:34]([CH:35]=[CH:36]3)[C@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)[CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: O=Cc1cccc(N2CCOCC2)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@H]1[C@@H](Nc2c(Cl)cnc(N)c2N)[C@@H]2C=C[C@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@H]1[C@@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(N5CCOCC5)c4)nc23)[C@@H]2C=C[C@H]1C2
Yield: 11 %

Procedure:
In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Morpholin-4-yl-benzaldehyde were reacted to produce the title compound (11%). 1H NMR (d-chloroform): 16.12 (br s, 1H), 8.42 (d, J=9 Hz, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.50 (m, 1H), 6.42 (m, 1H), 5.90 (br s, 1H), 5.65 (br s, 1H), 5.40 (t, J=8 Hz, 1H), 3.94 (m, 4H), 3.34 (m, 4H), 3.18 (s, 1H), 3.07 (s, 1H), 2.69 (d, J=8 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 1.69 (d, J=9 Hz, 1H). MS: 465.15 (M+H). HPLC retention time: 2.39 minutes (G Method).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>C(O)(C)C>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1cccc(I)c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(I)c3)c2c1
Yield: 26.8 %

Procedure:
3-Iodoaniline (12.57 grams, 57 mmol) was reacted with 4-chloro-6-nitroquinazoline (4 grams, 57 mmol), in iso-propylalcohol, as is described hereinabove, to give 4-[(3-iodophenyl)amino]-6-nitroquinazoline (5.99 grams, 78% yield), which was thereafter reacted (620 mg, 1.58 mmol) with hydrazine hydrate and Raney®Nickel, according to the procedure described hereinabove, to give 4-[(3-iodophenyl)amino]-6-aminoquinazoline (180 mg, 31% yield).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:11][C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[C@H:8]([OH:9])[C@@H:6]1[OH:7])=[N+]=[N-]>CO.[Pd].C(OCC)(=O)C>[NH2:1][CH2:4][C@H:5]1[O:11][C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[C@H:8]([OH:9])[C@@H:6]1[OH:7]
Reactant: [N-]=[N+]=NC[C@H]1O[C@H]([C@H](O)CO)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC[C@H]1O[C@H]([C@H](O)CO)[C@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 78.1 %

Procedure:
The azide (16) (0.12 g, 0.63 mmol) was stirred in methanol (5 ml) at room temperature under hydrogen in the presence of 10% palladium on carbon (10 mg). After 24 h, t.l.c. (5% methanol in ethyl acetate) indicated conversion of the starting material (Rf 0.3) to a single product (Rf 0.0). The reaction mixture was filtered through celite, the solvent removed in vacuo, and the resulting solid purified by ion exchange chromatography with Dowex 50W-X8 using 0.5M ammonia as eluant. After freeze drying, 1-amino-2,5-anhydro-1-deoxy-D-glycero-D-talo-heptitol (5) (95 mg, 8%) was obtained as a yellowish solid. The solid was taken up in water, and the solution neutralised with dilute aqueous hydrochloric acid. Freeze drying, followed by recrystallisation from methanol/chloroform, gave 1-amino-2,5-anhydro-1-deoxy-D-glycero-D-talo-heptitol hydrochloride (5) as a colourless crystalline solid, m.p. 189° C. (dec.). (Found: C, 36.61; H, 7.27; N, 5.42. C7H16O5NCl requires C, 36.61; H, 7.02; N, 6.10%); [α]D20 +38.6° (c 1.0 in CHCl3); δH (D2O) 3.00 (1H, dd, H-1, J1,1' 13.4 Hz, J1,2 8.8 Hz), 3.18 (1H, dd, H-1', J1',2 2.29 Hz), 3.52 (1H, dd, H-7, J6,7 5.0 Hz, J7,7' 12.1 Hz), 3.66 (1H, dd, H-7', J6,7' 2.7 Hz), 3.80 (1H, ddd, H-6, J5,6 9.0 Hz), 3.87 (1H, dd, H-3, J3,4 4.1 Hz), 4.17 (1H, dd, H-4); δC (D2O) 41.8, 63.1 (2 × t, C-1 , C-7), 69.0, 71.6, 74.3, 77.2, 79.6 (5 × d, C-2, C-3, C-4, C-5, C-6); m/z (NH3, DCI) 194 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]3)[S:10]2(=[O:18])=[O:19])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A solution of 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.29 g, 1.0 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.41 g, 1.5 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.47 g, 2.1 mmol) were added followed by diisopropylazodicarboxylate (0.3 mL, 1.5 mmol). The reaction mixture stirred for 2 hours at ambient temperature and then was evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-70% ethyl acetate/hexane) to provide tert-butyl 4-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.39 g, 76%) as a pink solid:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:47]([NH:49][C@H:50]([C:59]([NH2:61])=[O:60])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:20])[NH:16][N+]([O-])=O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>[Pd].C(O)(=O)C>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:47]([NH:49][C@H:50]([C:59]([NH2:61])=[O:60])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)=[O:48])[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:20])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O

Procedure:
In 30 ml. of acetic acid was dissolved 400 mg. of Z-Leu-Arg(NO2)-Gly-Phe-Phe-Tyr-NH2 and catalytic reduction was carried out with Pd-black as a catalyst for 10 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml. of water and the solution was passed through a column (2.6 × 22 cm) of carboxylmethyl-cellulose.