Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:5][CH:6]=1.[CH2:16]1[O:18][CH2:17]1.O>C1COCC1.[Li+].CC([N-]C(C)C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:5][C:6]=1[CH2:16][CH2:17][OH:18]
Reactant: CCc1ccc(Cc2cc(Br)cs2)cc1
Reactant: C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Cc2cc(Br)c(CCO)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under a nitrogen stream, to 4-bromo-2-((4-ethylphenyl)methyl)thiophene (2.80 g, 10.0 mmol) in anhydrous THF (40 ml), LDA (2.0 M, 5.50 ml, 11.0 ml) was added dropwise at −78° C. over 5 minutes. After the reaction mixture was stirred at 0° C. for 30 minutes, a THF solution of ethylene oxide (10 ml) was added dropwise at −78° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. After addition of water, the reaction mixture was extracted with ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:9)) to give the titled compound (2.55 g, 78%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:16]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(I)ccn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccccc2)ccn1

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (340 mg, 0.29 mmol, 0.050 equiv) was added to a deoxygenated mixture of tert-butyl 4-iodopyridin-2-ylcarbamate (1-1, 1.87 g, 5.84 mmol, 1 equiv), phenyl boronic acid (1.07 g, 8.76 mmol, 1.50 equiv), and aqueous saturated sodium carbonate solution (2.0 M, 8.8 mL, 18 mmol, 3.0 equiv) in dioxane (50 mL), and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled then concentrated. The residue was partitioned between half-saturated aqueous NaCl solution (100 mL) and EtOAc (100 mL). The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (dichloromethane, initially, grading to 40% EtOAc in dichloromethane) to give tert-butyl 4-phenylpyridin-2-ylcarbamate (1-2) as an off-white solid. LRMS m/z (M+H) Calcd: 214.3 (minus t-Bu), 171.3 (minus Boc); found 215.0 and 171.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])C.O>CN(C)C=O>[CH2:15]([CH:14]([CH2:17][CH3:18])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19])[CH3:16]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(N)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(=O)C(CC)CC)cc12)C(=O)OCC
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 73.7 %

Procedure:
A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (0.9 g) and diethyl ethoxymethylenepropanedioate (0.95 g) in N,N-dimethylformamide (4 ml) was stirred at 100° C. for 2 hours and 40 minutes. Water was added to the reaction mixture. The resulting crystals were collected, washed with water and dried. The crude crystals were chromatographed on silica gel with 20% ethyl acetate-chloroform and recrystallized from a mixture of ethyl acetate, chloroform and hexane to give crystaline diethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (1.1 g).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH2:4][CH:3]1[C:29]([NH:31][C:32]1C=CC=C[CH:33]=1)=[O:30].[CH3:38][O:39]CCN>>[OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH2:4][CH:3]1[C:29]([NH:31][CH2:32][CH2:33][O:39][CH3:38])=[O:30]
Reactant: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)Nc4ccccc4)C(O)C3O)c2n1
Reactant: COCCN
Product: COCCNC(=O)C1CC(n2nnc3c(NC4CC4c4ccccc4)nc(SC)nc32)C(O)C1O

Procedure:
The subtitle compound was prepared by the method of example 39, step a) using the product of example 20, step b) and methyoxyethylamine.
Reaction SMILES: CN(C=O)C.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=O)=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)(=O)C([Cl:24])=O>ClCCl>[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([Cl:24])(=[O:20])=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(O)c1ccc(N2CCCC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Yield: 19 %

Procedure:
DMF (0.5 mL) was added to solution of 4-(pyrrolidin-1-yl)benzenesulfonic acid (7.3 g, 32.16 mmol) in dichloromethane (40 mL). Oxalyl chloride (10 g, 78.74 mmol) was then dropwise and the resulting solution was maintained at room temperature for 1 hour. The reaction mixture was then quenched by the addition of 40 mL of iced water. The resulting solution was extracted using dichloromethane (3×20 mL), and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 1.5 g (19%) of 4-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.78 (d, 2H), 6.55 (d, 2H), 3.41 (t, 4H), 2.03 (t, 4H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:18]=2)[CH2:16][CH2:15][CH2:14]1.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCCC1>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH2:20][CH2:19][N:18]=[C:17]2[C:13]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: Clc1ccccn1
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C1(c3ccccn3)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (7.3 ml, 2.09M in hexanes) was added dropwise at ambient temperature to a solution of diisopropylamine (2.12 ml) in dry tetrahydrofuran (14 ml). After 15 minutes, the solution was cooled to -23° C. and a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (3 g) in tetrahydrofuran (34 ml) was added. After 30 minutes the mixture was cooled to -78° C., treated with 2-chloropyridine (1.56 ml), stirred for 1 hour then warmed to ambient temperature. The mixture was heated under reflux for 5 minutes, stirred for 16 hours at ambient temperature, then heated under reflux for 30 minutes. The reaction mixture was poured onto water and extracted with ethyl acetate. The extracts were dried and concentrated and the residual orange oil heated at 90° C. at 13.3 mbar to remove excess 2-chloropyridine. The residue was purified by flash chromatography over silica gel using a 5:1 mixture of light petroleum and triethylamine as eluant to give 7-methoxy-1-[1-(2-pyridyl)cyclobutyl]-3,4-dihydroisoquinoline as a solid (0.58 g).
Reaction SMILES: C1C2C(=CC=CC=2)C=[N:3][N:2]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=O)[O:18][C:16](=[O:17])[C:15]2=[CH:21][CH:22]=1.NN>C(O)(C)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:21][CH:22]=1)[C:16]([OH:17])=[N:3][N:2]=[C:19]2[OH:18]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: c1ccc2cnncc2c1
Agent: NN
Solvent: CC(C)O
Product: Oc1nnc(O)c2cc(Br)ccc12

Procedure:
The synthesis of phthalazine derivatives of general formulas 25-26 may be achieved as outlined in Scheme III. In general, a mixture of 4-bromophthalic anhydride and hydrazine may be refluxed in a suitable solvent, e.g., isopropyl alcohol, to provide 6-bromo-phthalazine-1,4-diol 21 in almost quantitative yield. Compound 21 may then be treated with phosphorus oxychloride to form 1,4-dichloro-6-bromo phthalazine 22. Treatment of compound 22 with a suitable nucleophile (where, for example, Y is NR1R2 or NaOR) affords two isomers of general formulas 23 and 24. Displacement of the bromine atom with a suitable amino or alcohol derivative A-B—X (where, for example, A is alkyl, aryl, arylalkyl, arylheteroalkyl, B is absent, CO, and X is OH, NH2), using a suitable Pd complex derivative in the presence of a base like sodium tert-butoxide in a suitable solvent, affords the desired 6-amino or 6-alkoxy phthalazine derivatives of general formula 25-26.
Reaction SMILES: [CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]([CH3:16])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([O:21]COC)=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.C([O-])(O)=O.[Na+]>CO.ClCCl>[CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]([CH3:16])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCC12CCCC(=O)C(C)=C1c1ccc(O)cc1C2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution of 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one(5 mg) in methanol (1 mL) was treated with aqueous 2N HCl (0.1 mL, 0.2 mmol). After stirring at 65° C. for two hours, the mixture was diluted with dichloromethane(2 mL), treated with solid NaHCO3, and purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 20% EtOAc in hexane. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 9a-butyl-2-hydroxy-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one as a foam.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8](=[O:35])[CH2:9][CH:10]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:5]=[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:10]=2[CH2:9][C:8]([O:7][CH3:6])=[O:35])=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COC(=O)Cc1[nH]c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc1-c1ccc(Br)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
Ammonium acetate (9.4 g, 157 mmol) was added to a solution of Example J7, (2S)-tert-butyl 2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate (7.6 g, 15.7 mmol) in xylene (80 mL) and stirred for 4 hours at 140° C. in a screw capped 150 mL pressure vessel. After being cooled, the reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3 and brine before being concentrated by rotory evaporation under high vacuum. The crude product was taken up in CH2Cl2 and charged to a 40 (M) Biotage silica gel cartridge. Gradient elution 15-100% B over 2 L (A=CH2Cl2; B=ethyl acetate) gave Example J8, (S)-tert-butyl 2-(4-(4-bromophenyl)-5-(2-methoxy-2-oxoethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 3.38 g (46%). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (s, 4H), 4.83-4.73 (m, 1H), 3.81 (br. s, 1H), 3.62 (s, 3H), 3.53-3.51 (m, 1H), 3.38-3.31 (m, 2H), 2.25-2.15 (m, 1H), 1.99-1.83 (m, 3H), 1.41/1.16 (s, 9H). RT=1.6 minutes (Condition 1). LCMS: Anal. Calcd. for C21H26BrN3O4 464.11; found: 464.40 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][N:2]1[C:6]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cn1nccc1-c1ccc(C=O)cc1
Product: Cn1nccc1-c1ccc(/C=C/C=O)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-5-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[Na].[CH2:13]([OH:18])[C:14]([F:17])([F:16])[F:15].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[O:18][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: OCC(F)(F)F
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Fc1nc(F)c(Cl)c(OCC(F)(F)F)c1F
Temperature: -78 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (18.0 g, 97.0 mmol) was dissolved in anhydrous THF (100 mL) under an N2 atmosphere and the resulting solution cooled to −78° C. To the cold solution was slowly added a solution of sodium 2,2,2-trifluoroehtoxide (97 mmol), prepared from trifluoroethanol (7.1 mL, 97.0 mmol) and NaH (3.88 g, 97.0 mmol, 60% dispersion in mineral oil), in anhydrous THF (100 mL). The resulting mixture was slowly warmed to ambient temperature. After 18 h at ambient temperature a GC analysis indicates all the starting material was consumed. The volatiles were evaporated and the residue dissolved in CH2Cl2 (200 mL). The organics were washed with H2O (3×100 mL), dried (MgSO4), filtered and concentrated to give the crude product as a yellow oil. The yellow oil was distilled at reduced pressure to afford 3-chloro-2,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridine as a clear oil (16.3 g, 63% yield): bp 48° C. (ca 0.2 mm Hg); 1H NMR (CDCl3) δ 4.81-4.78 (dq, J=1.6, 7.7 Hz); GC-MS (El, 70 eV) m/z (% relative intensity) 267 (33), 265 (100), 248 (5), 246 (16), 198 (22), 196 (60).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C)[N:16]=2)=[CH:10][CH:9]=1)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:17]1[N:18]=[C:19]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])[N:20]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:7])=[CH:9][CH:10]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCCCNc1nc(Nc2ccc(C(=O)NCCCCl)cc2)nc(OCC(F)(F)F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCCCCNc1nc(Nc2ccc(C(=O)NCCCCl)cc2)nc(OCC(F)(F)F)n1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
tert-butyl (8-((4-((4-((3-chloropropyl)carbamoyl)phenyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)octyl)carbamate (264 mg, 0.418 mmol) was dissolved in a 1:1 TFA (1 ml, 12.98 mmol)/DCM (1 mL). The reaction was stirred for 1 h. The solvent was removed under vacuum and the residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, then brine. The organic layer was collected and dried over sodium sulfate, and concentrated under vacuum to give 222 mg (100%) 4-(4-(8-aminooctylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(3-chloropropyl)benzamide as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[CH:4][C:3]=1[CH3:13].[Cl-:14].[P+]=O.[OH-].[NH4+]>CN(C)C=O>[Cl:14][C:6]1[C:5]2[C:10](=[CH:11][C:2]([I:1])=[C:3]([CH3:13])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: [Cl-]
Reactant: Cc1cc2c(=O)cc[nH]c2cc1I
Agent: O=[P+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc2c(Cl)ccnc2cc1I
Temperature: 60 °C
Reaction time: 1.33 h
Yield: 98 %

Procedure:
A mixture of 7-iodo-6-methyl-1H-quinolin-4-one (5.12 g, 18.0 mmol), phosphorus oxide chloride (14 mL) and N,N-dimethylformamide (1 mL) was stirred at 60° C. for 80 min, then poured onto ice and carefully neutralized with 25% aq. ammonium hydroxide solution. The suspension was extracted three times with dichloromethane, the combined organic phase was washed with brine, dried (MgSO4), and evaporated to afford the title compound (5.33 g, 98%). Light brown solid, ISP-MS: m/e=304.1 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>>[OH:27][C:21]1([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)[CH2:26][CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:22]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc([N+](=O)[O-])cc3)C2)c1

Procedure:
The compound of Example 17 was prepared according to the general preparation protocol A from 4-nitrobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[N:28]=[CH:29][NH:30][C:31]=1[C:32]#[N:33]>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[CH:29]=[N:30][C:31]([C:32]#[N:33])=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Reactant: N#Cc1[nH]cnc1N
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(OCC(F)(F)F)c(C(F)(F)F)c3)nc12
Yield: 40.1 %

Procedure:
Reaction of 1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (382 mg, 1.0 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (182 mg, 40%). MS (ISP) 453.0 [M+]; mp 189° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[N:19]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)(=[O:28])=[O:29])([CH3:26])[CH3:25])[N:21]=[C:20]([C:36]2[CH:37]=[CH:38][C:39]([NH:40][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:41][CH:42]=2)[N:19]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccncc2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccncc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Phenyl chloroformate (0.177 mL, 1.41 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-pyridin-4-ylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (0.640 g, 1.41 mmol) and sodium bicarbonate (0.178 g, 2.12 mmol) in dioxane (175 mL) at RT under air. The resulting slurry was stirred at RT for 2 hours. Two more portions of phenyl chloroformate (2×0.005 mL) were added and the reaction allowed to stir at RT. Water was then added to the reaction and the solids were filtered and dried in a vacuum oven at 55° C. overnight to give the desired material as a tan solid (0.758 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[CH2:7][NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[CH2:7][N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CNCc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1cc(F)ccc1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.15 g (3.95 mmol) of ethyl (5-fluoro-2-nitrobenzyl)aminoacetate was dissolved in 20 ml of dichloromethane. 0.61 ml (4.7 mmol) of 4-chlorobenzoyl chloride and 0.82 ml (5.9 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>ClCCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[O:41])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Reactant: O=C(Cl)c1ccncc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2c(C)nn(C)c2OC(=O)c2ccncc2)c(C)c2c1S(=O)(=O)CCC2(C)C
Yield: 76.9 %

Procedure:
1.0 Gram (2.7 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 10 ml of 1,2-dichloroethane, and further, 0.26 g (3.2 mmol) of pyridine, 0.57 g (3.2 mmol) of isonicotinic acid chloride hydrochloride and 10 mg of benzyltriethylammonium chloride were added. The mixture was allowed to react at room temperature for 3 hours. The extraction of the reaction mixture was carried out by adding ethyl acetate, and the extract was consecutively washed with 10% hydrochloric acid, with a saturated sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution. The solvent was removed by filtration under reduced pressure, and the resultant oily substance was washed with an ethyl acetate/n-hexane mixed solvent (1:1 (V/V)) to form a solid. The mixture was filtered to give 1.0 g (yield 80%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(pyridin-4-yl)carbonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 42).