Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:39])[CH3:41])[N:33]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2N2CCCCC2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3N3CCCCC3)cc2=O)n1
Yield: 55 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(2-piperidin-1-yl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 52) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-piperidin-1-yl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (0.79 g, 55%); ES+-HRMS m/e calcd for C30H40N6O4 [M+H+] 549.3184 found 549.3186. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.32 (m, 1H), 1.40 (br.s., 8H), 1.49-1.71 (m, 5H), 1.93 (m, 1H), 2.31 (m, 1H), 2.89 (m, 4H), 3.89 (s, 2H), 4.67 (s, 1H), 5.52 (dd, J=3.9, J=11.4 Hz, 1H), 5.71 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 7.09 (m, 1H), 7.13 (dd, Jo=8.1 Hz, Jm=1.3 Hz, 1H), 7.21 (dd, Jo=7.9 Hz, Jm=1.5 Hz, 1H), 7.28 (m, 1H), 7.52 (d, J=2.3 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>>[N:12]1([CH2:2][C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][N:4]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: BrCc1noc2ccccc12
Reactant: c1nc[nH]n1
Product: c1ccc2c(Cn3cncn3)noc2c1

Procedure:
Similarly condensation of 3-bromomethyl-1,2-benzisoxazole with 1,2,4-triazole affords 3-[(1H-1,2,4-triazol-1-yl)methyl]-1,2-benzisoxazole, m.p. 102°-104° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].O.[NH2:33][NH2:34].O>CN(C=O)C>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1)([O-:30])=[O:29]
Reactant: NN
Reactant: O=C(CCc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(CCc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(2-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (837 mg, 2.0 mmol, prepared in Synthetic Example 10) in DMF (20 ml) was added hydrazine monohydrate (80%, 350 μl, 8.74 mmol, 4.4 eq.), and the mixture was then stirred at 100 to 110° C. overnight. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (790 mg, 95%).
Reaction SMILES: N1C=CC(C2N([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)N=CN=2)=CC=1.[N:30]1[C:39]2C(=CC=CC=2)C=[CH:32][C:31]=1COC1C=CC(C(N)=O)=CC=1.[N:51]1[CH:56]=[CH:55][C:54]([NH:57][NH2:58])=[CH:53][CH:52]=1.COC(OC)(N(C)C)C>>[CH3:32][C:31]1[N:30]=[C:39]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)[N:57]([C:54]2[CH:55]=[CH:56][N:51]=[CH:52][CH:53]=2)[N:58]=1
Reactant: NC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: c1ccc2nc(COc3ccc(-n4ncnc4-c4ccncc4)cc3)ccc2c1
Reactant: NNc1ccncc1
Agent: COC(C)(OC)N(C)C
Product: Cc1nc(-c2ccc(OCc3ccc4ccccc4n3)cc2)n(-c2ccncc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline but substituting 4-(Quinolin-2-ylmethoxy)-benzamide, Pyridin-4-yl-hydrazine and N,N-dimethylacetamide dimethyl acetal provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=6.2 Hz, 2H), 8.21 (d, J=8.7 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.75 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (m, 1H), 7.56 (m, 1H), 7.41 (d, J=9.1 Hz, 2H), 7.29 (d, J=6.2 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 5.40 (s, 2H), 2.47 (s, 3H); MS: (M+H m/z=394.3).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][NH2:11])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([NH:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:12])=[N:15][CH:16]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCCCc1noc(C)c1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)OC)cn1
Temperature: 160 °C
Yield: 48.6 %

Procedure:
C-(3-Butyl-5-methyl-isoxazol-4-yl)-methylamine (320 mg, 1.90 mmol) was dissolved in DMSO (3 mL), methyl 6-chloronicotinate (326 mg, 1.90 mmol) and N,N-diisopropylethylamine (492 mg, 3.80 mmol) added, and the reaction mixture heated under microwave irradiation at 160° C. for 1 h. The reaction mixture was poured onto ice-water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 50% ethyl acetate in heptane) to give the title compound (280 mg, 49%) as a white solid. MS: m/e=348.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:17])(=[O:16])[NH:14][CH3:15].[ClH:18]>COCCOCCOC>[Cl:18][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:13](=[O:17])(=[O:16])[NH:14][CH3:15])[CH:4]=1)=[O:12]
Reactant: Cl
Reactant: CNS(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl
Solvent: COCCOCCOC
Product: CNS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl

Procedure:
12 g of 4'-chloro-3'-methylsulfamoyl-diazoacetophenone were reacted as prescribed in Example 66(b) with concentrated HCl in diethyleneglycol dimethyl ether und worked up. Colorless crystals, melting point: 153° C.
Reaction SMILES: Cl[CH:2]([Cl:4])C.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[O:15]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:15][CH2:2][Cl:4])=[O:10]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 10 ml of dichloroethane were added 1.32 g of zirconium tetrachloride and 1 g of 3-fluorobenzoyl chloride, and the mixture was stirred at room temperature for 20 minutes. The mixture was cooled to 0° C., 0.21 g of trioxane was added, and the mixture was stirred for 1 hour, and further stirred at room temperature for 1 hour. Water was added slowly at 0° C., the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 0.65 g of chloromethyl 3-fluorobenzoate.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH2:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-:14].[Na+]>CC(C)=O>[CH3:1][Si:2]([CH3:13])([CH2:9][CH2:10][CH2:11][I:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(CCCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[Si](C)(CCCI)c1ccccc1

Procedure:
Dimethyl(3-chloropropyl)phenylsilane [J. W. Wilt, W. K. Chwang, C. F. Dockus and N. M. Tomiuk, J. Am. Chem. Soc., 100, 5534, (1978)] (9 g, 48.8 mmol) and sodium iodide (29.5 g, 195 mmol) are refluxed in acetone during 24 hours. The mixture is filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in diethyl ether and washed with water. The organic layer is dried with sodium sulfate, filtered and concentrated under reduced pressure to afford pure dimethyl(3-iodopropyl)phenylsilane as a slightly yellow oil (12.5 g, 93%).
Reaction SMILES: [CH3:1]N.Cl[C:4]1[C:9]([C:10]#[N:11])=[C:8]([Cl:12])[N:7]=[C:6]([NH:13][CH2:14][CH3:15])[N:5]=1.[CH:16]([NH2:19])(C)C>>[Cl:12][C:8]1[C:9]([C:10]#[N:11])=[C:4]([NH:19][CH3:16])[N:5]=[C:6]([NH:13][CH:14]([CH3:15])[CH3:1])[N:7]=1
Reactant: CC(C)N
Reactant: CCNc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CN
Product: CNc1nc(NC(C)C)nc(Cl)c1C#N

Procedure:
This compound was prepared in the manner of Example XVII, substituting 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile and aqueous 40% methylamine for 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile and isopropylamine. The reaction product was recrystallized from methylcyclohexane to give 4-chloro-2-isopropylamino-6-methylamino-5-pyrimidinecarbonitrile; mp, 170°-173°.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:9]([OH:10])[CH2:8]1.[OH-].[K+].C[O:40][C:41]([C:43]1[O:49][C:46]([CH2:47]Cl)=[CH:45][CH:44]=1)=[O:42]>O1CCOCC1>[C:41]([C:43]1[O:49][C:46]([CH2:47][O:10][C@@H:9]2[C@@H:11]([CH2:12][OH:13])[O:33][C@@H:7]([N:6]3[CH:34]=[C:2]([F:1])[C:3](=[O:36])[NH:4][C:5]3=[O:35])[CH2:8]2)=[CH:45][CH:44]=1)([OH:42])=[O:40]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)o1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
To a solution of 5.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 100 ml of dioxane were added 5.74 g of fine powder of potassium hydroxide and 2.67 g of 5-methoxycarbonylfurfuryl chloride, and the mixture was stirred at temperature of 80° C. for 2.5 hours. The reaction mixture was concentrated and the residue was dissolved in 100 ml of water. The reaction mixture was adjusted to a pH of 4 with one normal hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried and concentrated To the residue was added 100 ml of 80% acetic acid The mixture was left to stand at a temperature of 80° C. for one hour. The solvent was distilled off and the residue was washed with ethyl acetate and methanol, giving 2.53 g (67%) of 3'-O-(5carboxyfurfuryl)-2'-deoxy-5-fluorouridine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=N[CH:7]=1.[CH:20](B1OB(C=C)OB(C=C)O1)=[CH2:21].[C:32](=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:5]2[CH:21]=[CH:20][C:2]([CH:7]=[CH2:32])=[CH:3][N:4]=2)=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(C)(CNc1ncc(Br)cn1)c1ccc(F)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(NCC(C)(C)c2ccc(F)cc2)nc1
Temperature: 115 °C
Yield: 73 %

Procedure:
To a 5 mL microwave reaction vessel was added 5-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine (255 mg, 0.8 mmol, 1.0 equiv), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (285 mg, 1.2 mmol, 1.5 equiv), Cl2Pd(dppf) (58 mg, 79 μmol, 0.1 equiv), potassium carbonate (1.2 mL of a 2N aqueous solution, 2.4 mmol, 3.0 equiv), and dioxane (4 mL). The reaction was heated in a microwave reactor at 115° C. for 20 min. The aqueous layer was removed from the reaction, and the organic layer was directly purified by reverse phase column chromatography to give 158 mg (73%) of N-(2-(4-fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.Cl>CC(O)C.C1COCC1>[OH:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:12])[F:13])=[N:9][CH:10]=1
Reactant: COCOc1cnc(C(F)(F)F)cc1C(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)c1cc(C(F)(F)F)ncc1O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanone (3.2 g, 13 mmol) and 5N HCl (40 ml) in i-PrOH/THF (1:1, 40 ml) was stirred at 45° C. overnight. The mixture was cooled, concentrated, taken up in H2O, neutralized with saturated NaHCO3, and extracted with DCM (3×). The organic layers were combined, dried over Na2SO4, and concentrated to give the title compound as a tan solid. MS (m+1): 206.2
Reaction SMILES: C[N+](CC)(CC)CC.[C:9]([C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[C:13]([O-])=[O:14])#[N:10].S(F)(OC(F)(F)C(F)=C(F)[F:27])(=O)=O>COCCOCCOC>[C:9]([C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[C:13]([F:27])=[O:14])#[N:10]
Reactant: N#CC(F)(F)C(F)(F)C(=O)[O-]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Agent: CC[N+](C)(CC)CC
Solvent: COCCOCCOC
Product: N#CC(F)(F)C(F)(F)C(=O)F
Reaction time: 1 h
Yield: 28.9 %

Procedure:
A solution of 53.9 g (0.2 mole) of methyltriethylammonium-3-cyanotetrafluoropropionate prepared as in Part A in 300 ml of diglyme was stirred at -10° to -5° while 46.0 g (0.20 mole) of perfluoroallyl fluorosulfate was rapidly added. The mixture was then stirred at -10° to -5° for 1 hr., and then at -5° to 0° for 4 hr. Removal of volatiles at 35° (5 mm, 6.7×10-1 kPa) through a liquid N2 trap and fractionation gave 10.0 g (29%) of 3-cyanotetrafluoropropionyl fluoride, bp 19°-20°. IR (gas phase):2265 (CN), 1888 (COF), and 1300-1100 cm-1 (CF) with traces of CO2, SO2F2 and SiF4 present. NMR (CCl4 ; 0°); 19F 25.8 (t of t, JFF 10.1, 5.0 Hz, 1F, COF), -106.7 (d of t, JFF 5.0, 4.6 Hz, 2F, CF2CN), and -118.5 ppm (d of t, JFF 10.1, 4.6 Hz, 2F, CF2C=O).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=[CH:19][CH2:18][CH2:17]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Dy+3]>C(#N)C>[C:2]1([C@@H:1]2[C@H:19]3[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:20]3[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Dy+3]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 30.8 %

Procedure:
Benzaldehyde (2.92 g, 28 mmol), aniline (2.56 g, 28 mmol), tert-butyl 2,3-dihydro-1H-pyrrole-1-carboxylate (3.4 g, 25 mmol) and Dy(OTf)3 (0.61 g, 1.38 mmol) were stirred in acetonitrile (50 ml) at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (150 g), and eluted with hexane-ethyl acetate (4:1, v/v). The title compound (3aR*,4R*,9bR*) (2.7 g, 31%) was obtained as an amorphous form from the first eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:20])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>O.O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:20])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[NH:28][CH2:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH]nc(OCCCSc2ccccc2)c(Cl)c1Cl
Reactant: NCc1cccnc1
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]nc(OCCCSc2ccccc2)c(NCc2cccnc2)c1Cl
Yield: 74.8 %

Procedure:
After 0.3 g of 4,5-dichloro-6-[3-(phenylthio)propyloxy]-3(2H)-pyridazinone and 0.243 g of 3-picolylamine were dissolved in a solvent mixture of water-dioxane (1:1), the mixture was heated to reflux for 8 hours. After completion of the reaction, the reaction mixture was poured onto water and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off. The resulting crystals were recrystallized from isopropanol to give 0.273 g of the objective compound. Yield, 73%, Melting point, 152°-155° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[NH:27][CH:28]=[CH:29][C:22]=23)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[NH:27]1[C:23]2=[N:24][CH:25]=[CH:26][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]3)=[C:22]2[CH:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccnc3[nH]ccc23)CC1
Reaction time: 2.5 h
Yield: 96.7 %

Procedure:
Trifluoroacetic acid (1 ml) was added dropwise to a solution of [1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (19 mg, 0.06 mmol) in dichloromethane (1 ml), with stirring and cooling on ice. After 2.5 hours, the solvents were concentrated in vacuo and the crude product was purified on a basic resin NH2 cartridge (2 g, 15 ml) eluting with methanol to afford the required compound (12.5 mg, 0.058 mmol, 96%). LC-MS (LCT) Rt 0.95 [M+H]+ 217
Reaction SMILES: [ClH:1].ClC1C=CC([NH:9][NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[N:18][N:17]([CH3:20])[C:16]=3[CH:21]=2)=CC=1.C(O)C.[OH-].[Na+].[OH:27][C@H:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30]>O>[OH:27][C@H:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30].[Cl:1][C:32]1[CH:37]=[CH:36][C:35]([CH:11]([NH:10][NH2:9])[C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[N:18][N:17]([CH3:20])[C:16]=3[CH:21]=2)=[CH:34][CH:33]=1
Reactant: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Reactant: Cl
Agent: O=C(O)[C@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nnc2ccc(C(NN)c3ccc(Cl)cc3)cc21
Temperature: 14 °C
Reaction time: 0.17 h
Yield: 163.7 %

Procedure:
To a mixture of 200 g of intermediate 2-a and 479 ml of ethanol at 23° C. was added a solution of 23.94 g of sodium hydroxide in 180 ml of water. After stirring for 10 min. there were added 50.2 g of (-)-(R)α-hydroxybenzeneacetic acid. The whole was stirred for 30 min. at 60° C. and the product was crystallized by adding some product crystals obtained in a previous low-scale set-up. Then the whole was stirred for 2 hours at 50° C. and overnight at room temperature. The reaction mixture was cooled (temp.14° C.) and stirred for 1 hour. The product was filtered off, washed with ethanol and dried in vacuo, yielding 118.8 g (87%) of (±)-6-[(4-chlorophenyl)-hydrazinomethyl]-1-methyl-1H-benzotriazole (R)-α-hydroxybenzeneacetate (1:1) monohydrate (interm. 3-a); diastereomeric excess: 92.6%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:17]=[C:16](O)[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:16]1[CH:15]=[C:14]([CH3:19])[N:13]=[C:12](/[CH:11]=[CH:10]/[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:17]=1
Reactant: Cc1cc(O)nc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Yield: 70.4 %

Procedure:
In analogy to example 12c), by heating was (E)-2-[2-(3-nitro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (1.28 g, 5 mmol) in POCl3 (9.16 ml, 0.1 mol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3-nitro-phenyl)-vinyl]-6-methyl-pyrimidine (0.97 g, 71%) as an off-white solid. EI mass spectrum, m/e: 275 (M calculated for C13H10ClN3O2: 275).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1Cl)=O.C(N)(C)(C)C.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCCCNC(OCC1C=CC=CC=1)=O.C1(NC2CCCCC2)CCCCC1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)N
Solvent: COc1ccccc1
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 24 h

Procedure:
Relative stability of amino-protecting groups, namely Xys, 2-chlorobenzyloxycarbonyl and Z against trifluoroacetic acid. Boc-Lys(Xys)-OH(41.4 mg, 0.1 m.mol), Boc-Lys(2-Cl-Z)-OH.t-butylamine salt (48.8 mg, 0.1 m.mol) and Boc-Lys(Z)-OH.dicyclohexylamine salt (56.1 mg, 0.1 m.mol) are each dissolved in trifluoroacetic acid (0.5 ml) containing anisole (0.03 ml) and the solutions are allowed to stand at room temperature for 24 hours. The trifluoroacetic acid is distilled off and the residue is made up to 20 ml with cold water. An aliquot of this solution is taken and its lysine content is determined by means of an amino acid analyzer. The yields of lysine (% cleavage of ε-amino-protecting groups) are calculated.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CC(C)=O>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)CCN1C(=O)CCc2c(OCC3CO3)cccc21
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)CCN1C(=O)CCc2c(OCC(O)CN3CCN(c4ccccc4)CC3)cccc21
Yield: 38.7 %

Procedure:
2.9 grams of 1-(3-methylbutyl)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 1.7 g of 4-phenylpiperazine are mixed with 50 ml of methanol and reacted at 50°-60° C. for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue thus obtained is dissolved in 50 ml of acetone. Into this solution, 20 ml of an acetone solution containing 1.1 g of oxalic acid are added, then the precipitate thus formed is collected by filtration, washed with acetone and dried. Recrystallization from ethanol-ether to obtain 2.1 g of 1-(3-methylbutyl)-5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril monooxalate in the form of colorless crystals. This product is confirmed as a single compound by a silica-gel thin layer chromatography-(developing solvent; chloroform:methanol=9:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:24]1([CH2:27][NH:28][CH3:29])[CH2:26][CH2:25]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:28]([CH2:27][CH:24]2[CH2:26][CH2:25]2)[CH3:29])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNCC1CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5) (5.11 g 15 mmol), cyclopropylmethyl-methyl-amine hydrochloride (5.47 g, 45 mmol) and Et3N (10.5 mL, 75 mmol) in DMSO (50 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (5.73 g).