Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[CH:19][CH:18]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:28][C:26]1[S:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24][N:25]=1)=[O:12])(=[O:3])=[O:4]
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)O)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 20 ml scintillation vial was added 5-(aminosulfonyl)-2,3-dichlorobenzoic acid (40 mg, 0.148mmol) and commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (28.9 mg, 0.148 mmol). To this was added EDC (28 mg, 0.148 mmol) and HOAt (20 mg, 0.148 mmol) followed by 3 ml DCM. The reaction mixture was stirred with a Teflon covered magnetic stir-bar at room temperature for overnight. The product was collected by vacuum filtration and air dried, yielding 5-(aminosulfonyl)-2,3-dichloro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide (31 mg, 47%) as light tan solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[N:4]=1.C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:9]1[N:6]2[N:7]=[CH:8][C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][C:5]2=[N:11][CH:10]=1
Reactant: FC(F)(F)c1cnn2ccnc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cnn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of 3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.2211 g, 1.18 mmol) in acetic acid (6 ml) was added sodium acetate (0.1470 g, 1.79 mmol), then bromine (90.8 μl, 1.76 mmol). The solution was stirred at room temperature for 6 h, then partitioned between saturated aqueous NaHCO3 (100 ml) and ethyl acetate (100 ml). The aqueous layer (pH 9) was further extracted with ethyl acetate (100 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane) to afford 0.2073 g (66%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 8.30 (1H, s), 8.83 (1H, s).
Reaction SMILES: [CH3:1]C(C)=O.[CH3:5]/[CH:6]=[C:7]1\[C:8]2[S:12][CH:11]=[C:10]([C:13]([NH:15][CH:16]([C:78]([OH:81])([CH3:80])[CH3:79])[C:17]3[S:21][CH:20]=[C:19]([C:22]([NH:24][CH:25]([CH:75]([OH:77])[CH3:76])[C:26]4[S:30][CH:29]=[C:28]([C:31]5[N:36]=[C:35]([C:37]6[S:41][CH:40]=[C:39]([C:42]7[S:46][CH:45]=[C:44]([C:47]([NH:49]/[C:50](/[C:53]([NH:55][CH2:56][CH:57]([OH:59])[CH3:58])=[O:54])=[CH:51]/[CH3:52])=[O:48])[N:43]=7)[N:38]=6)[CH:34]=[CH:33][C:32]=5[C:60]5[S:64][CH:63]=[C:62]([C:65]([NH:67][CH:68]([CH:72]([OH:74])[CH3:73])[C:69]([NH:71]\1)=[O:70])=[O:66])[N:61]=5)[N:27]=4)=[O:23])[N:18]=3)=[O:14])[N:9]=2>CO>[CH3:5]/[CH:6]=[C:7]1\[C:8]2[S:12][CH:11]=[C:10]([C:13]([NH:15][CH:16]([C:78]([OH:81])([CH3:80])[CH3:79])[C:17]3[S:21][CH:20]=[C:19]([C:22]([NH:24][CH:25]([CH:75]([O:77][CH3:1])[CH3:76])[C:26]4[S:30][CH:29]=[C:28]([C:31]5[N:36]=[C:35]([C:37]6[S:41][CH:40]=[C:39]([C:42]7[S:46][CH:45]=[C:44]([C:47]([NH:49]/[C:50](/[C:53]([NH:55][CH2:56][CH:57]([OH:59])[CH3:58])=[O:54])=[CH:51]/[CH3:52])=[O:48])[N:43]=7)[N:38]=6)[CH:34]=[CH:33][C:32]=5[C:60]5[S:64][CH:63]=[C:62]([C:65]([NH:67][CH:68]([CH:72]([OH:74])[CH3:73])[C:69]([NH:71]\1)=[O:70])=[O:66])[N:61]=5)[N:27]=4)=[O:23])[N:18]=3)=[O:14])[N:9]=2
Reactant: C/C=C(/NC(=O)c1csc(-c2csc(-c3ccc4c(n3)-c3csc(n3)C(C(C)O)NC(=O)c3csc(n3)C(C(C)(C)O)NC(=O)c3csc(n3)/C(=C\C)NC(=O)C(C(C)O)NC(=O)c3csc-4n3)n2)n1)C(=O)NCC(C)O
Reactant: CC(C)=O
Solvent: CO
Product: C/C=C(/NC(=O)c1csc(-c2csc(-c3ccc4c(n3)-c3csc(n3)C(C(C)OC)NC(=O)c3csc(n3)C(C(C)(C)O)NC(=O)c3csc(n3)/C(=C\C)NC(=O)C(C(C)O)NC(=O)c3csc-4n3)n2)n1)C(=O)NCC(C)O

Procedure:
Thus cultivated, 10 liters of the culture was controlled to have a pH of 7.0, to which was added 40 liters of acetone. The resulting extract was well stirred, and filtered, and acetone was removed from it under reduced pressure. 12 liters of ethyl acetate was added to it, and well stirred, and the ethyl acetate layer was concentrated under reduced pressure. Then, ethyl acetate was removed from it. The residue was subjected to column chromatography with Sephadex LH-20 (by Amersham Pharmacia Biotec, φ30 ×350 mm), and developed with N-hexane/dichloromethane/methanol (4/5/1) to obtain an active fraction. The active fraction was subjected to silica gel thin-layer chromatography (with Kieselgel 60F254, 20 mm×20 mm, by Merck), developed with chloroformlmethanol (15/1), and the active fraction was scraped out. The active fraction was then subjected to ODS column chromatography (φ20×250 mm, Develosilpack, by Nomura Chemical), and an active substance to give a peak was fractionated with an elution solvent of aqueous 70% methanol solution, at a flow rate of 9.0 ml/min and a detection wavelength of 210 nm. From it, the compounds of the invention, QN3323-A (5.0 mg) and QN3323-B (1.5 mg) were isolated. Similarly, known compounds, thiocillin I (11 mg) and thiocillin II (5.3 mg) were isolated.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.CN(C)C=O.[H-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[NH:6]1[CH:7]=[CH:8][N:9]=[C:5]1[CH2:4][NH:3][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ncc[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.34 g of 2-aminomethylimidazole dihydrochloride was added to 20 ml of N,N-dimethylformamide in a nitrogen atmosphere. Under ice-cooling, 0.40 g of sodium hydride (60% oily) was added thereto and the resulting mixture was subjected to ultrasonication for 30 minutes. To the reaction mixture were added 20 ml of pyridine and 10 ml of acetic anhydride and the obtained mixture was stirred at room temperature for 2 days. After concentrating under reduced pressure, the residue was distributed into water and ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure to thereby give 0.24 g of the title compound as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([N:31]=[C:32]=[S:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[S:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(=O)N(c2ccc(NC(=S)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Yield: 42 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190 mg, 0.6 mmol) obtained in Example 1, (3), phenyl isothiocyanate (243 mg, 1.8 mmol), and tetrahydrofuran (76 mL) were mixed, and the mixture was refluxed by heating for 24 hours. After the mixture was left to cool to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform=1/50) to obtain the title compound (114 mg, yield 42%) as slightly yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([S:27][CH2:28][C:29]#[CH:30])[CH3:26]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:30]#[C:29][CH2:28][S:27][CH2:25][CH3:26])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CCSCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
A mixture of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 5 (1.5 g), propargyl ethyl sulfide (1.04 g, 10.4 mmol), copper iodide (0.125 g), and dichlorobis(triphenylphosphine)-palladium(II) (0.462 g) in diethylamine are stirred at room temperature overnight. The reaction mixture is then concentrated in vacuo, and the residue is suspended in water (100 mL) and extracted with four 50-mL portions of EtOAc. The combined organic layers are then dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (elution with 5-10%MeOH/CH2Cl2) yielded the title compound as a solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][O:24]C(=O)C)[CH:16]=2)=[C:7]([NH:28][C:29]([NH:31][C:32]2[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=2[CH:41]([CH3:43])[CH3:42])=[O:30])[C:6]1=[O:44])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[CH:16]=2)=[C:7]([NH:28][C:29]([NH:31][C:32]2[C:37]([CH:38]([CH3:39])[CH3:40])=[CH:36][CH:35]=[CH:34][C:33]=2[CH:41]([CH3:43])[CH3:42])=[O:30])[C:6]1=[O:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCOC(C)=O)c2)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCO)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To a solution of N-[1-butyl-4-{3-(2-acetoxyethoxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (196 mg, 0.33 mmol) in methanol (10 ml) was added potassium carbonate (11 mg), and the mixture was stirred at room temperature for 4 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and crystallized from ether/hexane to give the title compound (145 mg, 0.26 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]2[CH:22]=[CH:21][O:20][C:19]=2[CH3:23])=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:22]=[CH:21][O:20][C:19]=3[CH3:23])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Cc1occc1COc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1occc1COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
A mixture of (4-fluoro-phenyl)-boronic acid (300 mg, 2.1 mmoles), 3-(4-iodophenoxymethyl)-2-methyl-furan (123) (500 mg, 1.6 mmoles) and potassium acetate (0.6 g) in N,N-dimethylformamide (70 mL) was degassed, treated with [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (90 mg) and the mixture was agitated at 95° C. for 12 hours under an argon atmosphere. The mixture was concentrated in vacuo, partitioned between water (100 ml) and diethyl ether (200 ml). The aqueous phase was re-extracted with diethyl ether, and the combined etheral phases were dried and evaporated. The residue was purified by flash chromatography, using diethyl ether as eluent, to afford compound 124 (200 mg) as a solid. This material was used directly.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:25]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(Br)cc4C3)c(F)cc2c1=O
Yield: 35.5 %

Procedure:
142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH2:30][CH3:31])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:27]1[C:28]([CH2:30][CH3:31])=[CH:29][C:25]([O:24][C:14]2[C:15]([Cl:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11])[CH3:8]
Reactant: CCc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
Potassium carbonate (0.46 g, 3.3 mmol) and ethyl isocyanate (0.21 g, 3.0 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-ethylpyrazole (0.98 g, 3.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-ethylpyrazole-1-carboxamide (0.79 g, yield: 66.5%). mp: 86-89° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.19 (t, J=7.3 Hz, 3H), 1.27 (t, J=7.5 Hz, 3H), 3.06 (q, J=7.5 Hz, 2H), 3.34 (dq, J=6.1 and 7.3 Hz, 2H), 5.75 (s, 1H), 6.60-6.85 (m, 1H), 7.68 (s, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O)(=O)C.[OH-].[Na+]>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: C=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(CCc2ccncc2)CC1
Temperature: 160 °C
Yield: 86 %

Procedure:
In a tube, 2 ml (19 mM) of 4-vinylpyridine, 3.16 ml (28.5 mM) of N-methylpiperazine, and 200 μl of acetic acid are mixed in 12 ml of ethanol. The tube is closed and heated for 10 minutes at 160° C. in a microwave oven. After cooling, 20 ml of 0.5N sodium hydroxide are added slowly and the mixture is extracted with dichloromethane. The separated organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The product sought after is thus obtained as a yellow oil (yield=86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].Br[C:37]1[CH:42]=[CH:41][N:40]=[N:39][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:37]2[CH:42]=[CH:41][N:40]=[N:39][CH:38]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20]
Reactant: Brc1ccnnc1
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: CC(c1ccc(-c2ccnnc2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with 4-bromopyridazine [CAS Reg. No. 115514-66-4]. MS (m/e)=464.1 [M+H+].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C@H:14]3[CH2:15][N:16](CC4C=CC=CC=4)[CH2:17][C@@H:13]3[C:12]=2[CH:32]=1>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C@H:14]3[CH2:15][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:17][C@@H:13]3[C:12]=2[CH:32]=1
Reactant: Clc1ccc2c(c1)[C@H]1CN(Cc3ccccc3)C[C@@H]1c1ccccc1O2
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1

Procedure:
Ethyl chloroformate (5 ml) was added to a solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-benzyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (470 mg, 1.3 mmol) in toluene (30 ml). The reaction mixture was heated to reflux overnight under inert nitrogen atmosphere to give complete conversion. The resulting dark reaction mixture was concentrated under vacuum to give crude title compound as a black oil. MS: M+1=344 found.
Reaction SMILES: [CH3:1][NH:2][NH2:3].CN([CH:7]=[C:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=O)C>>[CH3:1][N:2]1[C:9]2[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][C:13](=[O:14])[C:8]=2[CH:7]=[N:3]1
Reactant: CN(C)C=C1C(=O)CC(C)(C)CC1=O
Reactant: CNN
Product: Cn1ncc2c1CC(C)(C)CC2=O

Procedure:
Prepared analogously to Example 1 starting from methylhydrazine and 2-(dimethylaminomethylene)-5,5-dimethyl-cyclohexane-1,3-dione.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O>[CH:2]([S:4][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])([CH3:3])[CH3:1]
Reactant: CC(C)S
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(SC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (3.30 mL), potassium carbonate (6.60 g) and DMF (40 mL), 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction liquid was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene (6.60 g) as a yellow oil.
Reaction SMILES: O.Cl.C(OC([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:21][C:22]2[S:26][C:25]([Cl:27])=[N:24][C:23]=2[Cl:28])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]1)=O)(C)(C)C>C1COCC1>[CH3:19][CH:18]([CH3:20])[CH2:17][N:16]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][C:23]=1[Cl:28])[CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1
Reactant: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Reaction time: 0.67 h
Yield: 94.8 %

Procedure:
To a mixture of water (850 ml) and concentrated hydrochloric acid (240 ml) is added a solution of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester (304.5 g, 0.72 mol) in THF (600 ml) dropwise at 65° C. The addition and reaction are complete in 40 minutes. THF is then stripped under vacuum; residual aqueous layer is extracted with 2 L MTBE (to remove remaining (2,4-dichloro-thiazol-5-yl)-methanol). Neutralized by addition of NaOH (30%, 200 ml) and extracted twice with MTBE (1.5 L). Combined organic layers are washed with brine (3 L) then clarified (to remove insoluble). The organic layer is then concentrated under vacuum to afford 220 g of N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine as a pink powder. Yield 95% (HPLC=99% area). Mass spectrum (ion spray): m/z=322 (M+1); 1H NMR (400 MHz, CDCl3): δ=3.73 (2H, s), 3.17 (2H, m), 2.56 (3H, m). 2.31 (2H, d), 2.17 (1H, s, NH), 1.76 (2H, m), 1.68 (1H, m), 1.46 (2H, m), 0.92 (6H, d); 13C NMR (100 MHz, CDCl3): δ=20.6, 27.09, 28.88, 46.39, 47.20, 58.10, 58.52, 131.88, 137.30, 150.13.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:10]3[S:11][C:12]4[C:18](=[O:19])[CH2:17][C:16]([CH3:21])([CH3:20])[CH2:15][C:13]=4[N:14]=3)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:21][C:16]1([CH3:20])[CH2:15][C:13]2[N:14]=[C:10]([N:6]3[C:5]4[CH:22]=[CH:23][C:2]([NH:1][S:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)(=[O:32])=[O:31])=[CH:3][C:4]=4[O:9][CH2:8][CH2:7]3)[S:11][C:12]=2[C:18](=[O:19])[CH2:17]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(=O)c2sc(N3CCOc4cc(N)ccc43)nc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(=O)c2sc(N3CCOc4cc(NS(=O)(=O)c5ccccc5)ccc43)nc2C1
Yield: 35 %

Procedure:
A mixture of Example 13 (46 mg, 0.14 mmol), benzenesulfonyl chloride (0.023 mL, 0.182 mmol) and pyridine (0.022 mL, 0.28 mmol) in DCM (4 mL) was stirred at r.t. for 5 h. The reaction mixture was concentrated in vacuo. Purification by prep HPLC gave the title compound as an off-white solid (23 mg, 35%). δH (CDCl3) 1.14 (6H, s), 2.43 (2H, s), 2.74 (2H, s), 4.08-4.16 (2H, m), 4.26-4.33 (2H, m), 6.64 (1H, dd, J 8.9, 2.4 Hz), 6.80 (1H, d, J 2.4 Hz), 7.02 (1H, s), 7.42-7.61 (3H, m), 7.77-7.87 (3H, m). LCMS (ES+) 470.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23](=O)[C:24]#[CH:25])[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1.Cl.[OH:30][C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[NH:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][N:34]=[C:32]([C:31]([OH:30])([CH3:36])[CH3:35])[N:33]=3)[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Br)cs1
Temperature: 75 °C
Yield: 39.5 %

Procedure:
To a solution of 5-bromo-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(2-methyl-thiazol-4-ylmethoxy)-3H-pyrimidin-4-one of Step D (64 mg, 0.14 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (30 mg, 0.21 mmol) and potassium carbonate (60 mg, 0.42 mmol) and the slurry was heated at 75° C. for two hours and at ambient temperature for eighteen hours. The reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (30 mg, 39% yield). MS (M, M+2): 542, 544; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.16 (s, 3H), 2.21 (s, 3H), 2.76 (s, 3H), 5.59-5.67 (m, 2H), 7.26 (s, 1H), 7.54-7.58 (m, 2H), 7.92 (s, 1H), 8.14 (d, J=8.61, 1H), 8.78 (d, J=5.48, 1H).