Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([NH2:12])[N:5]=1.[CH2:14]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])[CH:18]=1)[CH3:15]>ClCCl>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([NH:12][C:31]([NH:30][S:27]([C:19]2[CH:18]=[C:17]([O:16][CH2:14][CH3:15])[CH:26]=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])(=[O:29])=[O:28])=[O:32])[N:5]=1
Reactant: CCOc1ccc(C(=O)OC)c(S(=O)(=O)N=C=O)c1
Reactant: COc1cc(OC(F)F)nc(N)n1
Solvent: ClCCl
Product: CCOc1ccc(C(=O)OC)c(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC(F)F)n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 4-difluoromethoxy-6-methoxypyrimidin-2-amine (0.56 g, 2.92 mmol) in dry dichloromethane (5 mL) was added a solution of methyl 4-ethoxy-2-(isocyanatosulfonyl)benzoate (crude, ca. 5.6 mL) in dichloromethane (5 mL). The reaction mixture was heated at reflux for 3 hours, during which time the solid dissolved. On stirring at room temperature for 12 hours a new solid formed. The crude reaction mixture was chromatographed directly on a column of silica gel using as eluant 40:1, 20:1, and finally 10:1 dichloromethane-ether, all containing 2 mL/L acetic acid. The appropriate fractions were diluted with toluene and rotary evaporated to give a solid. The solid was slurried in hexanes, collected, washed with butyl chloride, 1:1 butyl chloride-hexanes, hexanes and air dried. The product was a white crystalline solid melting at 195°-196° C. PMR (CDCl3, 200 MHz): δ 12.02 (bs, 1H); 7.91 (d, 1H); 7.78 (d, 1H); 7.52 (t, 1H); 7.34 (bs, 1H); 7.09 (dd, 1H); 5.97 (s, 1H); 4.17 (q, 2H); 4.12 (s, 3H); 3.87 (s, 3H); 1.46 (t, 3H). IR (Nujol): 1722 (vs, C=O) cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH3:57][O:58][C:59](=[O:90])[NH:60][CH:61]([C:65]([N:67]1[CH:73]([C:74]2[NH:75][C:76]([C:79]3[CH:88]=[CH:87][C:86]4[C:81](=[CH:82][CH:83]=[C:84](Br)[CH:85]=4)[CH:80]=3)=[CH:77][N:78]=2)[CH2:72][C:69]2([CH2:71][CH2:70]2)[CH2:68]1)=[O:66])[CH:62]([CH3:64])[CH3:63]>O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:57][O:58][C:59](=[O:90])[NH:60][CH:61]([C:65]([N:67]1[CH:73]([C:74]2[N:75]=[C:76]([C:79]3[CH:88]=[CH:87][C:86]4[C:81](=[CH:82][CH:83]=[C:84]([C:29]5[CH:28]=[CH:27][C:26]([C:23]6[NH:22][C:21]([CH:12]7[CH2:13][CH:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:33])[CH:6]([CH3:8])[CH3:7])=[N:25][CH:24]=6)=[CH:31][CH:30]=5)[CH:85]=4)[CH:80]=3)[CH2:77][N:78]=2)[CH2:72][C:69]2([CH2:71][CH2:70]2)[CH2:68]1)=[O:66])[CH:62]([CH3:64])[CH3:63]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: COCCOC1CC(c2ncc(-c3ccc(Br)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COCCOC1CC(c2ncc(-c3ccc(-c4ccc5cc(C6=NC(C7CC8(CC8)CN7C(=O)C(NC(=O)OC)C(C)C)=NC6)ccc5c4)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of {1-[2[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (169 mg), bis(pinacolato)diboron (107 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(24 mg) and potassium acetate (95 mg) in 1.6 mL of dioxane was heated to 90° C. for 1.5 hour. (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (170 mg) in 1 mL of dioxane and 2M tripotassium phosphate (565 μl) were added and stirred at 90° C. for overnight. The mixture was purified by a preparative HPLC (10-60% MeCN—H2O; 0.1% formic acid modifier) to afford the title product (119 mg, 41%). 1H NMR (DMSO-d6, 400 MHz) δ: 8.20-8.10 (m, 2H), 7.90-7.68 (m, 6H), 7.60-7.55 (m. 2H), 7.33-7.30 (m, 2H), 5.18 (m, 1H), 5.07 (m, 1H), 4.44 (m, 1H), 4.04-3.69 (m, 6H), 3.80-3.38 (m, 5H), 3.30 (m, 9H), 2.71 (m, 1H), 2.40-1.90 (m, 5H), 0.90-0.79 (m, 12H), 0.70-0.54 (m, 4H); MS (ESI) m/z 889.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH2:13].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH:13][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(OC)c(C)c1N
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
To an ice cold solution of the above ester (81) (1.5 g, 7.68 mmol) and TEA (2 ml) in dry DCM (30 ml) was added benzoyl chloride (1.4 g, 10 mmol) and the mixture was stirred for four hours at room temperature. Benzoyl chloride (0.14 g, 1 mmol) was added and the mixture was stirred for one hour more at room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried with sodium sulfate and evaporated under reduced pressure. The product was purified by column chromatography on silica gel with eluted with hexane-ethyl acetate which gave the title compound (1.6 g).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[S:21][S:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[S:22][S:21][C:15]1[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH2:33][CH:34]([CH3:35])[CH3:36])([OH:39])=[O:38]
Reactant: Cc1cccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1SSc1c(C)cccc1C(=O)NC(CC(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)NC(CC(C)C)C(=O)O)c1SSc1c(C)cccc1C(=O)NC(CC(C)C)C(=O)O
Yield: 54.9 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-6-methyl-phenyldisulfanyl]-3-methylbenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (0.9 g, 1.3 mmol) from Example 32, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The crude product was recrystallized from dimethylformamide/water to afford 0.4 g of the title compound, mp 210-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([OH:17])=O)=[N:8][C:7]=3[C:6]=2[CH:18]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH:33]([NH:36][CH2:37][CH2:38][OH:39])([CH3:35])[CH3:34]>>[OH:39][CH2:38][CH2:37][N:36]([CH:33]([CH3:35])[CH3:34])[C:15]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][C:6]=3[C:7]=2[N:8]=1)=[O:17]
Reactant: CC(C)NCCO
Reactant: O=C(O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reaction time: 2 h
Yield: 67.4 %

Procedure:
9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2.4 g, 7.4 mmol) was dissolved in N,N-Dimethylformamide (DMF, 50 mL, 600 mmol). Added N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uranium Hexafluorophosphate (3.1 g, 8.1 mmol) and N,N-Diisopropylethylamine (6.4 mL, 37 mmol) and let stir for 10 minutes. Added 2-(isopropylamino)ethanol (1.5 g, 15 mmol) and let the reaction stir for 2 hours. More N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uranium Hexafluorophosphate was added to the reaction (2.8 g, 7.4 mmol) and let the reaction stir for another 3 hours. Reaction was complete by LCMS. Concentrated in vacuo and flash purified on the ISCO 0 to 50% ethyl acetate in hexanes two times to give 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (2.05 g, 68% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]1[N:16]=[N:17][NH:18][N:19]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59])[CH2:54][CH2:55][CH3:56]>CN(C=O)C>[CH2:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][N:63]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH2:62][CH2:61]1)=[O:59])[CH2:54][CH2:55][CH3:56]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1nn[nH]n1)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 222 mg (S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyric acid in 5 ml DMF were added 300 mg HATU, 541 μl DIPEA and 245 mg piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate. After 1 h the solution was concentrated, taken up with dichloromethane and washed with aqueous LiCl (4%) and 0.1 M HCl. The crude product thus obtained was used in the next reaction step without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:39])[C@@H:15]([CH3:38])[C@H:16]([OH:37])[C@H:17]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH2:18][CH:19]([SeH])C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@H]1COC(=O)N1C(=O)[C@H](C)[C@@H](O)[C@H](OCC1C=CC(OC)=CC=1)CC([SeH])C1C=CC=CC=1)C1C=CC=CC=1.I([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:39])[C@@H:15]([CH3:38])[C@H:16]([OH:37])[C@H:17]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:18]=[CH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CO[C@H](CC([SeH])c2ccccc2)[C@@H](O)[C@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1ccc(CO[C@H](CC([SeH])c2ccccc2)[C@H](O)[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Product: C=C[C@@H](OCc1ccc(OC)cc1)[C@@H](O)[C@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
2.41 g (4.0 mmol, 1.0 eq) of a 7/3 mixture of (4R)-4-benzyl-3-[(2S,3S,4R)-2-methyl-3-hydroxy-4-p-methoxybenzyloxy-6-phenylselenylhexanoyl]-2-oxazolidinone and (4R)-4-benzyl-3-[(2R,3R,4R)-2-methyl-3-hydroxy-4p-methoxybenzyloxy-6-phenylselenylhexanoyl]-2-oxazolidinone are dissolved in 25 mL of chloroform in the presence of 2.45 g (5.6 mmol, 1.4 eq) of tetrabutylammonium periodate. The reaction is stirred at 65° C. for three hours. The chloroform is evaporated off and the residue is then chromatographed on silica gel: eluent (7/3 Cy/EtOAc).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](O)=[O:24])([CH3:19])([CH3:18])[CH3:17].C(NC1CCCCC1)(NC1CCCCC1)=O.ON1C2C=CC=CC=2N=N1.[CH3:60][CH:61]1[NH:65][CH2:64][C:63]2([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]2)[S:62]1>ClCCl.O>[C:30]([C:27]1[CH:26]=[C:22]([C:23]([N:65]2[CH2:64][C:63]3([CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]3)[S:62][CH:61]2[CH3:60])=[O:24])[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[C:28]=1[OH:29])([CH3:31])([CH3:33])[CH3:32]
Reactant: CC1NCC2(CCN(C)CC2)S1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC1SC2(CCN(C)CC2)CN1C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of dicyclohexylcarbodiimide (985 mg, 4.77 mmol) in dry and distilled dichloromethane (10 ml) was added to a stirred solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (1.14 g, 4.55 mmol) in dichloromethane (15 ml) at room temperature under an argon atmosphere. Dicyclohexylurea began to precipitate as a white solid. 1-Hydroxybenzotriazole (645 mg, 4.77 mmol) was added and the resulting solution was stirred at room temperature for 5 min. 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (846 mg, 4.55 mmol) in dichloromethane (5 ml) was then added and the resulting mixture was kept at room temperature overnight. The next day mixture was heated at 30° C. (temperature of water bath) for 5 hrs and then kept at room temperature for another 4 days. The resulting suspension was filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give two fractions: AF723 (224 mg, 99.16% chemical purity) and a mixture of AF723 with a by-product (943 mg). The mixture of AF723 with by-product was purified by flash chromatography in a COMBI-flash system using linear gradient (silica, CH2Cl2/EtOH/NH4OH 220/10/1 to 140/10/1). After evaporation and drying under vacuum, AF723 (516 mg, 100% chemical purity) was obtained as a white solid. 1H NMR. (CDCl3, 500 MHz) δ 7.27 (s, 2H, arom CH), 5.55 (m, 1H, CH—S), 5.44 (s, 1H, OH), 4.10 (m, 1H, CHH—N—CO), 3.40 (m, 1H, CHH—N—CO), 2.60 (m, 2H, CH2—NCH3), 2.28 (m, 1H, CHH—NCH3), 2.25 (s, 3H, NCH3), 2.11 (m, 1H, CHH—NCH3), 1.95-1.66 (m, 4H, two CH2—CS), 1.60 (d, J=6.15 Hz, 3H, CH3—CH), 1.44 (s, 18H, t-butyl) ppm; 13C NMR (CDCl3, 500 MHz) δ 170.78 (C═O), 155.52 (C), 135.93 (two C), 127.39 (C), 124.30 (two CH), 59.56 (C), 58.00 (CH), 56.40 (CH2), 54.23 (CH2), 52.82 (CH2), 45.88 (CH3), 37.68 (CH2), 36.50 (CH2), 34.28 (C), 30.21 (CH3), 23.99 (CH3) ppm; FUR(HATR) 2943.89, 1619.92, 1388.67 cm−1; GC-MS (EI) 7.31 min m/z: 419 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 0.34 g (2.0 mmol, 1.0 eq.) of 1-(chloromethyl)-4-nitrobenzene in 20 mL of acetonitrile was added 0.83 g (6.0 mmol, 3.0 eq.) of potassium carbonate and 0.4 mL (4.0 mmol, 2.0 eq.) of piperidine. The reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, filtered and the solvent removed in vacuo. The resulting residue was purified by preparative TLC to give 0.31 g (1.4 mmol, 70%) of 1-(4-nitrobenzyl)piperidine (I-27).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:13]1[C:22]([Cl:23])=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CS(C)=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:13]([CH:2]([C:1]#[N:5])[C:3]#[N:4])=[N:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CC(C#N)c1nc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Malononitrile B (0.66 g, 10 mmol) was dissolved in 20 ml DMSO. Cesium carbonate (4.87 g, 15 mmol) was added to the reaction mixture followed by addition of 2,3-dichloroquinoxaline (2.0 g, 10 mmol). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was diluted with 50 ml ethyl acetate and washed with 1N HCl (2×50 mL). the mixture was extracted with ethyl acetate (2×80 mL). The combined organic layer was washed with brine solution (2×50 mL). The organic layer was collected and the solvent was removed under reduced pressure to yield the crude product C 2-(3-chloroquinoxalin-2-yl)malononitrile (2.0 g) which was used in the next step without further purification. Compound C (0.22 g, 1 mmol) was transferred to a microwave vessel containing 1 ml butyl amine. The reaction mixture was subjected to microwave irradiation at 70° C. for 30 min. The resultant crude reaction mixture was purified using column chromatography to yield compound D as shown in Scheme 3 (0.20 g, 86% yield). ESI (m/z): 266 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:21])[C:11]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[Cl:22][S:23]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:4]=1)(=[O:25])=[O:24]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12
Reactant: O=S(=O)(O)Cl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3O)nc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
5-(2-Hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.239 g, 0.00084 mol) was added, in portions, to stirred chlorosulphonic acid (3 ml) cooled to 0° C. under a nitrogen atmosphere, and the resulting deep red solution stirred at room temperature for 18 hours. The reaction mixture was then added dropwise, with care, to stirred ice/water to give a brown solid. The latter mixture was extracted with dichloromethane (3×30 ml), the combined extracts dried (Na2SO4) and filtered, and the filtrate evaporated under vacuum to give a brown solid (0.24 g, 75%), used in the next step without further purification; Rf 0.3 (silica; dichloromethane, methanol; 95:5).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.O[C:20]([CH3:31])([CH3:30])[CH2:21][NH:22]C(=O)OC(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH3:30][C:20]1([CH3:31])[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[C:4](=[O:5])[NH:22][CH2:21]1
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CC1(C)CNC(=O)c2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and tert-butyl (2-hydroxy-2-methylpropyl)carbamate using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:18]([OH:20])=O.CN(C(ON1[N:37]=[N:36][C:31]2C=[CH:33][CH:34]=[CH:35][C:30]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NN1CCCCC1.O>CN(C=O)C>[N:36]1([NH:37][C:18]([C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:15])([F:17])[F:16])=[CH:11][CH:12]=3)[NH:6][C:2]=2[CH3:1])=[O:20])[CH2:33][CH2:34][CH2:35][CH2:30][CH2:31]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1[nH]c(-c2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Agent: F[B-](F)(F)F
Agent: NN1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(-c2ccc(OC(F)(F)F)cc2)nc1C(=O)NN1CCCCC1
Reaction time: 0.02 h
Yield: 89.5 %

Procedure:
To 1 g of 5-methyl-2-(4-trifluoromethoxy-phenyl)-1H-imidazole-4-carboxylic acid in 50 ml of DMF was added 1.12 g of TBTU and 3.0 ml of Hünigs' base and the reaction mixture was stirred for 1 minute. Then 0.38 ml of 1-aminopiperidine (as R1R2NH) was added and the reaction mixture was stirred for 4.5 hour at room temperature. After such time the reaction mixture was poured onto 250 ml of water and extracted with ethyl acetate (2×200 ml). The combined organic extracts were then washed with water (2×100 ml) and brine (50 ml), dried (MgSO4) and after filtration, concentrated in vacuo to yield an oil which crystallized during concentration. The residue (about 30 ml volume) was then treated with heptane (200 ml), the solid was filtered and dried to yield 1.15 g of the title compound, MS (ISP) 369.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][C:43]=1[F:44])[NH2:40]>C(#N)C.C1(C)C=CC=CC=1>[Cl:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][C:43]=1[F:44])[NH:40][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
In a 50 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 2.00 g (6.3 mmol) of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one, 1.19 g (7.6 mmol) of phosphorus oxychloride, 0.76 g (6.3 mmol) of triethylamine, and 8 mL of toluene in a nitrogen atmosphere. The mixture was then stirred at 70-80° C. for 3 hours. Subsequently, the mixture was cooled to room temperature, and 1.09 g (6.3 mmol) of 3-chloro-4-fluoroaniline and 6 mL of toluene were added. The resulting mixture was stirred at 110° C. for 10 hours, Further, the mixture was stirred at room temperature after addition of 8 mL of acetonitrile. After the reaction was complete, the precipitated crystalline product was collected by filtration, and washed with 5 mL of cooled acetonitrile. Subsequently, the crystalline product was placed in 16 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 4 hours at room temperature. The crystalline product was collected by filtration, washed with 50 mL of water and 5 mL of acetonitrile, and dried under reduced pressure, to give 2.28 g (isolated yield: 71%, purity 89% in terms of area percentage determined by high performance liquid chromatography) of 4-(3-chloro-4-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline as a sallowish crystalline product.
Reaction SMILES: [C:1]([NH:8][O:9][CH2:10][C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(OC(=O)C)(=O)C>[C:1]([NH:8][O:9][CH2:10][C:11]([O:13][C:11](=[O:12])[CH2:10][O:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NOCC(=O)OC(=O)CONC(=O)OC(C)(C)C

Procedure:
A further embodiment of the invention according to the above reaction of obtaining formula (A) is dissolving (Boc-aminoxy)acetic acid, (G), in acetic anhydride and heating the mixture to a temperature in the range of about 40° C. to about 70° C. for about 48 hours to about 72 hours to form (Boc-aminooxy)acetic anhydride, (H).