Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.C([Li])CCC.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH:25]=[O:26]>CCOCC>[Br:21][C:22]1[CH:23]=[C:24]([CH:25]([C:7]2[CH:2]=[CH:3][C:4]([F:15])=[CH:5][C:6]=2[O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[OH:26])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccc(F)c(Br)c1)c1ccc(F)cc1OC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (5.0 g, 17 mmol) in ether (40 mL) at −78° C. was added a solution of n-butyllithium (6.9 mL, 2.5 M, 17 mmol). The reaction mixture was stirred for 15 minutes and was added a solution of 3-bromo-4-fluorobenzaldehyde (3.5 g, 17 mmol) in ether (10 mL). The reaction was stirred at −78° C. for 2 h, then quenched with sat. NH4Cl and warmed to room temperature. The ether layer was separated and dried over magnesium sulfate, filtered and concentrated to yield (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol as an amber oil (6.5 g, 92% yield). The product was used in the next step without further purification. To a solution of (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (29.5 g, 71.3 mmol) in dichloromethane (600 mL) was added MnO2 (30 g, 345 mmol). The reaction mixture was stirred for 6 h, then another 30 g of MnO2 was added and the reaction continued to stir overnight. The MnO2 addition was repeated twice and the reaction was stirred for a total of 48 h when the reaction was complete. The suspension was filtered through a pad of celite, the filtrate vas concentrated and the residue was purified by ISCO flash chromatography to yield (3-bromo-4-fluorophenyl)(4-fluoro-2-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone as a yellow oil (60% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (1H, d, J=6.59 Hz), 7.76 (1H, ddd, J=6.48, 4.50, 2.20 Hz), 7.38-7.44 (2H, m), 7.21-7.29 (2H, m), 6.09-5.83 (1H, t).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:21]([O:23]CC)=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:20][CH2:19]1.[OH-].[Na+].Cl>CCO>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)c(N)c2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 98 %

Procedure:
A solution of ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylate (125 mg, 0.341 mmol) and 1M aq. NaOH (0.5 mL) in EtOH (1.5 mL) was stirred at 50° C. for 1 h. After 2M HCl was added to the reaction mixture to pH<3, the crude product was extracted with EtOAc, washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The residue was dried in vacuo to yield 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylic acid (113 mg, 98%) as a yellow solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.O=[C:21]([CH3:32])[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:22]([C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[C:25]([OH:27])=[O:26])=[C:21]2[CH3:32])=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1C(=O)O
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(-c1ccccc1C(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 65 °C
Yield: 36 %

Procedure:
A solution of the hydrazine from Example 1, Step 5, (675 mg, 2.2 mmol), 2-(2-oxopropyl)benzoic acid (425 mg, 2.4 mmol) and acetic acid (314 μL, 5.5 mmol) in toluene was warmed to 65° C. for 1-- h after what the mixture was evaporated and acetic acid was removed with the help of heptane in vacuo. To a portion of the residue (100 mg) in dioxane (1 mL) was added 4M HCl in dioxane (2 mL) and the mixture was heated to 65° C. for 1 h. It was then cooled to 25° C. and poured on a mixture of ice water and ethyl acetate. The organic layer was washed with brine and dried with MgSO4. Removal of the solvents yielded a residue which was purified by flash chromatography. The remaining portion of the intermediate was processed identically and combined to give the product (357 mg). Anal. Calcd. for C24H20BrNO3 : C, 64.01; H, 4.48; N, 3.11. Found: C, 63.92; H, 4.51; N, 3.04.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:29]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[N:30]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:29]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([C:39]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Clc1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)cc1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.043 g, 0.10 mmol) and EtOH (4.0 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 2%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.023 g, 40%); 1H-NMR (500 MHz, DMSO-d6) 2.66 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2C6H4Cl), 3.66 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=1.9 Hz, 1H, pyrazole 4-H), 7.35 (d, J=7.6 Hz, 2H) and 8.14 (d, J=8.3 Hz, 2H) (3,5-C6H4CH2N and 2,6-C6H4CH2N), 7.40 (m, 4H, C6H4Cl), 7.49 (d, J=1.5 Hz, 1H, pyrazole-H), 7.86 (d, J=1.8 Hz, 1H, pyrazole-H), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.54 (br s, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Yield: 100 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (compound [6]; 108.6 g) obtained in Example 3 was dissolved in toluene (600 mL), and methanesulfonyl chloride (45.4 mL) was added, which was followed by stirring under ice-cooling. To this solution was added dropwise triethylamine (81.7 mL) under ice-cooling. After stirring for 1 hr, toluene (1 L) was added and 1N hydrochloric acid (1 L) was added for partitioning. The aqueous layer was extracted again with toluene (0.5 L). The combined organic layers were washed successively with water (1 L), saturated sodium hydrogencarbonate solution (1 L) and saturated brine (1 L), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (compound [7]; 150 g, yield 100%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-tert-butyl 4′-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate (20 mg, 0.03 mmol) in TFA/DCM (1 mL, 30%) was stirred at rt for 2 h. The completion of the reaction was monitored by anal. HPLC. The solvent was removed to obtain the crude which was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z): 581/583 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[CH:32][C:23]=4[F:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccccc12)N1CCc2c(F)cccc2C1
Yield: 27 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 10 (27.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.88 and 3.13 (2t, 2H), 3.64 and 4.24 (2t, 2H), 4.58 and 5.14 (2s, 2H), 6.68-7.33 (m, 5H), 7.65-7.77 (m, 1H), 7.94-8.10 (m, 2H), 8.15-8.20 (m, 1H), 8.57-8.67 (m, 2H); 19F (282 MHz, DMSO-d6) δ −112.0, −121.0; MS (ESI) m/z 402 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(Br)CC
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)Oc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
A mixture of 5.0 g (32 mmole) of 2-methyl-3-nitrophenol, 4.8 ml (ca. 32 mmole) of ethyl 2-bromobutanoate, and 4.5 g (32 mmole) of potassium carbonate in 50 ml of dimethylformamide was stirred for 18 hours at room temperature. The mixture was then poured over ice, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 8.0 g of the title compound as an analytically pure solid. Structure assignment was supported by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH2:19][C:20]2[N:21]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:22]=[C:23]([CH2:25][C:26]4([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]4)[N:24]=2)([OH:18])[CH2:13][CH2:12]3)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][N:61]=1>CO.C1(C)C=CC=CC=1.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>[F:66][C:63]1[CH:64]=[CH:65][C:60]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH2:19][C:20]2[N:21]([C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:22]=[C:23]([CH2:25][C:26]4([C:29]([F:31])([F:30])[F:32])[CH2:28][CH2:27]4)[N:24]=2)([OH:18])[CH2:13][CH2:12]3)=[N:61][CH:62]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3(O)Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
Reactant: Fc1ccc(Br)nc1
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: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1(Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2cc(-c3ccc(F)cn3)ccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (264 mg, 0.23 mmol) was added to a degassed solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol (1.61 g, 2.29 mmol), potassium carbonate (411 mg, 2.97 mmol), and 2-bromo-5-fluoropyridine (483 mg, 2.74 mmol) in methanol/toluene (5 mL/50 mL). The solution was stirred at 90° C. for 2 h. The solvent was removed in vacuo and the residue was redissolved in EtOAc (200 mL). The solution was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography eluting with 0-100% EtOAc/hexanes to give 5-(5-fluoropyridin-2-yl)-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]4)=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:24]([NH2:27])[CH2:25][CH3:26]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]4)=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:27][CH2:24][CH2:25][CH3:26])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc4ccccc4cc3o2)c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc3ccccc3cc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)naphth[2,3-d]oxazole (277 mg, 0.9 mmol) and propylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (250 mg, 80%). 1H NMR (DMSO) δ 9.37(t, 1H), 8.90(d, 1H), 8.38(s, 1H), 8.33(s, 1H), 8.26(dd, 1H), 8.11(m, 2H), 7.56(m, 1H), 7.11(d, 1H), 3.50(q, 2H), 1.76(m, 2H), 1.09(t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:17].[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O>CS(C)=O>[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:17])[CH2:40][CH2:39]1
Reactant: COCCN1CCNCC1
Reactant: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCCl
Solvent: CS(C)=O
Solvent: O
Product: COCCN1CCN(CCCc2sc(-c3ccccc3)nc2C(=O)Nc2ccccc2-c2nc3cccnc3s2)CC1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A solution of 5-(3-chloropropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (316 mg, 0.67 mmol) and 1-(2-methoxyethyl)-piperazine (964 mg, 6.7 mmol) in DMSO (12 mL) was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature and poured into H2O. The resulting solid was collected by filtration and rinsed with H2O. The crude product was purified by MPLC eluting with DCM/MeOH+1% TEA (0-10% gradient) to give the title compound (374 mg, 96% yield). MS Calcd for C32H34N6O2S2: 598.22. Found (M+H)+ m/z=599.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc(Oc2ccc3ccc(N)nc3n2)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(Oc2ccc3ccc(NC(=O)c4ccccc4)nc3n2)cc1
Temperature: 4 °C
Yield: 73.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (11 g), N,N'carbonyldiimidazole (16.2 g) and 2-amino-7-(4-methoxyphenoxy)-1,8-naphthyridine (26.7 g). The product produced by precipitation in water (30.8 g; m.p. approximately 110° C.) is dissolved in boiling acetonitrile (150 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×5 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-[7-(4-methoxyphenoxy)-1,8-naphthyridin-2-yl]benzamide (24.7 g) is produced, m.p. 171° C. 2-Amino-7-(4-methoxyphenoxy)-1,8-naphthyridine can be prepared in the following manner:
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20].[OH-].[K+].C1COCC1>O>[NH:1]([C:8]1[N:13]=[C:12]([N:19]([CH3:20])[CH3:18])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC#Cc1cc(Cl)nc(Nc2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#Cc1cc(N(C)C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
2-Anilino-4-chloro-6-(1-propynyl)pyrimidine (1.7 g) prepared in Example 2, 1.9 g of 54% aqueous solution of dimethylamine and 0.7 g of KOH were added to 20 ml of THF and the mixture was stirred at room temperature for 24 hours. The reaction liquid was poured in water and extracted with benzene. Then, the benzen layer was dried over Glauber's salt and concentrated, the residue was recrystallized from n-hexane-ethanol to afford 1.5 g of 2-anilino-4-dimethylamino-6-(1-propynyl)pyrimidine (yield: 85%). Melting point: 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=O)[CH3:13].Cl.[NH2:27][OH:28].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:27][OH:28])[CH3:13]
Reactant: CC(=O)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 509.8 %

Procedure:
To a mixture of 1.67 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone and 30 ml of pyridine was added 8.60 g of hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 8.81 g (yield, 99%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, nD25.0 1.5460.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1OC
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1OC

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methoxy-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[OH:17])=[CH:3][N:2]=1.[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1F)#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)#[N:19]
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 712, 60.6 mg, 0.25 mmol) in dimethylsulfoxide (2.5 mL) was added 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 109.2 mg, 0.25 mmol) followed by potassium carbonate (101.7 mg, 0.74 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was poured into water (125 mL), and extracted with ethyl acetate (3×25 mL). The combined organic extract was washed successively with aqueous sodium hydroxide solution (1M, 15 mL) and saturated aqueous sodium chloride solution (4×25 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The resulting residue was purified by column chromatography using a gradient of 25-40% v/v ethyl acetate in heptane to give the title compound as a white foam (59.7 mg, 36%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH3:35])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:34].[ClH:34].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH3:35])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21
Yield: 296.1 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide dihydrochloride (750 mg) was prepared by following General Procedure L starting from 4-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (800 mg) in 4M HCl in dioxane (5 mL).