Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[C:13]#[N:14])=[CH:8][N:7]=2)=[CH:2]1.Cl.C(N(CC)CC)C.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>C1COCC1.CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])=[CH:8][N:7]=2)=[CH:2]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C#N)c1ccc(-c2ccsc2)nc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccsc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To an ambient temperature solution of 214 mg,(l mmol) of material prepared in step A in 5 ml of THF was added dropwise 0.11 ml of a 10 M solution borane-methyl sulfide complex (1.1 mmol) in THF. The mixture was stirred at ambient temperature for 2 h. Then, 0.1 ml of a 10 M solution borane-methyl sulfide complex (1.0 mmol) in THF were added and the mixture stirred overnight. A saturated solution of hydrochloric acid in methanol (5 ml) was added, and stirred for 10 min. The solution was concentrated in vacuo. The crude was disolved in dichloromethane (5 ml) and cooled to 0° C., triethylamine 0.44 ml (3.2 mmol) was added, followed by isopropylsulfonyl chloride (0.14 ml, 1.2 mmol). The ice-bath was removed and the solution was stirred at ambient temperature for 2 h. The organic solution was washed with 1N hydrochloric acid, sodium bicarbonate saturated solution, brine, dried over Na2SO4 filtered and concentrated in vacuo. Chromatography (50 g of silica gel, 33% ethyl acetate/hexane) of the residue afforded 25 mg (7%) of the title compound. Field Desorption Mass Spectrum: M=324.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 102.5 %

Procedure:
Using 6-bromonicotinic acid (2 g) and 1-(2,4-dimethylphenyl)piperazine (1.9 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (3.8 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1.C(N(CC)CC)C>O.CCOCC>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: COc1ccc2c(c1)CCC(N)C2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CCc1ncnc(NC2CCc3cc(OC)ccc3C2)c1Cl

Procedure:
1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 1.5 g (8.5 mmol) of 2-amino-6-methoxytetralin and 2 ml of triethylamine were heated for 10 hours at 85° C. The mixture was subsequently diluted with water and ether, the phases were separated, and the organic phase was washed with water and saturated NaCl solution. After the mixture had been dried and concentrated, the residue was purified by column chromatography with petroleum ether/ethyl acetate (8:1). This gave 2.4 g (89% of theory) of colorless crystals (melting point 70-71° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C(O)(C)C>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:19]=[CH:18][N:17]=[C:16]2[O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
3-Aminophenol (338 mg, 3.09 mmol) was treated with cesium carbonate (2 g, 6.2 mmol) in anhydrous isopropanol (10 mL) and the mixture stirred at room temperature for 30 minutes. 4-(2-(4-chloro-6-methoxyquinazolin-7-yloxy)ethyl)morpholine from the previous step (1 g, 3.09 mmol) was added and the mixture stirred at 80° C. for 2h. Cesium carbonate was filtered off, washed with isopropanol and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol 9:1) to afford 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline (236 mg, 22%) as a browish solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.09 (t, 1H), 6.50-6.37 (m, 3H), 5.30 (bs, 2H), 4.34-4.30 (m, 2H), 3.91 (s, 3H), 3.60 (s, 4H), 2.82-2.70 (m, 2H) 2.59-2.42 (m, 4H); LC-MS (ESI) m/z 397 (M+H)+.
Reaction SMILES: N#N.[FH:3].[F-:4].[K+].[C:6]1([S:12]([F:15])([F:14])[F:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([S:12]([F:4])([F:3])([F:15])([F:14])[F:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [F-]
Reactant: F
Reactant: FS(F)(F)c1ccccc1
Agent: N#N
Agent: [K+]
Product: FS(F)(F)(F)(F)c1ccccc1
Temperature: -20 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A dried 125 mL fluoropolymer (FEP) vessel was flowed with N2 gas and charged with 48.0 g (2.40 mmol) of liquid anhydrous hydrogen fluoride which was cooled at −20° C. The vessel was set with a condenser (made of fluoropolymer) and a thermometer, and cooled in a bath of −20° C. A coolant (−15° C.) was flowed through the condenser. Into the vessel, 8.6 g (0.11 mol) of KF.HF was added. While the mixture was warmed to +15° C., 22.1 g (96.2 mmol) (purity 96 wt % and the other was phenylsulfur trifluoride) of phenylsulfur chlorotetrafluoride was added to the mixture over 1 hour through a syringe. The temperature of the reaction mixture was 3.4° C. and 13.6° C. at the starting point and completing point of the addition, respectively. After the addition, the reaction mixture was stirred at 15° C. for 18 h. After that, the reaction mixture was warmed to 25° C. and hydrogen fluoride was removed under atmospheric pressure. The residue was neutralized with about 15% aqueous KOH and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated by distilling the solvent at 70° C. under atmospheric pressure. The resulting residue was distilled under reduced pressure to give 14.4 g (yield 73%) of phenylsulfur pentafluoride (boiling point 57.5° C./35 mmHg). The purity of the product was determined to be 100% by GC analysis. The product was identified by spectral comparison with an authentic reference sample.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc(C=O)c3ccccc23)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1ccc(-c2ccc(O)c(F)c2)c2ccccc12
Temperature: 195 °C
Yield: 104.4 %

Procedure:
To a 35 ml flask was added 4-(3-fluoro-4-methoxyphenyl)-naphthalene-1-carbaldehyde (720 mg ˜80% pure, 2.05 mmol), and pyridine hydrochloride (3 g, 26 mmol). The mixture was warmed to 195° C. for 2 h, cooled slightly, and the remaining pyridine hydrochloride was dissolved in water (50 ml). The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous Na2SO4, passed through a silica plug and concentrated to afford 570 mg (99%) of product as an off-white foam. The material was carried on to the next step without further purification: 1H NMR (300 MHz, DMSO-d6) δ 7.16 (2H, m), 7.35 (1H, d, J=12.00 Hz), 7.60–7.80 (3H, m), 7.98 (2H, d, J=8.3 Hz) 8.22 (1H, d, J=7.4 Hz), 9.28 (1H, d, J=8.4), 10.24 (1H, s), 10.43 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:24][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 20 °C

Procedure:
A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 250 g (1.097 mol, 140.4 mL, 1.0 eq.) of 5-bromo-2,4-dichloropyrimidine (A1h) and 1127 g, (1250 mL) of ethyl acetate. The content is stirred at 20° C. and 283.5 g (2.194 mol, 382.0 mL, 2.0 eq.) of N,N-diisopropylethylamine is added. A solution of 102.8 g (1.207 mol, 119 mL, 1.1 eq.) of cyclopentylamine (A1g) dissolved in 1127 g, (1250 mL) of ethyl acetate is added over 60 min. An 18° C. to 36° C. exotherm is observed. The solution is warmed to 40° C. This temperature is maintained for at least 6 h or until all the starting material A1h, is consumed as determined by HPLC analysis. The resulting slurry is cooled to 25° C. and 500 g (500 mL) of water is added. The content is stirred for 15 min and the phases are allowed to separate. The bottom (aqueous) layer is removed and the organic layer is washed once more with 500 g (500 mL) of water. The sample is stirred for 15 min, and the phases are allowed to separate. The bottom (aqueous) layer is removed. The organic phase is concentrated (atmospheric pressure) to a volume of 1500 mL (batch temp=82° C.). 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=85° C.). Again, 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=96° C.). The sample is cooled to 50° C. and seeded. The cooling is continued to 4° C. and the temperature is maintained at 4° C. for 1 h. The solids are filtered and the filter cake is washed once with 137 g (200 mL) of cold (4° C.) heptane. The solids are dried at 50° C. for 16 h, to afford 259.0 g (88.0%, corrected) of Compound A1f as a white, crystalline solid, mp=95-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#N)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:12]S(O)(=O)=O.[CH3:17][OH:18]>O>[CH3:17][O:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(CC#N)cc1C
Reactant: CO
Solvent: O
Product: COC(=O)Cc1ccc(C)c(C)c1
Yield: 98 %

Procedure:
A mixture solution of 2-(3,4-dimethylphenyl)acetonitrile (2) (9.395 g, 64.7 mmol) in methanol was refluxed with H2SO4 3.5 ml (64.7 mmol) for 3 days. The mixture was cooled, diluted with H2O and concentrated in vacuo under sodium bicarbonate. The residue was separated H2O and CH2Cl2 and the H2O layer was extracted with CH2Cl2 several times. The combined organic layers were washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (1:10) as an eluant to give compound 4.
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C:5](OC)=O.[Na].ClC1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].Cl>O.O1CCOCC1>[Cl:20][C:18]1[N:19]=[C:5]([CH2:4][C:3]([OH:2])=[O:9])[C:13]([C:14]#[N:15])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(Cl)nc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(Cl)nc1CC(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of malonic acid dimethyl ester, sodium salt (8.067 g, 52.4 mmol), as prepared in the previous step, 2,6-dichloro-nicotinonitrile (4.53 g, 26.2 mmol), as prepared in Example 6b, and dioxane (40 mL) was stirred at 80° C. for 1 h. The resulting easily stirred reddish-brown opaque thin slurry was allowed to cool to rt, 6 M HCl (aq) (80 mL) was added, and the mixture was vigorously stirred at 65-70° C. for 5 h open to air. The resulting clear dark amber solution containing a small amount of dark material was allowed to cool to rt, diluted with water (80 mL), and extracted with DCM (3×100 mL). The organic layers were combined, dried (2×Na2SO4), and concentrated under reduced pressure at 60° C. to provide the crude title compound as a dark brown oil (6.2 g, quantitative yield). A NMR spectrum of the reaction following malonate addition indicated a ˜1:2 mixture of desired/undesired regioisomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[CH2:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of piperidine-4-carboxylic acid in a 1:1 mixture of H2O/dioxane (0.4 M), 5 eq of K2CO3 were added before dropwise introduction at 0° C. of 1.1 eq of benzyl chloroformate. The reaction was stirred at RT overnight. The reaction was first washed with Et2O. The aqueous phase was acidified to pH 2 with aqueous HCl (6N) before being extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the product (91%); MS (ES+) m/z 264 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([S:16][CH3:17])[CH:15]=2)=[CH:6][C:5]([N:18]=[CH:19][N:20](C)C)=[C:4]([C:23]#[N:24])[CH:3]=1.[CH:25](N)([CH3:27])[CH3:26].ClCCl.CO>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([S:16][CH3:17])[CH:15]=1)[N:18]=[CH:19][N:20]=[C:23]2[NH:24][CH:25]([CH3:27])[CH3:26]
Reactant: CSc1cncc(COc2cc(N=CN(C)C)c(C#N)cc2Br)c1
Reactant: CC(C)N
Solvent: CO
Solvent: ClCCl
Product: CSc1cncc(COc2cc3ncnc(NC(C)C)c3cc2Br)c1
Yield: 77 %

Procedure:
According to GWP 5, the reaction of N′-(4-bromo-2-cyano-5-{[5-(methylsulphanyl)-pyridin-3-yl]methoxy}phenyl)-N,N-dimethylformimidamide (540 mg, 1.33 mmol) with isopropylamine (0.14 mL, 1.6 mmol) and chromatography (silica gel, dichloro-methane/methanol: 0→30% methanol) gives the desired product in 77% yield (430 mg)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]1=2)=[O:4].[CH2:18]([N:20](CC)CC)[CH3:19].Cl.C(N)C>O1CCOCC1.O>[CH2:18]([NH:20][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]1=2)=[O:4])[CH3:19]
Reactant: CCN(CC)CC
Reactant: O=C(CCl)N1CCSc2ccc([N+](=O)[O-])cc21
Agent: CCN
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCNCC(=O)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a stirred solution of 2-chloro-1-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanone (855 mg, 3.14 mmol) in dioxane (15 mL) and triethylamine (0.881 mL, 6.27 mmol) was added ethanamine hydrochloride (1.278 g, 15.68 mmol) as a solution in water (7.50 mL). The resulting mixture was stirred vigorously at room temperature over the weekend. The mixture was then diluted with water and extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:9 (2M NH3 in methanol):ethyl acetate, giving the desired product (775 mg, 88%). 1H NMR (DMSO-d6) δ 8.37 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 3.97-3.90 (m, 2H), 3.52 (s, 2H), 3.37-3.33 (m, 2H), 2.58-2.50 (m, 2H), 2.07 (brs, 1H), 1.00 (t, J=7.0 Hz, 3H); ESI-MS (m/z, %): 282 (MH+, 100).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[C:19](O)([CH3:28])[CH2:20][NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23]>C(Cl)Cl>[F:7][C:19]([C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[F:10])([CH3:28])[CH2:20][NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23]
Reactant: COc1ccc(C(C)(O)CNS(=O)(=O)C(C)C)c(F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)(F)CNS(=O)(=O)C(C)C)c(F)c1
Yield: 64.1 %

Procedure:
A dry CH2Cl2 solution (10 mL) of (diethylamino)sulfur trifluoride (DAST) (0.419 mL, 3.17 mmol) was cooled to −78° C. while stirring under N2. A CH2Cl2 solution (5 mL) of propane-2-sulfonic acid [2-(2-fluoro-4-methoxyphenyl)-2-hydroxy-propyl]-amide (0.79 g, 2.64 mmol) was added dropwise via syringe and the reaction was immediately brought to 0° C. The reaction was quenched with water and diluted with diethyl ether. The organic layer was separated and washed with water and saturated NaCl solution, dried (MgSO4), filtered, and concentrated to a yellow oil. The crude residue was purified by silica gel chromatography, eluting with 30% ethyl acetate/hexanes, to provide the final title compound, propane-2-sulfonic acid [2-fluoro-2-(2-fluoro-4-methoxy-phenyl)-propyl]-amide, (0.52 g, 64%) as a light yellow oil.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36]Cl)[CH:31]=1>CN(C)C=O>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:31]=1
Reactant: ClCc1cc(Cl)ccn1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cc(Cl)ccn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.1 mg, 12%) as a trifluoro acetic acid salt.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:3]=1[NH2:4].[Br:14]N1C(=O)CCC1=O>CN(C=O)C>[Br:14][C:7]1[C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Nc1cc(OC(F)(F)F)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1cc(OC(F)(F)F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a mixture of 2-fluoro-5-(trifluoromethoxy)aniline (1 g, 5 mmol) dissolved in DMF (2 mL) was slowly added a solution of N-bromosuccinimide (1.1 g, 6.2 mmol) dissolved in DMF (2 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluted 0-10% ethyl acetate:hexanes) to produce the title intermediate as a red oil (818 mg, 58% yield). (m/z): [M+H]+ calcd for C7H4BrF4NO 273.94, 275.94. found 276.1.
Reaction SMILES: [C:1]([C:6]1[C:7](=O)[C:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36]CC.[C:39]1(C)C=CC=CC=1>>[CH2:31]([C:7]1[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:9]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C1=C(c2ccc(F)cc2)C(c2ccc(F)cc2)=C(C(=O)OCC)C1=O
Reactant: C#CCCCCCC
Product: CCCCCCc1cc(C(=O)OCC)c(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1C(=O)OCC
Reaction time: 0.08 h

Procedure:
A 250 mL 3 neck round-bottom flask equipped with a condenser was flushed with nitrogen and then loaded with 2,5-dicarboethoxy-3,4-di(4-fluorophenyl)-cyclopentadienone (10 g, 24.3 mmol) and toluene (35 mL) and stirred for 5 min to give a deep orange solution. 1-Octyne (2.67 g, 24.3 mmol) was then added via a syringe to the solution. The reaction was then heated and refluxed for 3 days. The solvent was removed by rotary evaporation and the orange oily liquid was passed through a silica gel column (chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:11][CH2:12][C@H:13]2[CH2:15][O:14]2)=[C:6](CC=O)[CH:7]=1.C1C=C(Cl)C=[C:19]([C:24]([O:26]O)=[O:25])C=1>C(Cl)(Cl)Cl>[C:24]([O:26][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:16])[C:5]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)(=[O:25])[CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=CCc1cc(Br)cc(F)c1OC[C@H]1CO1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(Br)cc(F)c1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 7 using 1-(5-bromo-3-fluoro-2-[(2R)-oxiran-2-ylmethoxyphenyl)ethanone (19.5 g, 67 mmol), CHCl3 and m-CPBA (77%, 60.5 g, 27 mmol). The mixture was heated at reflux for 24 h. The crude product was further used (Preparation 25). MS m/z (rel. intensity, 70 eV) 306 (M+, 4), 304 (M+, 4) 262 (bp), 69 (69), 57 (99).