Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:6]=1)=[O:4])[NH2:2].Cl.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[N:1]([C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:6]=1)=[O:4])=[N+:2]=[N-:21]
Reactant: NNC(=O)c1nc(-c2cccc3ccccc23)no1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1nc(-c2cccc3ccccc23)no1
Yield: 86.2 %

Procedure:
5-Hydrazinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole (6.47g.) was dissolved in acetic acid (125 ml.) and 2N-hydrochloric acid (75 ml.). A solution of sodium nitrite (2.0g) in water (6 ml.) as added at 0° with stirring. After 15 minutes the precipitate was filtered off and dissolved in chloroform. The chloroform solution was washed with water and dried (MgSO4). Evaporation to dryness gave title compound (5.82 g.), m.p. 114° (decomp.), λmax. (EtOH) 300 nm. (ε 8,250), νmax. (CHBr3) 1710 (C=O), 2150 and 2190 cm.-1 (N3).
Reaction SMILES: [CH3:1][C@:2]12[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1.[CH3:15][C:16]12[C:24](=[O:25])[O:23][C:22](=[O:26])[C:21]1([CH3:27])[CH:20]1[O:28][CH:17]2[CH2:18][CH2:19]1>>[CH3:1][C@:2]12[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1.[CH3:15][C:16]1([C:24]([OH:23])=[O:25])[C:21]([C:22]([OH:9])=[O:26])([CH3:27])[CH:20]2[O:28][CH:17]1[CH2:18][CH2:19]2
Reactant: CC12C(=O)OC(=O)C1(C)C1CCC2O1
Agent: C[C@@]12C(=O)OC(=O)[C@]1(C)[C@H]1CC[C@@H]2O1
Product: CC1(C(=O)O)C2CCC(O2)C1(C)C(=O)O

Procedure:
Cantharidin is 2,6-Dimethyl-4,10-dioxatricyclo-[5.2.1.02,6]decane-3,5-dione. Its chemical formula is C10H12O4 and its chemical structure is:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C(=O)C.O.CO>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]([C:16](=[O:18])[CH3:17])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CNc1ccc(O)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CN(C(C)=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl(3-fluoro-4-hydroxyphenylamino)acetate (0.84 g, 4 mmol) was dissolved in N,N-dimethylacetamide (4 mL). To the resulting solution was added acetyl chloride (0.6 mL, 10 mmol), and the resulting solution was stirred at room temperature for 1 hour. Water (1 mL), methanol (10 mL) and saturated sodium carbonate (10 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the solution. 10% hydrochloric acid was employed to turn the solution acidic, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1), to thereby yield 0.84 g of the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>CN(C=O)C>[CH2:36]([N:38]([CH2:39][CH3:40])[C:14](=[O:16])[C:13]1[CH:12]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]([Cl:21])=[CH:9][C:8]=1[NH:7][CH2:6][C:3]1[O:4][CH:5]=[CH:1][CH:2]=1)[CH3:37]
Reactant: CCNCC
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
In a similar manner to Example 7, furosemide can be reacted with EDC, HOBt and diethylamine in DMF to yield N,N-diethyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)-amino]benzamide.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.0 g, 9.73 mmol), 2-(trifluoromethyl)phenylboronic acid (2.032 g, 10.7 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (562 mg, 5% mmol), and sodium carbonate (5.15 g, 48.6 mol, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline-3-carb-aldehyde was obtained as a white solid. 1H NMR (DMSO-d6) δ ppm 9.93 (1 H, s), 9.04 (1 H, s), 8.13 (1 H, d, J=8.1 Hz), 7.93 (1 H, d, J=7.3 Hz), 7.85 (1 H, d, J=7.1 Hz), 7.72-7.82 (2 H, m), 7.64-7.71 (1 H, m), 7.59 (1 H, d, J=7.3 Hz), 2.67 (3 H, s). Mass Spectrum (ESD m/e=316.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([C:28]#[N:29])=[CH:23][C:22]=2[F:30])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.N[OH:33].C([N:36]([CH2:39]C)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([C:28]3[N:36]=[CH:39][O:33][N:29]=3)=[CH:23][C:22]=2[F:30])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1cc(F)c(CN([C@@H]2CCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1cc(F)c(-c2ncon2)cc1F)[C@@H]1CCCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (198 mg, 0.44 mmol), hydroxylamine hydrochloride (153 mg, 2.2 mmol), and triethylamine (300 uL, 2.2 mmol) was refluxed in 5 mL ethanol for 3 h. The reaction was concentrated and the residue was partitioned between ethyl acetate and sat, sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated. The crude intermediate was stirred in 3 mL triethylorthoformate with two drops of boron trifluoride etherate at room temperature overnight. The reaction was purified by preparative HPLC followed by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane to yield 4-chloro-N-(2,5-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (100 mg, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (s, 1H), 7.69-7.82 (m, 3H), 7.58 (dd, J=10.20, 5.92 Hz, 1H), 7.50 (d, J=8.56 Hz, 2H), 4.49-4.58 (m, 1H), 4.35-4.45 (m, 1H), 3.62-3.73 (m, 2H), 3.08-3.19 (m, 1H), 2.54 (br. s., 1H), 1.60-1.76 (m, 3H), 1.38-1.49 (m, 2H), 0.99-1.24 (m, 4H). Analytical HPLC R.T.=22.87 min. MS [M+H]+=498; [M+Na]+=520. HRMS [M+H]+ calc'd 498.1066, found 498.1063.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[C:3]=1[C:8]([O:10]CC)=O.C([O-])=O.[NH4+].[CH:17]([NH2:19])=O>>[CH3:7][C@H:4]1[C:3]2[C:8]([OH:10])=[N:19][CH:17]=[N:1][C:2]=2[CH2:6][CH2:5]1
Reactant: NC=O
Reactant: CCOC(=O)C1=C(N)CC[C@H]1C
Agent: O=C[O-]
Agent: [NH4+]
Product: C[C@@H]1CCc2ncnc(O)c21
Temperature: 150 °C
Reaction time: 17 h
Yield: 65 %

Procedure:
A solution containing (R)-ethyl 2-amino-5-methylcyclopent-1-enecarboxylate (161.61 g, 955.024 mmol) and ammonium formate (90.3298 g, 1432.54 mmol) in formamide (303.456 ml, 7640.19 mmol) was heated to an internal temperature of 150° C. and stirred for 17 hours. The reaction mixture was cooled, and transferred to a 2 L single neck flask. Then excess formamidine was removed by high vacuum distillation. Once formamidine stopped coming over, the remaining oil in the still pot was dissolved in DCM and washed with brine (3×200 mL). The combined aqueous washes were extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The resulting brown oil was dissolved in minimal DCM, and this solution was added using a separatory funnel to a stirred solution of ether (ca. 5 vol of ether vs. DCM solution), causing some brown precipitate to form. This brown precipitate was removed by filtration through a medium frit funnel which was rinsed with ether and disposed. The filtrate was concentrated, the trituration from ether repeated two more times and then dried on high vacuum line to give (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (93.225 g, 65.00% yield) as a brown-yellow pasty solid. LC/MS (APCI−) m/z 149.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH:15]=[C:14]([O:17][Si](C)(C)C)[CH2:13][CH2:12]1.C(=O)(OC)OCC=C.O>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH2:16]1
Reactant: C[Si](C)(C)OC1=CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd+2]
Agent: C=CCOC(=O)OC
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1C=CN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirring solution of 1-(2-fluoro-4-nitrophenyl)-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine (Step 2, 100.0 g, 322 mmol) and allyl methyl carbonate (43.6 g, 386 mmol) in DMSO (625 ml) at ambient temperature is added Pd(OAc)2 (7.20 g, 32 mmol). The resulting solution is stirred under N2 at ambient temperature overnight. H2O (1 liter) is added and solvent allowed to cool to ambient temperature. The aqueous layer is extracted with EtOAc (2×800 ml), and the combined organic layers are washed with saline (800 ml) and dried over MgSO4. The solvent is removed and the residue recrystallized from EtOAc/MTBE to afford 53.6 g (70%) of the title compound as a yellow solid, 1H NMR (CDCl3) δ 2.71 (m, 2 H), 4.06 (m, 2 H), 5.41 (d, 1 H), 7.25 (m, 1 H), 7.35 (d, 1 H), 8.08 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Reactant: NCCc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1

Procedure:
A solution of 4-chloro-7-(3-chloro-propoxy)-quinazoline (synthesized as reported in J. Med. Chem. 2007, 50, 2213-2224) (100 mg, 0.389 mmol), 2-(4-aminophenyl)ethyl amine (63.6 mg, 0.467 mmol) and triethylamine (118.1 mg, 1.167 mmol) in ethanol (3 mL) was heated at 120° C. for 3 hours. The solution was cooled and the solid formed was filtered, washed with ethanol and then with dichloromethane to give the title compound as light yellow solid product (34 mg, 25%). 1H-NMR (300 MHz, CD3OD): 7.93-8.37 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.07-7.13 (m, 2H), 7.00-7.03 (d, J=8.1 Hz, 2H), 6.66-6.69 (d, J=8.4 Hz, 2H), 4.24-4.28 (t, 2H), 3.71-3.81 (m, 4H), 2.84-2.89 (t, 2H), 2.27-2.31 (m, 2H). LC-MS (ESI) m/z 357.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 56.7 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 4-chlorophenylboronic acid (0.058 g; 0.37 mmol) in DME-water (1 mL) for 2.5 h. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.056 g (51%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:27]=3)[CH:17]=2)=[CH:11][C:10]=1[CH3:40])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:27]=3)[CH:17]=2)=[CH:11][C:10]=1[CH3:40]
Reactant: [H][H]
Reactant: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc(C)c1O

Procedure:
0.35 g of 5-(4-benzyloxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 2 h in 15 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and chromatography on silica gel using methylene chloride/methanol 10:1, after crystallization from methylene chloride, 5-(4-hydroxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine having an m.p. of 150°-152° C. is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH:11]=1)[NH2:10].[O-:20][C:21]#[N:22].[Na+]>C(O)(=O)C.O.Cl>[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([NH:10][C:21]([NH2:22])=[O:20])[CH:11]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(N)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NCCc1ccc(OCc2ccccc2)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
2.4 g of 5-(2-aminoethyl)-2-benzyloxyaniline, hydrochloride, is dissolved in a mixture of 20 ml of acetic acid, 5 ml of water and 0.5 ml of 2N hydrochloric acid. A solution of 0.72 g of sodium cyanate in 5 ml of water is added and the mixture is stirred for one hour at room temperature. Thereafter, the mixture is diluted with 100 ml of water, the product is extracted by shaking with methylene chloride and recrystallized from isopropanol, thus obtaining 0.56 g of N-[5-(2-aminoethyl)-2-benzyloxyphenyl]urea, mp 176°-180° C.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[Cl:35][CH2:36][C:37]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:8][CH2:7]1)=[O:38]
Reactant: O=C(Cl)CCl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
(5R)-3-(4-(piperazin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one dihydrochloride (4.19 g, 10 mM) was suspended in dry dichloromethane (100 ml) under nitrogen and treated with triethylamine (3.03 g, 30 mM) to give a solution. After cooling to 4°, chloroacetyl chloride (1.14 g, 10 mM) was added and the mixture stirred for 15 minutes. The volume was reduced to 20 ml, and the solution chromatographed on silica, eluting with dichloromethane (30 ml). Relevant fractions were combined, washed with water (50 ml) and dried (magnesium sulfate). Evaporation gave the desired product (2.86 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:49]([NH:51][C@H:52]([C:58]([OH:60])=[O:59])[CH2:53][CH2:54][C:55](=[O:57])[OH:56])=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4].C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:49]([NH:51][C@H:52]([C:58]([OH:60])=[O:59])[CH2:53][CH2:54][C:55](=[O:56])[OH:57])=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:6])[CH2:3][OH:4]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 13 h

Procedure:
1.84 Grams of Z-Ser-Leu-Arg-Ser-Lys(Tos)-Glu-OH was suspended in a mixture of 30 ml of methanol with 30 ml of 10%-acetic acid, and a small amount of palladium black was added to the suspension and stirred for 13 hours under introducing hydrogen gas. After the reaction was completed, the catalyst was removed by suction filtration to obtain the filtrate. Then filtrate was distilled under a reduced pressure and the thus obtained residue was pured into water and then lyophilized to obtain the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1.[CH2:22]1C[O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C.C(=O)(O)[O-].[Na+]>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:24](=[O:25])[CH:23]=[CH2:22])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])=[CH:16][CH:17]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)cc3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 500 mg (1.47 mmol) 6-amino-4-[(4-bromophenyl)amino]-3-quinolinecarbonitrile in 1 ml hot DMF, added 6 ml THF and chilled to 0° C. under N2. Added 226 μl (1.62 mmol) triethylamine and 135 μl (1.62 mmol) acryloyl chloride. Removed ice bath at 15 minutes. At 1.5 hours, stripped solvent, slurried residue in dilute sodium bicarbonate, collected solids, and dried in vacuo. Boiled solids in ethyl acetate, collected, and dried in vacuo, giving 194 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=393.1, 395.1.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[BH4-].[Na+]>C1COCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1N
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A solution of 1-(2-fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (15.94 g, 43.50 mmol) in THF (200 mL) and MeOH (300 mL) was cooled to 0° C. Nickel(II) chloride hexahydrate (5.18 g, 21.80 mmol) was added in one portion. The solution was stirred for 30 min followed by portion-wise addition of NaBH4 (3.29 g, 87.00 mmol). Prior to warming the reaction to rt additional nickel(II) chloride hexahydrate (5.18 g, 21.80 mmol) and NaBH4 (3.29 g, 87.00 mmol) was added to the reaction. The solvent was removed in vacuo and the residue was taken up in DCM, filtered through Celite®, and washed with EtOAc. Purification by flash chromatography provided the title compound of step E (13.46 g, 40.10 mmol, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (qd, J=11.9, 3.6 Hz, 2H), 1.76 (d, J=12.1 Hz, 2H), 2.12-2.20 (m, 1H), 2.35-2.45 (m, 10H), 2.53 (dt, JHF=28.6 Hz, J=4.9 Hz, 2H), 3.37 (d, J=12.1 Hz, 2H), 3.68 (s, 3H), 4.14 (br. s., 2H), 4.47 (dt, JHF=47.9 Hz, J=4.94 Hz, 2H), 6.24 (dd, J=8.2, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:38]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:38])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CO)cn4c3-c3ccccc3)cc2)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {1-[4-(6-hydroxymethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (67 mg) in DMF (0.6 mL) under argon at 0° C. was treated with sodium hydride (8.4 mg of a 60% dispersion in mineral oil) and stirred for 30 minutes. Methyl iodide (0.007 mL) was added dropwise, the mixture warmed to rt and stirred for 3 hours. The mixture was partitioned between ethyl acetate and water and the organic phase washed with brine, dried and concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[S:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[C:24](N)=[CH:23]1>>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[S:22][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1csc2ncccc12
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2csc3ncccc23)c1=O

Procedure:
Obtained, (27%) from 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and thieno[2,3-b]pyridin-3-ylamine (Klemm, L. H., Zell, R., Barnish, I. T., Klemm, R. A., J. Het. Chem, 1970, 373-379) following the procedure of Example 67.