Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([C:38](F)(F)F)[CH:30]=2)[C:3]1=[O:42].CC1(C)C(=O)N(C2C=CC([NH:57][S:58](N)(=[O:60])=[O:59])=C(C)C=2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F>>[CH3:43][C:2]1([CH3:1])[C:3](=[O:42])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:58]([NH2:57])(=[O:60])=[O:59])=[C:31]([CH3:38])[CH:30]=2)[C:5](=[O:28])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[O:17]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Product: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Yield: 62 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 30 replacing the compound of Example 1. A white solid is obtained with a yield of 62%.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][O:23][C:24]([NH:26][O:27][CH3:28])=[O:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.Cl>CC(O)C>[ClH:21].[NH2:8][CH:9]([CH2:22][O:23][C:24]([NH:26][O:27][CH3:28])=[O:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CONC(=O)OCC(COc1noc2ccc(Cl)cc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: CONC(=O)OCC(N)COc1noc2ccc(Cl)cc12

Procedure:
3-(2-tert-Butoxycarbonylamino-3-methoxyaminocarbonyloxypropoxy)-5-chloro-1,2-benzoisoxazole is dissolved in 10 ml of 2-propanol, and 12.8 ml of a 2-propanol solution (7.5N) of hydrogen chloride is added, after which they are subjected to reaction at 20°-25° C. overnight. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the crystals obtained are washed with 2-propanol and then collected by filtration, to obtain 0.46 g of colorless, crystalline 3-(2-amino-3-methoxyaminocarbonyloxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 199°-200° C.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4].CCN(CC)CC.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][O:16][S:26]([CH3:29])(=[O:28])=[O:27])[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(CO)co1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-methanol (326 mg, 1.33 mmol) in dry CH2Cl2 (8.0 mL) was treated at 0° C. with Et3N (0.24 mL, 1.70 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.67 mmol). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.50. LC-MS-conditions 02: tR=1.05 min; [M+H]+=322.25.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=4)[C:20]#[N:21])[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:20]([C:19]1[CH:22]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][N:1]4[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:14]=2)[CH:16]=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])#[N:21]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C#N
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 80 °C
Yield: 41.4 %

Procedure:
A mixture of 5-[3-(1H-indol-4-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D49) (100 mg, 0.29 mmol), ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and cesium carbonate (189 mg, 0.58 mmol) in DMF (2 ml) was heated at 80° C. for 1 hour. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and heated overnight at 80° C. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and cesium carbonate (189 mg, 0.58 mmol) and heated for 24 hours. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and heated for 24 hours. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and heated for 6 hours. Added EtOAc (20 ml) and washed with water (20 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from ethanol to give the title compound (55 mg) as a white solid. MS (ES) C26H26N4O4 requires 458; found 459 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH:18]1([NH2:25])[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:24][CH:20]4[CH2:21][CH2:22][CH2:23][CH:18]([NH2:25])[CH2:19]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCCC(N)C1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NC1CCCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)C1
Temperature: 180 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.38 mmol) and cyclohexane-1,3-diamine (43 mg, 0.38 mmol) in NMP (1.0 mL) was added NaHCO3 (32 mg, 0.38 mmol), the mixture was stirred at 180° C. for 60 mins under microwave irridation. The mixture was purified by flash chromatograph to give N1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,3-diamine (30 mg, 0.088 mmol, 23%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:26]=3)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: BrCc1cccnc1
Reactant: CCCn1cnc2nc(-c3cn[nH]c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3cnn(Cc4cccnc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
A mixture of 1-Propyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (100 mg, 0.2 mmol), 3-Bromomethylpyridine (55 mg, 0.3 mmol), K2CO3 (50 mg, 0:3 mmol) and DMF were stirred at 60° C. for 2 hours. Organic volatiles were evaporated and purified to obtain pure 1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (8 mg, 6%) as an colourless oil.
Reaction SMILES: I[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[F-].[K+].[F:12][C:13]([Si](C)(C)C)([F:15])[F:14].N>CN1C(=O)CCC1.[Cu]I>[Br:8][C:7]1[C:2]([C:13]([F:15])([F:14])[F:12])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Brc1cnc(I)c(Br)c1
Agent: [Cu]I
Agent: N
Agent: [F-]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ncc(Br)cc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a solution of 2-iodo-3,5-dibromopyridine (4.21 g, 11.60 mmol) in NMP (25 mL) were added copper(I)iodide (4.42 g, 23.21 mmol), potassium fluoride (1.35 g, 23.21 mmol), and (trifluoromethyl)trimethylsilane (5.61 mL, 35.90 mmol). The resulting mixture was allowed to stir overnight at 50° C. The mixture was poured into 12% aqueous ammonia, and then extracted with Et2O (2×120 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3,5-dibromo-2-(trifluoromethyl)pyridine (1.63 g, 46%) as a liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O:18][C:19]([NH:21][C@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>C(O)CCCC>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:23]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c2n1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A mixture of 8-bromo-2-methoxy-[1,5]naphthyridine (1.50 g, 6.27 mmol, prepared as in WO 2006/032466) and (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (1.17 g, 6.27 mmol) in pentanol (5 mL) and DIPEA (1.24 mL, 1.2 eq) was heated at 80° C. over night. The majority of the solvent was removed in vacuo at elevated temperature (50-60° C.). The residue was triturated with ether to remove residual amine. The mother liquor was concentrated and the residue was chromatographed over SiO2 (DCM-MeOH—NH4OH 1000:50:4) to afford the desired intermediate as a beige foam (1.86 g, 86%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][CH:14]2[CH:21]3[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[O:12])[C:5]=1[CH3:24].[OH-].[Na+]>CO>[CH:15]12[CH2:23][CH:19]3[CH2:18][CH:17]([CH2:22][CH:21]([CH2:20]3)[CH:14]1[NH:13][C:11](=[O:12])[NH:10][C:6]1[C:5]([CH3:24])=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:25])=[O:2])[CH2:16]2
Reactant: COC(=O)c1cccc(NC(=O)NC2C3CC4CC(C3)CC2C4)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(NC(=O)NC2C3CC4CC(C3)CC2C4)cccc1C(=O)O

Procedure:
A solution of 3-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic acid methyl ester 70 mg (0.204 mmol), 0.408 ml NaOH 1N in 2 ml methanol was stirred overnight at 55° C. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The aqueous phase was acidified to pH 1 and the precipitate was filtered and dried under vacuum to give 53 mg (79%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C@@H:8]([CH3:12])[C:9]([NH:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: C[C@@H](C(=O)O)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of (S)-2-(tert-butoxycarbonyl)propanoic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (49 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-((S)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (95 mg, 69%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:13]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]1([N:14]2[C:13]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16][CH2:17][CH2:18]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1C1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a solution of [(S)-1-(1-cyclobutyl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (728 mg, 2.2 mmol) in DCM (15 mL) was added TFA (8 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min and the organic layer dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a white solid (251 mg, 49%). LCMS (Method C): RT 2.07 min [M+H]+ 234.1.
Reaction SMILES: COC(=O)CC1C(C)=NN([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)C=1C.[C:23]([O:27][C:28](=[O:39])[CH2:29][C:30]1[C:31]([CH2:37][CH3:38])=[N:32][NH:33][C:34]=1[CH2:35][CH3:36])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:39])[CH2:29][C:30]1[C:34]([CH2:35][CH3:36])=[N:33][N:32]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:31]=1[CH2:37][CH3:38])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCc1n[nH]c(CC)c1CC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Product: CCc1nn(Cc2ccc([N+](=O)[O-])cc2)c(CC)c1CC(=O)OC(C)(C)C

Procedure:
[3,5-Diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid tert-butyl ester was prepared according to the preparation of intermediate 1.1.2, using in the alkylation reaction (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester (preparation according to WO2007/141267) instead of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester.
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][C:35]1[CH:51]=[CH:50][C:38]([CH:39]=[N:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C.C[Si](Cl)(C)C.S([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH:10]([CH:39]([C:38]1[CH:50]=[CH:51][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[NH:40][C:41]1[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=1)[C:11]([N:13]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(Nc2ccc([N+](=O)[O-])cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To 5.4 g (12.0 mmol) of product 1 and 6.2 g (24 mmol) of product 2 in 135 ml of methylenehloride 8 ml of diisopropylethylamine is added at 10° C. and 4.8 ml of trimethylsilylchloride is added dropwise. After 1 h 14 ml of a 1 molar solution of titantetrachloride in methylenehloride is added dropwise at −10° C. It is stirred for 3 h at −10° C. and further 12 h at −30° C. stored without stirring. Afterwards 8 ml of acetic acid and 140 ml of a 7% aqueous solution of tartratic acid is added and it is stirred for further 2 h at room temperature. After addition of 50 ml of a 20% aqueous solution of sodiumhydrogensulfit it is stirred for another 1 h and extracted with methylenehloride. The organic phase is dried by magnesium sulfate, evaporated and purified by chromatography on silica gel/Ethylacetate/heptane=1/3->1/1. 6.3 g (74%) of product 3 is obtained in form of a light yellow solid compound: C40H47N3O7Si (709.92) MS (ESI+) 710 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]#[N:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:17]>>[N+:1]([C:4]1[C:5]([C:14]([NH2:15])=[O:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Product: NC(=O)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A round bottom flask was charged with 3-nitro-5-(trifluoromethyl)picolinonitrile (910 mg, 4.19 mmol) and sulfuric acid (4192 μl, 4.19 mmol), and the mixture was stirred at 60° C. for 16 h. Upon cooling to RT the crude mixture was poured onto ice, and the resulting solids were filtered, washed with water and dried. 3-nitro-5-(trifluoromethyl)picolinamide (850 mg, 3.62 mmol, 86% yield) was isolated as a light yellow solid. LC/MS (ESI+) m/z=236.1 (M+H).
Reaction SMILES: ClC1C([N+]([O-])=O)=C(Cl)N=CN=1.Cl.[Cl:13][CH2:14][CH2:15][NH2:16].C(=O)(O)[O-].[Na+].Cl[CH2:23][CH2:24][NH:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.[N+](C1C(CCCl)=NC=NC=1CCCl)([O-])=O>CCOCC.C(Cl)(Cl)Cl>[Cl:13][CH2:14][CH2:15][NH:16][C:30]1[N:29]=[CH:28][N:27]2[CH2:23][CH2:24][N:25]=[C:26]2[C:31]=1[N+:32]([O-:34])=[O:33]
Reactant: NCCCl
Reactant: O=[N+]([O-])c1c(Cl)ncnc1NCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: O=[N+]([O-])c1c(CCCl)ncnc1CCCl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])C1=C(NCCCl)N=CN2CCN=C12
Reaction time: 0.5 h

Procedure:
A solution of 20 g. of 4,6-dichloro-5-nitropyrimidine was prepared in ether. An aqueous solution containing 14 g. of β-chloroethylamine hydrochloride and 24 g. of sodium bicarbonate were added thereto and the subsequent mixture agitated for about 30 minutes. The ether layer was separated, and the separated layer washed with water and dried. Removal of the ether in vacuo yielded an oil containing chiefly 4-(β-chloroethylamino)-5-nitro-6-chloropyrimidine plus a small quantity of 5-nitro-4,6-bis(β-chloroethyl)pyrimidine (the disubstituted product) and a very small quantity of starting material. The oily residue was allowed to stand in chloroform for about one day. A solid comprising 7-(β-chloroethylamino)-8-nitro-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride precipitated and the precipitate was separated by filtration, 7-(β-chloroethyl)amino-8-nitro-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride thus prepared decomposed at 135° C. after recrystallization from chloroform; yield=5.378 g.
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][C:9]2[C:18]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(Cl)([Cl:33])=O>>[Cl-:33].[Cl-:33].[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:18]2[C:9]([O:8][C:7]3[CH:29]=[CH:30][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=2)=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1ccc(Oc2cc3ccccc3cc2Oc2ccc(C(=O)O)cc2)cc1
Product: [Cl-]

Procedure:
The compound 2,3-bis-(4-carboxyphenoxy)naphthalene dichloride was prepared by reacting 2,3-bis-(4-carboxy-phenoxy)napthalene with thionyl chloride according to the procedure of Example 20. After initial crystallization, the product was again recrystallized from cyclohexane/toluene (1;1) to give a 96.5% yield of the title compound with the formula: ##STR24##
Reaction SMILES: C([O-])(=O)C1C=CC=CC=1.[F:10][C:11]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:12]=1[C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:20])([F:19])[F:18])=[O:14].CN(C1C=CC=CN=1)C.[CH2:41]([O:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62](Cl)=[O:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:41]([O:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]([O:31][C:29]3[CH:28]=[CH:27][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:19])([F:20])[F:18])=[O:14])=[C:11]([F:10])[CH:30]=3)=[O:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F
Agent: CN(C)c1ccccn1
Agent: O=C([O-])c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)c(F)c3)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of the benzoate (1.6 g) obtained in (1) above, triethylamine (0.5 g) and dimethylaminopyridine (0.5 g) in methylene chloride (10 ml) was slowly added under cooling a solution of 4-n-octyloxybiphenyl-4'-carboxylic acid chloride (1.7 g) in methylene chloride (10 ml). The mixture was left to stand until it reached room temperature and stirred overnight. The mixture was poured in water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. After the solution was distilled under reduced pressure to remove the solvent, the residue was purified by silica-gel column chromatography and recrystallized from anhydrous ethanol to obtain the titled compound (0.8 g, [α]D20 =+25.6° ). ##STR62##
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[N:31][CH:30]=[CH:29][C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[N+:31]([O-:6])[CH:30]=[CH:29][C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(N2CCC3CCc4ccncc4C3=N2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2c(c1)C1=NN(c3ccc(Cl)cc3)CCC1CC2
Yield: 72.1 %

Procedure:
3-Chloroperoxybenzoic acid (60%) (35 mg) was added to a solution of 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyrido[4,3-h]cinnoline (example 17, 25 mg) in dichloromethane (5 ml) at 25° C. After 4 hours the reaction was diluted with dichloromethane and sequentially washed with an aqueous solution of sodium metabisulfite, saturated sodium bicarbonate solution, brine, dried and evaporated. Purification by chromatography, eluting with ethyl acetate/methanol (4:1) afforded the title compound (19 mg).