Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[C:20]([F:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:7]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.CCOC(C)=O>[N:33]([CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[C:20]([F:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:7]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(OS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(N=[N+]=[N-])C4)cc3)ncc2F)n1C(C)C
Temperature: 80 °C
Yield: 50.2 %

Procedure:
To a solution of 1-(4-{[5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}phenyl)azetidin-3-yl methanesulfonate (Example 138; 876 mg, 1.90 mM) in dry DMF (7.3 ml), sodium azide (619 mg, 9.5 mM) was added. The reaction was stirred and heated at 80° C. under nitrogen for 18 hours. The reaction mixture was diluted with EtOAc and the solution extracted with water (twice), saturated sodium chloride and then dried with anhydrous sodium sulphate filtered and evaporated. The crude product was purified by silica chromatography eluting with MeOH:DCM (2:98) to give the title compound as a brown foam (389 mg, 50%). NMR 1.4 (d, 6H), 2.53 (s, 3H+DMSO), 3.65 (m, 2H), 4.1 (m, 2H), 4.44 (m, 1H), 5.4 (m, 1H), 6.44 (d, 2H), 7.33 (m, 3H), 8.35 (d, 1H); m/z 408.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[CH2:14][OH:15]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: OCc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 3-phenoxyphenyl methanol (4.0 g, 0.020 mol) in anhydrous acetonitrile was added 1-bromo-2,5-pyrrolidinedione (3.73 g, 0.021 mol) at room temperature. The mixture was stirred at room temperature for one and a half hour under an atmosphere of nitrogen. The solvents were removed under the reduced pressure. Tetrachloromethane (100 mL) was added to the residue, and the mixture was filtered. The filtrate was concentrated into the residue, and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (1:5) as mobile phase to yield (2-bromo-5-phenoxyphenyl)methanol (4.7 g, 0.017 mol): RP-HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 10 min with 0.1 M ammonium acetate, 1 mL/min) Rt 11.7 min. TLC (ethyl acetate/heptane 1:5) Rf 0.18.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cc2C#N)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Ammonium chloride (5.9 g) and iron powder (32 g) were added to a mixed solvent of water (160 ml) and ethanol (470 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-tert-butoxycarbonylhomopiperazin-1-yl)benzonitrile (56 g) was added in parts over 30 min and the mixture was stirred at a refluxing temperature for 1 h. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (32 g), melting point: 38° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1cccc(Nc2cc(Nc3cccc(O)c3)ncn2)c1
Reactant: CN(C)CCCCl
Product: Cc1cccc(Nc2cc(Nc3cccc(OCCCN(C)C)c3)ncn2)c1
Yield: 16 %

Procedure:
Using an analogous procedure to that described in Example 27, 4-(3'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine (0.5 g) was reacted with 3-dimethylaminopropyl chloride to give 4-[3'-(3-dimethylaminopropoxy)anilino]-6-(3'-methylanilino)pyrimidine in 16% yield, m.p. 142°-144° C.;
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.[Br:32]N1C(=O)CCC1=O>CN(C=O)C>[Br:32][C:28]1[CH:29]=[CH:30][C:31]2[N:19]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:18]=4[CH:1]=3)[C:20]3[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)c1ccccc1c1cc(-n3c4ccccc4c4ccccc43)ccc21
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccc2c3ccccc3c3ccccc3c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of 9-(triphenylen-2-yl)-9H-carbazole (4.7 g, 11.9 mmol) in DMF (24 mL) at 0° C. under N2, NBS (N-bromosuccinimide) (2.1 g, 11.9 mmol) in DMF (24 mL) was added dropwise. After the completion of addition, the reaction mixture was warmed to room temperature overnight with vigorous stirring. The reaction mixture was precipitated with water and the solid was filtered. The pale grey solid was re-dissolved in a small amount of THF, added on a silica plug and flushed with 30% DCM/hexane. The filtrate was dried under vacuum and the white solid was used without further purification (5.5 g, 98 N.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([O:1][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)=[CH:10][CH:9]=1)[C:11]([O:13][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=1)=[O:12]
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1cccc(F)c1)c1ccc(OCc2cccc(F)c2)cc1C(=O)OCc1cccc(F)c1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A mixture of 4-hydroxyphthalic acid (5.0 g, 27.5 mmol), 3-fluorobenzylbromide (31.14 g, 164.7 mmol) and potassium carbonate (15.18 g, 109.8 mmol) in THF:water (1:1, 200 mL) was heated under reflux for 72 h. After cooling to RT, the mixture was then half evaporated and the residue extracted with ethyl acetate (100 mL). The organic layer was then washed with brine, dried over sodium sulfate, filtered and evaporated. The mixture was then heated in a Kugelrohr apparatus (160° C. at 15 mmHg) to remove the excess 3-fluorobenzylbromide to leave the title compound (13.1 g, 94%) as a light yellow liquid. MS m/e=506.1 (M).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([S:30]([O-:32])=[O:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.[Na+]>>[Cl:29][C:27]1[CH:26]=[C:25]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:32])[CH:24]=[C:23]([Cl:22])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: O=S([O-])c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cc(Cl)cc(Cl)c4)cc3c2C1
Yield: 43 %

Procedure:
The product of Example 29, step B and sodium 3,5-dichlorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 85:15 hexane/ethyl acetate) provided tert-butyl 8-(3,5-dichlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (147 mg, 43%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 8.07 (s, 1H), 7.85-7.78 (m, 3H), 7.56 (d, J=8.7 Hz, 1H), 7.50 (t, J=1.8 Hz, 1H), 4.59 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.93-2.82 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:7]2[CH:15]=[CH:16][C:17]([C:19](F)(F)F)=[CH:18][C:6]=2[N:5]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].N>>[S:30]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:19]1[C:17]1[CH:16]=[CH:15][C:7]2[N:8]([CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]=2[CH:18]=1
Reactant: Nc1ccccc1S
Reactant: COCc1nc2cc(C(F)(F)F)ccc2n1C1CCOCC1
Agent: N
Product: COCc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 8.2 %

Procedure:
An eggplant flask was charged with 2-methoxymethyl-1-(tetrahydropyran-4-yl)-5-trifluoromethylbenzimidazole (see Working Example 6-1) (0.102 g, 0.32 mmol), 2-aminobenzenethiol (0.041 g, 0.33 mmol) and polyphosphoric acid (approx. 2 g), and this was heated to 120° C. and stirred for 48 hours. After being allowed to cool, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. Chloroform extraction, drying over anhydrous magnesium sulfate, and the solvent being distilled off gave a crude product (0.21 g), which was purified by silica gel column chromatography (MeOH/CHCl3=1/20) to yield the title compound (0.010 g, 8.1% yield) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to example 16.4, 2-fluoro-4-hydroxy-benzaldehyde (CAS-No: 348-27-6) was alkylated with benzylbromide/potassium carbonate in DMF to give 4-benzyloxy-2-fluoro-benzaldehyde. Off-white solid. MS 230.1 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3](=[O:27])[CH2:4][O:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[NH:8][N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:42](O)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[C:42]([N:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([O:5][CH2:4][C:3](=[O:27])[C:2]([CH3:29])([CH3:28])[CH3:1])=[N:7]1)(=[O:44])[CH3:43]
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)n1nc(OCC(=O)C(C)(C)C)c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 19 %

Procedure:
A mixture of 3,3-dimethyl-1-[(5-(4-(methylsulphonyl)phenyl)-4-phenyl-1H-pyrazol-3-yl)oxy]butan-2-one (145 mg, 0.35 mmol), prepared according to the method of Example 32B, p-toluene-sulfonic acid hydrate (15 mg), and molecular sieves (4 g) in toluene (35 mL) and acetic acid (5 mL) was refluxed for 24 hours. The mixture was concentrated in vacuo, and the residue was purified by chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 30 mg; 19%). MP 189-191° C.; MS (APCI+) m/z 455 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.22 (s, 9H), 2.48 (s, 3H), 3.28 (s, 3H), 5.37 (s, 2H), 7.23 (m, 5H), 7.60 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H); Anal. calc. for C24H26N2O5S.0.5 H2O: C, 62.18; H, 5.87; N, 6.04. Found: C, 62.38; H, 5.81; N, 5.83.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:14][CH2:15][CH2:16][OH:17])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 4-bromo-2,5-difluorobenzenesulfonyl chloride (1.17 g, 4 mmol) in CH2Cl2 (3 mL) was added to a solution of 2-aminoethanol (0.36 mL, 6 mmol) and triethylamine (1.67 mL, 12 mmol) in CH2Cl2 (12 mL) at ambient temperature. The mixture was stirred at ambient temperature for 1 h and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 884 mg (70%) of 4-bromo-2,5-difluoro-N-(2-hydroxyethyl)benzenesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, 1H, Ja=7.2 Hz, Jb=6.0 Hz), 7.47 (dd, 1H, Ja=8.7 Hz, Jb=5.1 Hz), 5.39-5.14 (m, 1H), 3.78-3.64 (m, 2H), 3.26-3.10 (m, 2H), 1.73 (bs, 1H); LRMS (ESI), m/z 314/316 (M−H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:14]([CH:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C1([O:51]C)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH:17]([O:19][C:20](=[O:51])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(OCc1ccccc1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OC(=O)c1ccccc1)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
To a solution of diphenylmethyl 7-(2-thienylacetamido)-3-(1-benzyloxyethyl)-3-cephem-4-carboxylate (stereoisomer A: 160 mg) in methylene chloride (1.6 ml) are added anisole (0.32 ml) and trifluoroacetic acid (0.32 ml). After 15 minutes, the reaction mixture is evaporated to dryness, and the obtained residue is dissolved in ethyl acetate. The solution is extracted with aqueous sodium hydrogen carbonate solution. The extract solution is evaporated with ethyl acetate, cooled with ice, stirred and neutralized with 1N-hydrochloric acid to pH 2.0, and is extracted with ethyl acetate. The extract solution is washed with saline, dried over sodium sulfate, and evaporated to give 7-(2-thienylacetamido)-3-(1-benzoyloxyethyl)-3-cephem-4-carboxylic acid (stereoisomer A: 60 mg). m.p. 114°-118° C. RF: same with the benzylamine salt described below.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([C:15]1[S:16][C:17]2[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]>>[CH:12]([C:15]1[S:16][C:17]2[CH2:23][CH2:22][CH:21]([CH2:24][O:25][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1nc2c(s1)CCC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3sc(C(C)C)nc3C2)cc1
Yield: 71 %

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. M.p.=82°-83° C. Yield: 71%
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][CH:4]=5)=[CH:8][CH:9]=4)=[O:27])[CH2:24][CH2:25]3)=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: Cc1nc(-c2ccc(N)cc2)cs1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2)cs1
Reaction time: 16 h

Procedure:
4-(2-Methylthiazol-4-yl)aniline (19 mg, 0.10 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in acetonitrile (1.0 mL) containing triethylamine (42 μL, 0.30 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)cyclopropane-carboxamide. ESI-MS m/z calc. 378.1, found; 379.1 (M+1)+; Retention time 2.72 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.04-1.10 (m, 2H), 1.40-1.44 (m, 2H), 2.70 (s, 3H), 6.03 (s, 2H), 6.88-6.96 (m, 2H), 7.01 (d, J=1.4 Hz, 1H), 7.57-7.61 (m, 2H), 7.81-7.84 (m, 3H), 8.87 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29]>O1CCCC1>[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: NCc1ccccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNc1cc2ncnc(NCc3ccccc3N)c2cc1[N+](=O)[O-]
Yield: 78.1 %

Procedure:
4-Chloro-7-ethylamino-6-nitroquinazoline (5.00 g, 19.8 mmol), triethylamine (8.3 ml, 60.9 mmol), and 2-aminobenzylamine (2.9 g, 23.8 mmol) were stirred at room temperature overnight in tetrahydrofuran. After the reaction was completed, the solution was concentrated under reduced pressure, and the resulting solids were washed with methanol to give the title compound (5.23 g, 78%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([I:8])[CH:7]=1.[CH3:11][CH:12]([CH3:16])[C:13](=O)[CH3:14]>C(O)(=O)C>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]2[C:3]=1[C:12]([CH3:16])([CH3:11])[C:13]([CH3:14])=[N:9]2
Reactant: CC(=O)C(C)C
Reactant: NNc1cc(I)cc(I)c1
Solvent: CC(=O)O
Product: CC1=Nc2cc(I)cc(I)c2C1(C)C
Yield: 61.9 %

Procedure:
2 g of 3,5-diiodophenylhydrazine (5.5 mmol), and 1 mL (9.3 mmol) of 3-methyl-2-butanone were refluxed in 15 mL of acetic acid for 20 hours. The acetic acid was evaporated and the residue was dissolved in ether. Insoluble precipitate was filtered off, and the etheric solution was washed with aqueous solutions of NaHCO3, followed by Na2S2O3 and water. The organic layer was dried with CaCl2 and ether was removed under reduced pressure by a rotary evaporator to give 1.4 g of 4,6-diiodo-2,3,3-trimethyl-3H-indole. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.92 (1H, d, 1.1 Hz, arom.), 7.79 (1H, d, 1.1 Hz, arom.), 2.22 (3H, s, 2-CH3), 1.32 (6H, s, C(CH3)2).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[OH:11]S(O)(=O)=O>>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[O:11])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc(CBr)cc1

Procedure:
Stirred the solution of 4-(bromomethyl)benzonitrile (1.5 g) in cocn.H2SO4 at 100° C. for 3-4 h. After completion of the reaction, the reaction mass was quenched in ice and filtered to afford 0.900 of desired product. 1H NMR (400 MHz, DMSO d6): δ 4.71 (s, 2H), 7.26 (br s, 1H), 7.49 (d, J=7.8 Hz, 2H), 7.82 (d, J=7.8 Hz, 2H), 7.89 (br s, 1H); MS (m/z): 214.36 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1.C(=O)(O)[O-].[Na+]>C(O)C.O>[N:14]1([C:10]2[C:9]3[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Cc1cc(Cl)c2cccc(C)c2n1
Reactant: c1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-n2cncn2)c2cccc(C)c2n1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 1.91 g of 2,8-dimethyl-4-chloro-quinoline and 1.38 g of 1,2,4-triazole is melt at 120° C. and stirred for 2 hours. The solidified melt is dissolved in a mixture of ethanol and water. The solution is poured into a solution of 0.84 g of sodium bicarbonate and 20 ml of water. The precipitated product is filtered. Thus 1.97 g of the desired compound are obtained, yield 88%, m.p.: 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:12]2[C:13]([C:21]([OH:23])=O)=[N:14][N:15]([CH:18]3[CH2:20][CH2:19]3)[C:16]=2[CH3:17])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:12]3[C:13](=[N:14][N:15]([CH:18]4[CH2:19][CH2:20]4)[C:16]=3[CH3:17])[C:21]2=[O:23])[CH:3]=1
Reactant: Cc1c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)nn1C1CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1c2c(nn1C1CC1)C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylic acid (Step 17.7). tR: 4.28 min (HPLC 1); tR: 0.96 min (LC-MS 2); ESI-MS: 429/431 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.19 (m, 4H) 2.14 (s, 3H) 3.43 (s, 3H) 3.57-3.68 (m, 1H) 6.13 (s, 1H) 7.27 (d, J=8.6 Hz, 2H) 7.36 (d, J=8.6 Hz, 2H) 7.89 (d, J=2.3 Hz, 1H) 7.92 (d, J=2.3 Hz, 1H).