Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:32]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[CH:46]([C:50](O)=[O:51])[CH2:45][C:44]3=[O:53])[CH:33]=1.[C:54]([C:58]1[CH:59]=[C:60]([NH2:69])[N:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[N:62]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C>[C:54]([C:58]1[CH:59]=[C:60]([NH:69][C:50]([CH:46]2[C:47]3[C:43](=[CH:42][C:41]([N:34]4[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:40]5[N:32]=[CH:33]4)=[CH:49][CH:48]=3)[C:44](=[O:53])[CH2:45]2)=[O:51])[N:61]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[N:62]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: O=C1CC(C(=O)O)c2ccc(-n3cnc4cccnc43)cc21
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)C2CC(=O)c3cc(-n4cnc5cccnc54)ccc32)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
HATU (46.7 mg, 0.12 mmol) and triethylamine (29.5 μL, 0.21 mmol) are added to a solution of (R/S)-5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (30 mg, 0.1 mmol) in DMF (2.5 mL). The reaction is stirred at rt for 2 min then 5-tert-butyl-2-phenyl-2H-pyrazol-3-ylamine (21.5 mg, 0.1 mmol) is added. After stirring at rt for 8 h, DMF is removed in vacuo. The residue is purified by reversed phase MPLC using ACN/Water as eluant and 5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-amide is obtained as a white solid. Title compound: ES-MS: 491.00 [M+H]+, tR=1.6 min (System 2).
Reaction SMILES: O=S(Cl)Cl.[F:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([F:16])[C:7]=1[C:8]([OH:10])=[O:9].[CH3:17]O>>[F:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([F:16])[C:7]=1[C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: O=C(O)c1c(F)cc(O)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(F)cc(O)cc1F
Yield: 99 %

Procedure:
SOCl2 (4.16 g, 30.1 mmol) was added to a solution of 2,6-difluoro-4-hydroxybenzoic acid (1.50 g, 8.62 mmol) in MeOH (20 mL) and the resulting mixture was heated at reflux for 24 h. After cooling the solvent was removed in vacuo to give the title compound (1.62 g, 99%) as a white crystalline solid; mp 177.5-180° C.; 1H NMR (270 MHz, DMSO-d6) 3.80 (3H, s, CH3), 6.50-6.60 (2H, m, ArH), 11.16 (1H, s, OH)
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([O:16][C:17]([NH:19][C@@:20]([CH3:32])([CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][OH:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].CCOCC>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C@@:20]([CH3:32])([CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCCCC(=O)OC[C@@](C)(CO)NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(=O)OC[C@@](C)(C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Molecular sieve 4A (220 g) and pyridinium chlorochromate (43.6 g, 0.202 mol) were added to a solution of (2R)-2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol (30.7 g, 0.101 mol) obtained in Reference example 1 (1a) in methylene chloride (600 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction mixture, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-5:1) to obtain the title compound (28.8 g, yield: 95%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([C:11]2[CH:21]=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[C:12]=2[S:22]([CH3:24])=[O:23])=[O:10])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([C:11]2[CH:21]=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[C:12]=2[S:22]([CH3:24])(=[O:33])=[O:23])=[O:10])[CH2:2][CH2:3]1
Reactant: CS(=O)c1c(C(=O)c2cnoc2C2CC2)ccc2c1OC(F)(F)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1c(C(=O)c2cnoc2C2CC2)ccc2c1OC(F)(F)O2
Yield: 89.9 %

Procedure:
A solution of 5-cyclopropyl-4-(2,2-difluoro-4-methylsulphinyl-1,3-benzodioxol-5-oyl)isoxazole (1.0 g) in dichloromethane was stirred with m-chloroperbenzoic acid (55%, 1.33 g) for 5 hours, then washed in turn with sodium metabisulphite solution, saturated sodium bicarbonate solution and water. The solution was dried (magnesium sulphate), evaporated to dryness and the residue recrystallised from toluene/cyclohexane to give 5-cyclopropyl-4-(2,2-difluoro-4-methylsulphonyl-1,3-benzodioxol-5-oyl)isoxazole (compound 6, 0.94 g) as a colourless solid, m.p. 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:41][S:42]([C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][CH:54]=1)[C:48]([NH:50][NH2:51])=[O:49])(=[O:44])=[O:43]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([NH:51][NH:50][C:48](=[O:49])[C:47]2[CH:52]=[CH:53][CH:54]=[C:45]([S:42]([CH3:41])(=[O:43])=[O:44])[CH:46]=2)=[O:15])=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: COC(=O)c1cc(C(=O)O)n(-c2ccccc2Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)NNC(=O)c2cccc(S(C)(=O)=O)c2)n(-c2ccccc2Cl)n1
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a stirred solution of compound 7 (500 mg, 1.78 mmol) in DMF (20 mL at 0° C., EDCI (500 mg, 2.6 mmol) was added and stirred for 15 min. HOBt (351 mg, 2.6 mmol) was added to the reaction mixture and after 30 min stirring 3-(methylsulfonyl)benzohydrazide 3 from Example 1 (450 mg, 2.1 mmol) was added. Reaction mixture was allowed to attain room temperature and stirred for over night. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL×4). Combined organic layer was washed with water, brine, dried over sodium sulphate and concentrated. The crude product on column chromatographic purification using 2% methanol in dichloromethane afforded the title compound 8 (452 mg, 52%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C([O-])([O-])=O.[K+].[K+].[NH:21]1[CH2:25][CH2:24][N:23]=[C:22]1S(O)(=O)=O>CO>[NH:23]1[CH2:24][CH2:25][N:21]=[C:22]1[N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(O)C1=NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2=NCCN2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.86 of Boc-piperazine were combined with 25 ml of water, 25 ml of methanol, 2.77 g of K2CO3 and 1.5 g of imidazoline-2-sulphonic acid and stirred for 2 days at RT. After dilution with water the mixture was extracted with EE and chromatographed over silica gel. 0.8 g of 1-(imidazolin-2-yl)-4-Boc-piperazine were obtained. This substance was combined with 6.2 ml of DMF and 136 mg of NaH dispersion (60%). After one hour, 0.214 ml of methyl iodide was added dropwise and the reaction mixture was left for three days at RT. It was combined with water, extracted with EE and chromatographed over silica gel. In this way, 0.47 g of 1-(1-methylimidazolin-2-yl)-4-Boc-piperazine was obtained, which was treated with 5 ml of 4N HCl in dioxane at RT. After one hour, the mixture was concentrated by evaporation, stirred with ether and evaporated to dryness in vacuo. 0.38 g of 1-(1-methyl-imidazolin-2-yl)-piperazine dihydrochloride was thus obtained as a solid substance (yield 15%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 40 °C
Yield: 49.6 %

Procedure:
A mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3-chloro-4-methylphenyl isocyanate (0.26 g, 1.6 mmol) and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at this temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.35 g of the product in 50% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.22 (s, 3H), 2.36-2.43 (m, 1H), 2.57-2.64 (m, 1H), 2.86-2.98 (m, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.40 (d, J=17.3 Hz, 1H), 4.54 (d, J=17.3 Hz, 1H), 5.15 (dd, J=13.1 Hz, J=5.0 Hz, 1H), 6.77 (t, J=5.6 Hz, 1H), 7.09-7.19 (m, 2H), 7.48-7.57 (m, 2H), 7.61-7.64 (m, 2H), 8.72 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 18.7, 22.6, 31.2, 39.7, 46.2, 51.6, 116.5, 117.7, 121.6, 127.5, 128.3, 130.4, 131.0, 131.7, 133.0, 135.5, 139.5, 139.9, 155.1, 168.1, 171.0, 172.8; Anal. calcd for C22H21ClN4O4.0.2H2O: C, 59.45; H, 4.85; N, 12.60. Found: C, 59.28; H, 4.83; N, 12.39.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH2:10][C:9]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:8][N:7]=1.C(N(CC)CC)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:13]2[CH2:14][CH2:15][C:9]3([O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:10]3)[CH2:11][CH2:12]2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: c1csc(C2=NOC3(CCNCC3)C2)n1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(c2nccs2)=NO3)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 52 %

Procedure:
Compound O (0.150 g, 0.578 mmol) was dissolved in toluene (15 ml) and mixed successively with triethylamine (0.12 ml, 0.867 mmol) and 4-tert-butylphenyl isocyanate (0.102 ml, 0.578 mmol). The reaction mixture was heated to boiling point and boiled under reflux for 3 h. After cooling to RT, the mixture was stirred for 36 h. The reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. After purification of the residue by column chromatography (hexane:EtOAc 1:1), the desired product was obtained in a yield of 52% (0.120 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl.Cl.C[Si](C)(C)CCOC[N:16]1[C:20]2[N:21]=[CH:22][N:23]=[C:24]([C:25]3[CH:26]=[N:27][N:28]([C:30]4([CH2:34][C:35]#[N:36])[CH2:33][NH:32][CH2:31]4)[CH:29]=3)[C:19]=2[CH:18]=[CH:17]1.Br[C:40]1[CH:53]=[CH:52][C:43]([C:44]([NH:46][C@@H:47]([CH:49]2[CH2:51][CH2:50]2)[CH3:48])=[O:45])=[CH:42][C:41]=1[F:54]>>[C:35]([CH2:34][C:30]1([N:28]2[CH:29]=[C:25]([C:24]3[C:19]4[CH:18]=[CH:17][NH:16][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:26]=[N:27]2)[CH2:31][N:32]([C:40]2[CH:53]=[CH:52][C:43]([C:44]([NH:46][C@@H:47]([CH:49]3[CH2:51][CH2:50]3)[CH3:48])=[O:45])=[CH:42][C:41]=2[F:54])[CH2:33]1)#[N:36]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: C[C@@H](NC(=O)c1ccc(Br)c(F)c1)C1CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1)C1CC1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 3, Step 2-3 starting from {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride and 4-bromo-N-[(1R)-1-cyclopropylethyl]-3-fluorobenzamide (from Step 1, above). LCMS (M+H)+: m/z=485.2. 1H NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 9.01 (s, 1H), 8.88 (s, 1H), 8.46 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.71 (t, J=2.5 Hz, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 7.17 (d, J=2.5 Hz, 1H), 6.61 (t, J=8.4 Hz, 1H), 4.53 (d, J=8.0 Hz, 2H), 4.28 (d, J=8.0 Hz, 2H), 3.63 (s, 2H), 3.28 (m, 1H), 1.04 (d, J=6.5 Hz, 6H), 0.82 (m, 1H), 0.30 (m, 1H), 0.20 (m, 1H), 0.06 (m, 1H), 0.01 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[Cl:16].[CH2:17](N(CC)CC)[CH3:18]>C(O)C>[Cl:16][C:7]1[C:6]2[C:11](=[C:2]([CH:17]=[CH2:18])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=1
Reactant: FC(F)(F)c1cc(Cl)c2cccc(Br)c2n1
Reactant: CCN(CC)CC
Solvent: CCO
Product: C=Cc1cccc2c(Cl)cc(C(F)(F)F)nc12
Yield: 72.7 %

Procedure:
A suspension of 2.00 g (6.25 mmol) 8-bromo-4-chloro-2-trifluoromethylquinoline (commercially available from Maybridge, Cornwall, UK), 258 mg (0.31 mmol) PdCl2dppf CH2Cl2, 1.29 g (9.37 mmol) potassium vinyl tetrafluoroborate and 0.88 ml (6.28 mmol) triethylamine in 40 ml ethanol was heated at reflux for 3 h. The resulting yellow suspension was filtered and the filtrate evaporated to dryness. The residue was suspended in ethyl acetate, filtered and the filtrate extracted with water. The organic layer was evaporated to dryness and the isolated crude product purified by silica gel chromatography (hexane) to yield 1.17 g (72%) of the title compound as white crystals. MS: 257.1 (M+). 1H-NMR (300 MHz, CDCl3): 5.58 (dd, J=11.1, 1.1 Hz, 1H); 6.07 (dd, J=17.8, 1.1 Hz, 1H); 7.75 (t, J=7.7 Hz, 1H); 7.81 (s, 1H); 7.99 (dd, J=17.8, 1.1 Hz, 1H); 8.09 (d, J=7.2 Hz, 1H); 8.23 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[O:19])C(F)(F)F)=[C:4]1[CH3:20])[CH3:2].[OH-:21].[K+].Cl>C(O)C.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:19])=[O:21])=[C:4]1[CH3:20])[CH3:2]
Reactant: CCn1c(C)c(C(=O)C(F)(F)F)c2ccc(OC)cc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCn1c(C)c(C(=O)O)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 1-(1-ethyl-6-methoxy-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone 71b (580 mg, 2.03 mmole) in 10 ml ethanol was added a solution of KOH (1.1 g, 20 mmole) in 10 ml water. The mixture was heated to reflux for 1 hour and cooled to room temperature. Concentrated HCl was added to adjust pH to 1. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was further purified by column chromatography (eluting with 1–2% MeOH in CH2Cl2) to give 350 mg product as brown solid (74% yield). 1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J=8.7 Hz), 6.90 (1H, dd, J=2.2, 8.7 Hz), 6.80 (1H, d, J=2.2 Hz), 4.14 (2H, q, J=7.2 Hz), 3.88 (3H, s), 2.77 (3H, s), 1.37 (3H, t, J=7.2 Hz).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:29][CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCc1cccnc1
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3cccnc3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted with 3.0 g of 3-picolyl amine and 5 g of triethyl amine according to Example 76, the solvent was distilled off under reduced pressure and the residue was taken up in 70 ml of water. Three extractions followed with 60 ml of ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue crystallized under diisopropyl ether. Melting point: 152° - 153° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:41][CH:42]=2)O1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C:40]1[CH:39]=[CH:38][C:37]([C:2]2[N:7]3[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:4][CH:3]=2)=[CH:42][N:41]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 48 %

Procedure:
Compound 2b (500 mg, 1.15 mmol) was subjected to Suzuki coupling conditions with tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-ylcarbamate using the reaction conditions described in Example 1, Step G to obtain compound 13a as a yellow solid (300 mg, 48% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H31N7O3: 550.2 (M+H). Found 550.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Cl.Cl[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Agent: Cl
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2cccnc2)c1=O
Yield: 38.5 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 3-(chloromethyl)pyridine hydrochloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 38.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][C:21]=3[OH:30])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:47]([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][C:21]=3[O:30][CH:47]([CH3:49])[CH3:48])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: CC(C)N1CCN(C(CN2CCN(CCCCc3c(O)ccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2ccccc2c1CCCCN1CCN(CC(c2ccc(F)cc2)N2CCN(C(C)C)CC2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
0.05 g of 1-[2-(4-Fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-[4-(2-hydroxynaphthalen-1-yl)butyl]piperazine obtained in Example 7 was dissolved in 5 ml of dimethylformamide, and 0.19 g of potassium carbonate and 0.068 ml of 2-iodopropane were added, followed by stirring at 70° C. for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=1:1) to give 0.03 g of 1-[2-(4-fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-[4-(2-isopropoxynaphthalen-1-yl)butyl]piperazine as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:49]=[CH:48][C:34]([O:35][CH2:36][C:37]([NH:40]C(=O)OC(C)(C)C)([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=O>>[NH2:40][C:37]([CH3:39])([CH3:38])[CH2:36][O:35][C:34]1[CH:48]=[CH:49][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)cc2)c1
Yield: 36.5 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (33 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]([O-:12])=O.[Na+].Cl.[Cl:15][C:16]1[CH:32]=[CH:31][C:19](/[CH:20]=[CH:21]/[S:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[ClH:15].[Cl:15][C:16]1[CH:17]=[CH:18][C:19](/[CH:20]=[CH:21]/[S:22]([N:25]2[CH2:30][CH2:29][N:28]([C:10]([C:2]3[S:3][C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:9]=4[N:1]=3)=[O:12])[CH2:27][CH2:26]2)(=[O:23])=[O:24])=[CH:31][CH:32]=1
Reactant: O=S(=O)(/C=C/c1ccc(Cl)cc1)N1CCNCC1
Reactant: O=C([O-])c1nc2ccncc2s1
Agent: Cl
Agent: [Na+]
Product: O=C(c1nc2ccncc2s1)N1CCN(S(=O)(=O)/C=C/c2ccc(Cl)cc2)CC1

Procedure:
In a similar manner to Example 4 except for the use of sodium thiazolo[5,4-c]pyridine-2-carboxylate and 1-[(E)-4-chlorostyrylsulfonyl)piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (1.47 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (218 mg) in anhydrous DMF (8 ml), and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.37 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for another 1 hour. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane to obtain N-(4-iodophenyl)-N-methylpyrimidin-2-amine (1.38 g). NMR (H1, CDCl3): δ 3.49(3H, s), 6.58 (1H, t, J=4.6 Hz), 7.07-7.09 (2H, m), 7.67-7.69 (2H, m), 8.32 (2H, d, J=4.6 Hz)