Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][C:5]([CH3:45])([CH3:44])[CH:6]([NH:36]C(OC(C)(C)C)=O)[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][N+:15]([O-:19])=[CH:14][C:13]=1[Cl:20])=[O:8])(=[O:3])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[C:1]([S:4][C:5]([CH3:45])([CH3:44])[CH:6]([NH2:36])[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:13]([Cl:20])=[CH:14][N+:15]([O-:19])=[CH:16][C:17]=1[Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)SC(C)(C)C(N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
4-((2S)-2-(3-(acetylthio)-2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (118 mg, 0.170 mmol) was dissolved in DCM (1 ml). HCl 4N in dioxane (425 μl, 1.70 mmol) was added and the mixture stirred for 30 minutes at RT. The reaction mixture was diluted with DCM. The organic layer was washed with NaHCO3 sat. sol. (2×) and brine, dried over Na2SO4 and evaporated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give 101 mg of the desired compound (quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH:11](Br)[CH2:12][CH2:13][CH3:14])[CH:5]=1.[C:18]([NH2:21])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:21]=[C:18]([CH3:19])[O:20][C:11]=2[CH2:12][CH2:13][CH3:14])[CH:5]=1
Reactant: CC(N)=O
Reactant: CCCC(Br)C(=O)c1cccc(C(=O)OC)c1
Product: CCCc1oc(C)nc1-c1cccc(C(=O)OC)c1
Yield: 36.1 %

Procedure:
A sample of rac-3-(2-bromo-pentanoyl)-benzoic acid methyl ester (1.50 g) and acetamide (0.89 g) were heated together to 130° C. for 15 h. The mixture was partitioned between AcOEt and brine, the organic layer was dried and evaporated and the residual oil was chromatographed on silica gel using AcOEt/hexane (1:3) as eluent to give 3-(2-methyl-5-propyl-oxazol-4-yl)-benzoic acid methyl ester (0.47 g) as a light-yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:3][CH2:4]4)=[O:10])=[C:12]([CH3:32])[NH:13][C:14]=23)[CH2:30][CH2:31]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f5) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.Cl[CH2:13][CH:14](Cl)[CH2:15][CH3:16].C(O)CCC>>[CH2:13]([P:6]1(=[O:5])[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCC(Cl)CCl
Reactant: CC1=CCP(OCCCCl)C1
Solvent: CCCCO
Product: CCCCP1(=O)CC=C(C)C1
Yield: 65.3 %

Procedure:
To a solution of 26.4 g. (0.137 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene in 57 ml. of 1,2-dichlorobutane was added 30.4 g. (0.411 mole) of n-butanol. The mixture was heated under reflux for 4 hours and then the solvent was removed by evaporation. The residue was distilled under reduced pressure to obtain 15.4 g. (65.3% yield) of 1-butyl-3-methyl-3-phospholene-1-oxide in the form of a liquid having a boiling point of 106° - 116° C at 0.2 mm. of mercury.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH3:7].[CH3:8][N:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl[Sn](Cl)(Cl)Cl.Cl>C(Cl)Cl>[CH3:8][N:9]1[C:13]([C:14]([C:6]2[N:2]([CH3:1])[C:3]([CH3:7])=[CH:4][CH:5]=2)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: Cc1cccn1C
Reactant: Cc1cc(CC(=O)OC(C)(C)C)n(C)c1C(=O)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CC(=O)OC(C)(C)C)n(C)c1C(=O)c1ccc(C)n1C
Temperature: 0 °C
Yield: 50 %

Procedure:
Ten mmole (0.95 g) of 1,2-dimethyl-pyrrole and an equivalent amount of t-butyl 1,4-dimethyl-5-chlorocarbonyl-2-pyrrole acetate were dissolved in 10 ml of methylene chloride and stirred at 0° C. under nitrogen atmosphere. Three grams (12 mmole) of SnCl4 in 10 ml methylene chloride was added dropwise and the resulting mixture was stirred at room temperature for three hours followed by pouring into 25 ml 6 N HCl at 0° C. with vigorous stirring. The resulting suspension was extracted three times with 20 ml portions of methylene chloride. The crude extract was column chromatographed and crystallized from ether/hexane to give 1.6 g (50%) of t-butyl 1,4-dimethyl-5-(1,5-dimethylpyrrol-2-oyl)pyrrole-2-acetate.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[C:13]([Cl:30])[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:30][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:8][C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]3)=[CH:15][C:14]=12
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C#CC1CCCN(C(=O)OC(C)(C)C)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc3c(Cl)ccnc3[nH]2)C1
Temperature: 65 °C

Procedure:
To a solution of product of Example 1E (250 mg, 0.573 mmol) in toluene (5 mL) was added potassium tert-butoxide (161 mg, 1.434 mmol) followed by 18-crown-6 (15 mg, 0.057 mmol) and the mixture was heated at 65° C. for 12 hours. The mixture was dissolved in ethyl acetate (25 mL), washed with water and brine, and dried over anhydrous sodium sulfate. Filtration followed by concentration of the filtrate afforded crude product which was purified by column chromatography (silica gel, 40% ethyl acetate in hexane) to afford the title compound. LCMS: 336.0 (M+H-Boc)+.
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].[H-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[C:15]([O:14][C:12]([N:11]1[CH:10]([CH3:19])[C:9](=[O:8])[CH:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:22]1[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(/C=C/C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1C(=O)C(C(=O)OCc2ccccc2)C(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5.59 g (20.0 mmol) of (R)—N-tert-butoxycarbonylalanine benzyl ester and 5.92 g (20.0 mmol) of dibenzyl fumarate in 60 mL of toluene was added 1.60 g (40 mmol) of 60% NaH in mineral oil. The reaction was stirred at ambient temperature under N2 for 24 h, then diluted with 300 mL of diethyl ether. The solution was extracted with 1M HCl(aq.)(1×50 mL), saturated NaHCO3(aq) (3×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated to provide the titled compound as an oil.
Reaction SMILES: N[C@@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=O.[CH:13]1([NH:20][C:21]([NH2:23])=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:20][C:21]2[S:22][C@H:2]([CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:3](=[O:5])[N:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)S[C@@H]1CC1CCCCC1

Procedure:
Synthesis was performed from (2S)-2-amino-3-cyclohexylpropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[O:30][N:29]=1>O=P(Cl)(Cl)Cl>[Cl:8][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:31]2[O:30][N:29]=[C:28]([CH3:27])[CH:32]=2)[CH:7]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: COC(=O)c1cc(-c2ccc(-c3ccc(OC)cc3)cc2)c(Cl)cc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(-c3ccc(OC)cc3)cc2)c(Cl)cc1NC(=O)Cc1cc(C)no1
Temperature: 80 °C
Yield: 30.5 %

Procedure:
A stirred suspension of methyl 4-amino-6-chloro-4″-methoxy-[1,1′:4′,1″-terphenyl]-3-carboxylate (Intermediate 49) (520 mg, 1.41 mmol)) and 2-(3-methylisoxazol-5-yl) acetic acid (Aldrich, 219 mg, 1.56 mmol) in POCl3 (6 mL) was heated at 80° C. for 2 h and then cooled to room temperature. The solution was concentrated under reduced pressure. The crude material was taken up with ethyl acetate and saturated NaHCO3, the organic phase was washed with water and dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified on silica gel column chromatography using cyclohexane to cyclohexane/ethyl acetate 75:25 as eluant to give the title compound methyl 6-chloro-4″-methoxy-4-(2-(3-methylisoxazol-5-yl)acetamido)-[1,1′:4′,1″-terphenyl]-3-carboxylate (210 mg, 0.43 mmol, 30.4%). LCMS: (M+H)+=491; Rt=1.37 min.
Reaction SMILES: Br.[Cl:2][C:3]1[N:8]=[N:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[C:16]([NH:10][CH2:9][C:6]2[N:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCc1ccc(Cl)nn1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1ccc(Cl)nn1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A solution of compound 10C (1.00 g, 4.46 mmol) and 4-bromo-2-fluoro-1-nitro-benzene (10D) (0.97 g, 4.40 mmol) in DMF (50 mL) with DIEA (1.30 g, 10 mmol) was stirred at 65° C. for two hours. The reaction was poured into ice/water and the solid precipitate was collected by filtration, washed with water and dried in vacuum over P2O5 overnight to give 1.5 g of desired product (10E). ESI-MS:m/z 342.9 (M+H)+.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]1([CH2:22][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:26]1([C:24]2([CH2:23][CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:25][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCc1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=CCC(CCc2ccccc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of 3-phenylpropiophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 130°-130.55,° C.). 1H NMR (CDCl3) δ 2.2-2.4 (m, 2 H), 2.4-2.6 (m, 1 H), 2.6-2.8 (m, 1 H), 2.9 (d, 1 H), 3.0 (d, 1 H), 3.3 (d, 1 H), 3.4 (d, 1 H), 7.0-7.5 (m, 15 H).
Reaction SMILES: O=O.[CH3:3][C:4]([CH3:16])=[C:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].C(N(CC)CC)C>O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:5]([CH:4]([CH3:16])[CH3:3])[C:6]([OH:8])=[O:7])=[CH:14][CH:13]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(F)cc1
Agent: O=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
In a glove box (argon-atmosphere, O2 -content<1 ppm) a 10 ml measuring flask was charged with 16.9 mg (0.013 mmol) of ((S)-MeOBIPHEP-TS-Na)Ru(OCOF3)2 and filled to the graduation mark with 10 ml of degassed water. The suspension was stirred with a magnetic stirring bar for 15 min at room temperature A clear yellow solution formed. In the glove box a 30 ml stainless steel autoclave fitted with a magnetic stirring bar was charged with 0.5 g (2.57 mmol) of 3-methyl-2-(p-fluorophenyl)crotonic acid, 7.5 ml of degassed water and 0.26 g (2.57 mmol) of degassed triethylamine. To this suspension 2.0 ml of the above catalyst solution was added and the autoclave was then sealed, pressurized with 6 bar of argon and removed from the glove box. The autoclave was connected to a hydrogenation line, which was thoroughly flushed with hydrogen. The argon in the autoclave was replaced by 60 bar of hydrogen and the hydrogenation was carried out by stirring at 20° and 60 bar. After a reaction time of 21 h the autoclave was vented. The light yellow reaction mixture was transferred to a 50 ml separatory funnel, acidified at 20-25° by adding 2.7 ml of 1N aqueous hydrochloric acid and extracted with ether. The combined ether extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness by rotary evaporation. Distillation of the reddish residue at 160° and 0.1 mbar afforded 0.48 g of (R)-2-(4-fluorophenyl)-3-methylbutyric acid as a colorless oil, which solidified on standing at room temperature; ee 84% (determined by GC on a chiral permethylated β-cyclodextrin column); purity>99 GC-area %.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.Cl[CH2:30][C:31]1[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[O:33][N:32]=1>C(O)(CC)(C)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:30][C:31]4[CH2:35][CH:34]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=5)[O:33][N:32]=4)[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: FC(F)(F)c1ccc(C2CC(CCl)=NO2)cc1
Solvent: CCC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CC4=NOC(c5ccc(C(F)(F)F)cc5)C4)CC3)ccc2s1
Temperature: 95 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To a stirred mixture of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (30 mg, 0.08 mmol) in tert-amylalcohol (5 mL) was added triethylamine (40 μL, 0.30 mmol), followed by 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole (20 mg, 0.08 mmol). The resulting mixture was stirred at 95° C. for 12 hours, concentrated under reduced pressure, and purified by preparative chromatograph (1:19 MeOH:CH2Cl2) to afford (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol (10 mg, M+1=535.1).
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][C:7](=[O:33])[CH2:8][NH:9][C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.CCN(CC)CC.[C:47]1([CH3:56])[C:48]([C:53](Cl)=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1>C(Cl)Cl>[C:47]1([CH3:56])[C:48]([C:53]([N:9]([CH2:8][C:7](=[O:33])[CH2:6][N:5]2[C:4](=[O:34])[C:3]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]3[C:1]2=[O:39])[C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N(CC(=O)CN1C(=O)c2ccccc2C1=O)[C@@H](c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To 2-[(R)-1-(3-phthalimido-2-oxo-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.88 g, 1.5 mMol) in CH2Cl2 (10 mL) was added Et3N (0.23 mL, 1.6 mMol) and toluoyl chloride (0.21 mL, 1.6 mMol). The reaction was stirred at RT for 18 h, concentrated under vacuum, taken up in EtOAc, washed with 1 N HCl, brine, dried (MgSO4) and evaporated to dryness. Purification by flash chromatography on silica gel (5-15% EtOAc/hexane) followed by trituration with pet, ether, filtration and drying under vacuum gave the title compound (0.89 g, 90%) as a white solid: MS (ES) m/e 661.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1nc2ccccc2o1
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To 3-[3-(piperidinomethyl)phenoxy]propylamine (0.28 g) and triethylamine (0.40 g) in ethanol (2 ml), at 0° C., under nitrogen, was added 2-chlorobenzoxazole (0.17 g). The reaction mixture was stirred for one hour at 0° C., stirred at room temperature for 16 hours, evaporated under reduced pressure and subjected to column chromatography on silica (chloroform:methanol 25:1) to give the title compound as an oil (0.35 g). This was treated with anhydrous oxalic acid (2.1 equivalents) in methanol (5 ml). Addition of diethyl ether gave 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]benzoxazole dioxalate (0.245 g), m.p. 172°-4° C. (recrystallised from isopropanol-ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][NH:30]2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.N#N>O1CCOCC1>[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][N:30]2[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: C1NC2CNC1C2
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: N#N
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CC5CC4CN5)ccc2OCC3)c(F)c1
Temperature: 120 °C
Reaction time: 0.1 h
Yield: 13 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol) Pd(OAc)2 (22.4 mg, 0.1 mmol), 2,5-Diaza-bicyclo[2.2.1]heptane (120 mg, 1.2 mmol), X-phos (47 mg, 0.10 mmol), tert-butoxide (200 mg, 20 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 6 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 310. (61.4 mg, yield=13%). 1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 1H), 7.89-7.88 (m, 1H), 7.72-7.99 (m, 1H), 7.41-7.39 (m, 1H), 7.28-7.16 (m, 2H), 6.39 (d, J=8.8 Hz, 1H), 4.41 (s, 1H), 4.16 (s, 2H), 3.46-3.41 (m, 6H), 2.74 (s, 2H), 1.06 (t, J=6.8 Hz, 2H). LC-MS (ESI): m/z=479 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9](N3C=NC=N3)[C:10]=2[N:11]=1.[CH2:18]([Mg]Br)[CH2:19][CH3:20]>O1CCCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9]([CH2:18][CH2:19][CH3:20])[C:10]=2[N:11]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: CCC[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCCc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of the intermediate of example 1 (0.47 g, 1.9 mmol) and iron tris(acetylacetonate) (34 mg, 0.095 mmol) in tetrahydrofuran (50 ml, hereinafter THF) and N-methylpyrrolidone (20 ml, hereinafter NMP) was added n-propylmagnesium bromide (1.9 ml, 3.8 mmol as a 2.0 M solution in THF). After stirring at room temperature for 40 minutes, the solution was diluted with THF and then quenched by adding a solution of 1N HCl. The mixture was extracted with ethyl acetate (150 ml), then dried over Na2SO4 and concentrated to afford 6-chloro-4-n-propyl-pyrido[3,2-d]pyrimidin-2-ylamine as a brown solid (0.32 g), which was used in the next step without purification. Its mass spectrum data was as follows: MS (m/z) 223.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[SH:19][CH2:20][CH2:21][OH:22]>CN(C=O)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([F:9])=[CH:8][C:2]=1[S:19][CH2:20][CH2:21][OH:22]
Reactant: OCCS
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])c(F)cc1SCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred suspension of 2,4-difluoro-5-nitroaniline (100 mg, 0.574 mmol) and potassium carbonate (159 mg, 1.149 mmol) in DMF (1 mL) was added 2-mercaptoethanol (0.081 mL, 1.149 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed (1:1 EtOAc:hexanes) to give the major product. Ethyl acetate was then used as the eluent to give a minor product. The major product was determined to be the desired product (112 mg, 84%). 1H NMR (DMSO-d6) δ 7.32 (d, J=3.5 Hz, 1H), 7.27 (d, J=10.7 Hz, 1H), 4.39 (s, 2H), 3.85-3.76 (m, 2H), 3.16-3.08 (m, 2H), 2.13-2.05 (m, 1H); ESI-MS (m/z, %): 233 (MH+, 100), 215 (14), 187 (100), 129 (65).