Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][CH2:13][C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[Cl:12][CH2:13][C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:31])([F:32])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(CCl)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(CCl)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 89 %

Procedure:
1.03 ml (0.011 mol) of acetic anhydride and 0.56 ml (0.013 mol) of 98 percent strength nitric acid are added successively to 4.2 g (0.011 mol) of 5-chloroacetamido-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of glacial acetic acid at 15° C. After stirring for 6 hours, the mixture is concentrated in vacuo, the residue is taken up in 100 ml of dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed of solvent in vacuo. 4.1 g (89% of theory) of 5-chloroacetamido-4-nitro-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 130° C.-133° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]=[CH2:22]>CC(C)=O>[CH2:22]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:21]=[CH2:20]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(F)ccc1C(=O)OC
Temperature: 25 °C

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (0.27 mol), K2CO3 (0.41 mol), and KI (27 mmol) were charged in a 1-l reactor under N2. Acetone (500 ml) was added, followed by 3-bromo-propene (0.33 mol). The mixture was refluxed for 6 h under N2. The mixture was cooled to room temperature and filtered to remove the solid. The solvent was removed under vacuum, and the residue dissolved in water (200 ml) and CH2Cl2 (300 ml). The organic and aqueous layers were separated and the aqueous phase extracted with CH2Cl2. The organic layers were combined and dried with Na2SO4. The solvent was removed under vacuum to give Intermediate I-40 as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:51]=[CH:50][N:49]=[CH:48][C:47]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1cnccc1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccncc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-chloropyridine hydrobromide and isolated as yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(Cl)n1
Reaction time: 60 h
Yield: 71.4 %

Procedure:
A mixture of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine (715 mg, 2.65 mmol), p-tolylboronic acid (722 mg, 5.3 mmol), copper (II) acetate (962 mg, 5.3 mmol), triethylamine (1.5 ml, 10.6 mmol) and molecular sieves (4 angstrom) in dichloromethane (40 ml) was stirred under oxygen atmosphere for 60 hours. The mixture was filtered through a pad of celite under suction. The filtrate was purified by flash chromatography eluting with ethyl acetate-hexane (1:3 followed by 2:5) to provide the title compound (680 mg, 72% yield). 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 3.91 (s, 3H, CH3), 6.73 (d, 1H, J=1.9 Hz, Ar), 7.14 (d, 2H, J=8.4 Hz, Ar), 7.18 (d, 1H, J=8.9 Hz, Ar), 7.22 (d, 2H, J=8.2 Hz, Ar), 7.44–7.48 (m, 2H, Ar), 7.75 (d, 1H, J=2.8 Hz, Ar), 9.1 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([Br:22])=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([Br:22])=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1)=[O:9]
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-bromo-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-bromo-4-(trifluoromethyl)thiazole: refer to J. Heterocycl. Chem., 1991, 28, 1017.)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][O:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][O:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH:28]/[C:13](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccccc1N
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1N/C(=C1\C(=O)Nc2ccccc21)c1ccccc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 2-methoxyaniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]([O:26][CH3:37])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(NCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(NCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylamino]acetic acid (85.4 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.O>[Br:13][C:9]1[C:8]([CH3:11])=[CH:7][C:6]([OH:12])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-t-butyl-5-methylphenol (24.6 g, 150 mmol) in CCl4 (100 mL) at 0° C. was added a solution of bromine (7.7 mL, 150 mmol) in CCl4 (100 mL) over a 4 hour period. The mixture was stirred at room temperature for 30 minutes and then diluted with H2O. The organic phase was separated, washed with saturated sodium bisulfite and brine, and dried (MgSO4). Concentration gave a residue which was chromatographed on silica gel, eluting with 6:1 hexanes:EtOAc, to give the title compound. 1H NMR (CDCl3) δ 1.34 (s, 9 H), 2.24 (s, 3 H), 5.20 (s, 1 H), 6.54 (s, 1 H), 7.32 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:15][C:14](=[O:26])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34]([O:40][CH2:41][CH2:42]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=3)=[CH:15][C:14](=[O:26])[C:10]([C:11]([O:13][CH:41]([O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:42])=[O:12])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCI
Reactant: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(OC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(N(C)C)cc2)cc1=O)OC(=O)C(C)(C)C
Yield: 44 %

Procedure:
In 10 ml of chloroform was dissolved 1 g of 1-(4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid, and to the resulting solution were then added 0.32 g of triethylamine and 0.76 g of pivaloyloxyethyl iodide at room temperature, after which the resulting mixture was subjected to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was washed successively with 20 ml of a 0.1N aqueous sodium hydroxide solution and 20 ml of water and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure, and to the residue was added 20 ml of a diethyl ether/n-hexane (1:1 by volume) mixed solvent, after which insolubles were removed by filtration to obtain 0.6 g of 1-pivaloyloxyethyl 1-(4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 117°-120° C.
Reaction SMILES: [C:1]1([Se:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[Cl:13][CH2:9][CH2:8][Se:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCC[Se]c1ccccc1
Solvent: ClCCl
Product: ClCC[Se]c1ccccc1

Procedure:
One gram of the resulting 2-hydroxyethyl phenyl selenide was dissolved in 15 ml of CH2Cl2. One ml of thionyl chloride was dissolved in 5 ml of CH2Cl2 and was added to the solution of the 2-hydroxyethyl phenyl selenide. The reaction mixture was refluxed for 1 h. The solvent was evaporated off and the remaining product transferred to a separatory funnel using CHCl3. Twenty ml of water was added to the separatory funnel and was made weakly basic with 5% aqueous NaHCO3. The CHCl3 layer was removed from the separatory funnel, dried with sodium sulfate and removed from the product by rotary evaporation and then in vacuo.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.N[C:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=C[NH:21][N:20]=1>C(O)(=O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[N:21]3[N:20]=[CH:19][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(OC)c(OC)c3)ccnc12

Procedure:
A mixture of 2.35 g. of 3-dimethylamino-3',4'-dimethoxyacrylophenone and ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 20 hours and worked up to give the product, m.p. 148°-149° C.
Reaction SMILES: [C:1]1([NH:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=1.[ClH:23]>>[ClH:23].[C:1]1([NH:11][C:12]([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=2)[CH3:14])=[NH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CNc1cccc2ccccc12
Reactant: CNc1cccc(I)c1
Agent: Cl
Product: CN(C(=N)Nc1cccc2ccccc12)c1cccc(I)c1

Procedure:
N-(1-naphthyl)-N'-(3-iodophenyl)-N'-methyl guanidine HCl was prepared from 1-naphthyl cyanamide and N-methyl-3-iodo aniline.HCl by the method similar to the one described in Example 10.C.
Reaction SMILES: [NH2:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C(OCC)(=O)C.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:32]#[N:33])[CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1ncccc1C(=O)NCc1ccc(Oc2cccc(Br)c2)s1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccc(CNC(=O)c3cccnc3N)s2)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
Next, to a solution of a mixture of 2-amino-N-(5-(3-bromophenoxy)-thiophen-2-ylmethyl)-nicotinamide and debrominated compound (100 mg, 0.247 mmol) in N,N-dimethylformamide (3.0 mL) were added zinc cyanide (58 mg, 0.495 mmol) and tetrakis(triphenylphosphine)palladium(0) (285 mg, 0.247 mmol) under nitrogen atmosphere, and the solution was stirred at 140° C. from 3 hours and a half. The reaction solution was allowed to room temperature, ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (9 mg, 10%) was obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:15]>>[NH2:15][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2ccncc2)ccn1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1cc(-c2ccncc2)ccn1
Temperature: 180 °C

Procedure:
The mixture of 2-chloro-4,4′-bipyridine (2.40 g, 12.59 mmol) and concentrated ammonium hydroxide (100 mL) in a steel bomb was heated to 180° C. for 36 h. The volatiles were then removed in vacuo to give 2-amino-4,4′-bipyridine as a solid. 1H NMR (CDCl3) δ 8.71 (m, 2H), 8.18 (d, 1H, J=5.3), 7.48 (m, 2H), 6.8 (m, 1H), 6.72 (s, 1H). LRMS m/z (M+H) Calcd: 172.2, found: 172.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[I-].[Na+].[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1>CN(C)C=O>[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[O:34])=[CH:41][CH:42]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Reaction time: 7 h
Yield: 24.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g), triethylamine (2.1 cc), sodium iodide (2.2 g) and 4-(4-fluorobenzoyl)piperidine (3.1 g) in dimethylformamide (50 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 7 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallizatior from boiling acetonitrile (15 cc), 2-{3-[4-(4-fluorobenzoyl)piperidino]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (1.65 g) is obtained, m.p. 132° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([N:28]3[C:32]([CH3:33])=[N:31][N:30]=[N:29]3)[CH:19]=2)[C@@H:11]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+].O>CS(C)=O>[N:1]([CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([N:28]3[C:32]([CH3:33])=[N:31][N:30]=[N:29]3)[CH:19]=2)[C@@H:11]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nnnn1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nnnn1-c1cc(CO[C@H]2CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
Sodium azide (14 mg, 0.21 mmol) was added to a solution of [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine (90 mg, 0.18 mmol) in dimethyl sulphoxide (3 ml) and the solution was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give [2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow oil (89 mg, 98%) 1H (CDCl3) δ 7.54 (2H, s), 7.43-7.08 (6H, m), 4.62 (1H, d, J=13.2 Hz), 4.18 (1H, d, J=13.2 Hz), 3.92 (2H, s), 3.61-3.30 (4H, m), 3.02 (1H, m), 2.69 (1H, m), 2.55 (3H, s), 2.14 (2H, m), and 1.62 (2H, m). m/z 511 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][C:10]#[N:11])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C>C1COCC1>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][CH2:10][NH2:11])[CH3:2]
Reactant: CC(=O)N1CCC[C@H]1CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN1CCC[C@H]1CCN
Temperature: 0 °C
Yield: 64.2 %

Procedure:
((S)-1-Acetylpyrrolidin-2-yl)acetonitrile (Intermediate 137, 1.0 g) was added portionwise to a stirred, cooled solution of lithium aluminium hydride (0.36 g) in THF (30 mL) under an atmosphere of nitrogen while maintaining the temperature at 0° C. The mixture was allowed to warm to room temperature then heated at reflux for 2 hours. After cooling, ethanol (4 mL) was added dropwise and the resultant solid was filtered off. The filtrate was evaporated to dryness to give 2((S)-1-ethylpyrrolidin-2-yl)ethylamine (0.6 g) as a colourless oil.
Reaction SMILES: [Br:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](=O)[CH3:13].N1CCCCC1>C(Cl)Cl>[CH:12](=[C:4]([C:3](=[O:10])[CH:2]([Br:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)C(C)Br
Reactant: CC=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC=C(C(=O)OCC)C(=O)C(C)Br

Procedure:
A solution of 100 g (0.45 mol) of ethyl 4-bromo-3-oxovalerate in 100 ml of absolute methylene chloride is cooled to -20° C. under nitrogen, and 50 g (1.12 mol) of acetaldehyde are added. 1 g of piperidine, dissolved in 10 ml of methylene chloride, is then added dropwise at -20° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@:18]3([CH3:29])[O:22][C:21]4=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]4[CH2:19]3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C=O.[B-][C:35]#N.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH3:29][C@@:18]1([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([N:10]([CH3:35])[C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)[CH2:12][CH2:13]2)[O:22][C:21]2=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]2[CH2:19]1
Reactant: C[C@]1(CN2CCC(Nc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: [B-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(c1ccc(OC(F)(F)F)cc1)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
(S)-2-[4-(4-Trifluoromethoxyphenyl)aminopiperidin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 282 (400 mg, 0.90 mmol) was dissolved in methanol (10 ml). To the solution, a 37% formaldehyde solution (0.13 ml, 4.52 mmol), sodium cyanotrihydroborate (170 mg, 2.71 mmol) and acetic acid (0.17 ml, 2.71 mmol) were added followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into a saturated sodium hydrogencarbonate solution and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and recrystallized from methylene chloride-diisopropyl ether to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-N-methyl-4-trifluoromethoxyaniline (309 mg, yield 78%) as a light yellow crystals.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:4]([C:12]([NH:14][C@@H:15]([C:26]([NH:28][C@H:29]([C:45]([O:47]C)=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>O1CCOCC1.O>[NH:3]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:4]([C:12]([NH:14][C@@H:15]([C:26]([NH:28][C@H:29]([C:45]([OH:47])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1.5 h

Procedure:
26 ml 1 N NaOH are added to a suspension of 16 g BOC-Phe-(D)Trp-Lys(Z)-OMe in dioxane/H2O (8:2) and the reaction mixture stirred for 1.5 hrs. at room temperature. The obtained solution is diluted to ca. 500 ml by the addition of H2O and then concentrated under vacuum. The pH is adjusted to 1.5 to 2 by the addition, with stirring, of 1 N HCl, the precipitated product is filtered off, washed with H2O until neutral and dried to yield the title compound: