Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:10]#[N:11])=[C:5]([CH3:9])OCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][NH2:23].C(N(CC)CC)C>C(O)(=O)C.C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:9])=[N:23][N:22]([C:15]2[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[C:10]=1[NH2:11])=[O:12]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(C)=C(C#N)C(=O)OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Yield: 45.5 %

Procedure:
To a solution of 2-cyano-3-methyl-3-ethoxy-acrylic acid methyl ester (3.5 g, 0.021 mol) in glacial acetic acid (20 ml), 2,4,6-trichlorophenylhydrazine (4.38 g, 0.021 mol) was added with stirring, followed by triethylamine (2.0 ml, 1.46 g, 0.014 mol). The reaction was refluxed for 13 hours. Solvent removal in vacuo afforded a dark oil, which was dissolved in methylene chloride/water (100 ml of each). The separated organic phase was extracted with an equal volume of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to an orange oil (5.8 g). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:3 in volume) afforded the title compound (3.20 g) as a light-orange amorphous solid. Thin layer chromatography (TLC) Rf (silica gel plates, u.v. detection, ethyl acetate/hexane=1:3 in volume): 0.43.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:41]=[C:42]([S:46][CH2:47][CH2:48]Br)[CH:43]=[CH:44][CH:45]=1>O.C(OCC)(=O)C>[F:39][C:40]1[CH:41]=[C:42]([S:46][CH2:47][CH2:48][N:24]2[CH2:25][CH2:26][C:21]([CH2:20][CH2:19][CH2:18][N:15]3[C:16]4[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=4)[CH:12]=[CH:13][C:14]3=[O:32])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:23]2)[CH:43]=[CH:44][CH:45]=1
Reactant: Fc1cccc(SCCBr)c1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccc(F)c2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
To 2.5 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 74 mg of potassium carbonate and 69 mg of 1-(3-fluorophenyl)thio-2-bromoethane were added at room temperature, and stirred at 60° C. for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform : methanol=10:1], to give 95 mg of ethyl 1-(2-((3-fluorophenyl)thio)ethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1.[H-].[Na+].[CH:25]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1OC
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Reaction time: 1 h
Yield: 46.5 %

Procedure:
(2-Chloro-9H-purin-6-yl)-(3,4-dimethoxy-benzyl)-amine (799 mg, 2.5 mmol) was dissolved in dry DMF (10 mL). NaH (78 mg, 3.25 mmol) was added in portions and the resulting mixture was stirred for 1 h. Cyclopentyl bromide (633 mg, 4.25 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine (2×25 mL), dried over MgSO4, and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/Et2O) to afford the title compound as a white powder (451 mg, 46.5%). TLC (95:5 CH2Cl2/Et2O): RF=0.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27](O)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)[N:44]([OH:51])N=1.Cl.NO.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:44][OH:51])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)NO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 30 mg (0.07 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 35) in DMF (0.5 mL, c=0.14 M) was treated with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.03 g, 0.1 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.02 g, 0.1 mmol), hydroxylamine hydrochloride (0.006 ml, 0.1 mmol) and sodium hydrogencarbonate (0.02 g, 0.2 mmol) successively. After being stirred at 25° C. for 12 h, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were successively washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase HPLC (10 to 90% AcCN/H2O with 0.1% TFA in 45 min) to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(#N)C>[CH3:17][C:13]1[CH:12]=[C:11]([C:9](=[O:10])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(C(=O)Cc2ccnc(N)c2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1cccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
To a solution of 2-(2-amino-4-pyridyl)-1-(3-methylphenyl)ethanone (24.0 g, 0.106 mol) in acetonitrile (500 mL) was added benzoylchloride (27.0 mL, 0.233 mol) at 0° C. Triethylamine (35.6 mL, 0.256 mol) was added dropwise to the obtained mixture and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the precipitated solids were collected by filtration. The aqueous layer was extracted with ethyl acetate and the extract was washed with aqueous sodium hydrogen carbonate solution. The extract was dried and concentrated. The obtained residue and the solid were dissolved in a mixture of tetrahydrofuran (450 mL) and methanol (110 mL) and 1N aqueous sodium hydroxide solution (256 mL) was added. The reaction mixture was stirred for 2 hrs. and concentrated. The residue was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1), and the obtained oil was crystallized from ethyl ether to give the title compound (19.5 g, yield 56%).
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:25][CH:26]=1)#[N:2]
Reactant: ON=Cc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reaction time: 3 h
Yield: 28.5 %

Procedure:
1-[1-(4-Hydroxyiminomethylphenethyl)piperidin-4-yl]indoline (0.466 g) was dissolved in methylene chloride (6.5 ml) and triethylamine (0.35 ml) was added thereto. In a nitrogen atmosphere at −78° C., trifluoroacetic anhydride (0.14 ml) was added dropwise into the resultant solution followed by stirring for 3 hr. After adding a saturated aqueous solution of sodium bicarbonate, the resultant mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride/methanol system) to give the title compound (0.126 g) as a pale yellow oil (yield: 28.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:14]C(C)(C)C)=[CH:12][CH:13]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]>C1COCC1.FC(F)(F)C(O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: COC(=O)c1nc(-c2ccc(OC(C)(C)C)nc2)cc(N)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccc(O)nc2)cc(N)c1Cl
Yield: 83.9 %

Procedure:
Methyl 4-amino-3-chloro-6-(6-t-butoxy-3-pyridinyl)pyridine-2-carboxylate (0.50 g, 1.49 mmol) was dissolved in a 1:1 mixture of THF and trifluoroacetic acid (5 mL) and heated to reflux for 30 minutes. The volatiles were removed in vacuo and the crude material was purified by HPLC (linear gradient, 100% water to 100% acetonitrile) to give of methyl 4-amino-3-chloro-6-(6-hydroxy-3-pyridinyl)pyridine-2-carboxylate (0.35 g, 1.25 mmol): Mp 251-52° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10](Br)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].N1C2C(=CC=C(C(OC)=O)C=2)C=C1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[C:38]([CH2:45][O:46][Si:47]([CH:54]([CH3:56])[CH3:55])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])[CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:15]1([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[NH:11][C:10]=2[C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=2[CH2:45][O:46][Si:47]([CH:48]([CH3:50])[CH3:49])([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(B(O)O)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Temperature: 110 °C
Yield: 81 %

Procedure:
2-Bromo-3-cyclohexyl indole-6-carboxylic acid methyl ester (1 eq., prepared as described in WO2004/087714 from commercially available methyl indole-6-carboxylate) and (4-methoxy-2-{[(triisopropylsilyl)oxy]methyl}phenyl)boronic acid (1.1 eq.) were dissolved in dioxane (0.125M solution) and 2M aq. sodium carbonate solution (3.3 eq.) was added. The mixture was degassed and flushed with argon. Then bis(triphenylphosphine)palladium dichloride (0.1 eq.) was added and the mixture was heated under argon atmosphere to 110° C. After 5 h at this temperature all volatiles were evaporated in vacuo and the residual material was dissolved in EtOAc. The solution was extracted with water and with brine, then dried over Na2SO4 and evaporated in vacuo. The residual material was purified by flash chromatography (PE:EtOAc, 9:1). After evaporation of the solvents the product was obtained as an off-white foam (81%). The material was used without further characterization in the next reaction.
Reaction SMILES: [Li+].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O-])=[O:25])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:61]([C:64]1[CH:69]=[CH:68][C:67]([NH:70][CH:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)=[CH:66][C:65]=1[C:77]([F:80])([F:79])[F:78])([O-:63])=[O:62]>CN(C)C=O.ClCCl.O1CCCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([N:74]3[CH2:75][CH2:76][CH:71]([NH:70][C:67]4[CH:68]=[CH:69][C:64]([N+:61]([O-:63])=[O:62])=[C:65]([C:77]([F:78])([F:79])[F:80])[CH:66]=4)[CH2:72][CH2:73]3)=[O:25])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Benzyloxy-phenyl)-piperazin-1-yl]-propionic acid lithium salt (134 mg; 0.39 mmol, prepared in accordance with Example 22), diisopropylethyl amine (174 μL; 0.35 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (133 mg; 0.35 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (114 mg; 0.35 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (61 mg; 0.10 mmol). The structure was confirmed using Protocol II-A. Calculated mass=612; observed mass=612; HPLC retention time=3.57 min.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[CH3:7][C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2.C(N(CC)CC)C>C1COCC1>[CH3:7][C:8]1([O:18][CH2:2][O:3][CH2:4][CH2:5][Cl:6])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2
Reactant: ClCCOCCl
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(OCOCCCl)C2CC3CC(C2)CC1C3
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of chloroethyl chloromethyl ether obtained in Example 1 (1), 1.66 g (10 mmol) of 2-methyl-2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 2-methyl-2-adamantanol was converted by 46.2% and that 2.04 g (7.9 mmol, isolation yield: 78.8%) of a colorless liquid which was the intended product was obtained at a selectivity of 97.3%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[Mg].II.[CH3:10][N:11]([CH3:24])[C:12]1(C#N)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1.[NH4+].[Cl-]>O.C1COCC1.C(OCC)C>[CH3:6][O:5][CH2:4][CH2:3][CH2:2][C:12]1([N:11]([CH3:24])[CH3:10])[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: COCCCCl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COCCCC1(N(C)C)CCC2(CC1)OCCO2

Procedure:
A solution of 1-chloro-3-methoxy-propane (10.0 g, 92 mmol) in abs. ether (15 ml) was added dropwise, under an argon atmosphere and with intermittent heating, to magnesium (10.0 g, 92 mmol) and I2 in abs. diethyl ether (30 ml). Then the mixture was stirred under reflux for 60 min., following which the magnesium had not dissolved completely. While cooling with ice, a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile B-1 (9.68 g, 46 mmol) in abs. THF (30 ml) was added dropwise. A viscous precipitate formed, and 100 ml of THF were then added for the purpose of better mixing. The mixture was stirred for 24 h at room temperature. 20% NH4Cl solution (100 ml) and water (120 ml) were added to the mixture, while cooling with ice, the organic phase was separated and the aqueous phase was extracted with ether (3×120 ml). The combined organic phases were washed with saturated NaCl solution (120 ml) and water (120 ml), dried over Na2SO4 and concentrated in vacuo. The crude yield was 10.8 g of brown oil. 9.8 g of crude product were purified by flash chromatography with CHCl3/MeOH (50:120:19:1).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[S:23]([C:26]2[CH:27]=[CH:28][C:29]3[NH:34][CH2:33][CH2:32][O:31][C:30]=3[CH:35]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.BrC1N=C(N(CC2C=CC(OC)=CC=2)S(C2C=CC3N(C4C=CC(C(F)(F)F)=CC=4Cl)CCOC=3C=2)(=O)=O)SN=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[S:23]([C:26]2[CH:27]=[CH:28][C:29]3[N:34]([C:2]4[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=4[O:4][C:5]4[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=4)[CH2:33][CH2:32][O:31][C:30]=3[CH:35]=2)(=[O:25])=[O:24])=[CH:41][CH:42]=1
Reactant: Brc1ccccc1Oc1ccncc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: COc1ccc(CN(c2nc(Br)ns2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Cl)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2Oc2ccncc2)cc1
Yield: 38.4 %

Procedure:
A microwave vial containing a suspension of 4-(2-bromophenoxy)pyridine (0.180 g, 0.719 mmol), N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 0.2 g, 0.479 mmol), sodium t-butoxide (0.117 ml, 0.958 mmol), Xantphos (0.111 g, 0.192 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.088 g, 0.096 mmol) in toluene (4.79 ml) was purged with nitrogen and was microwave irradiated at 100° C. for 45 min. Reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by preperative LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min5-50% shallow; 10 min10-60% shallow to obtain N-(4-methoxybenzyl)-4-(2-(pyridin-4-yloxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.108 g, 0.184 mmol, 38.4% yield) as yellow solid. The material was then dissolved in DCM (1 mL) and TFA was added (1 ml). The reaction mixture was concentrated and purified by MPLC (Biotage Isolera One; PuriFlash HP, 15p., 80 g), eluting with DCM:MeOH (90:10) to obtain 4-(2-(pyridin-4-yloxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.03 g, 0.064 mmol, 13.42% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.57 (br. s., 1 H) 8.30-8.34 (m, 2 H) 7.50-7.54 (m, 1 H) 7.41-7.45 (m, 2 H) 7.33-7.38 (m, 1 H) 7.23 (d, J=4.60 Hz, 1 H) 7.13 (dd, J=8.51, 2.15 Hz, 1 H) 7.02 (d, J=2.15 Hz, 1 H) 6.79 (d, J=4.60 Hz, 1 H) 6.64-6.68 (m, 2 H) 6.43 (d, J=8.51 Hz, 1 H) 3.56 (br. s., 2 H) 3.29 (br. s., 1H); MS (ESI, positive ion) m/z; 467.1 (M+1)
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)#[N:25]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: N#Cc1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2C#N)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-hydroxy-benzonitrile via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2=[CH:17][C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[N:15]2[CH2:14][CH2:13][NH:12]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([N:12]2[CH2:13][CH2:14][N:15]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=[C:16]3[C:11]2=[O:24])[N:9]=[CH:8][CH:7]=1
Reactant: O=C1NCCn2c1cc1c2CCCC1
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 90 °C
Yield: 104 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 114a (800 mg, 3.5 mmol), 3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101g (665 mg, 3.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (320 mg, 0.35 mmol), XantPhos (400 mg, 0.7 mmol), Cs2CO3 (2.3 g, 7.0 mmol), and 1,4-dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1) to afford 114b as yellow solid (1.2 g, 50%). MS: [M+H]+ 330.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([CH3:10])[CH3:9])[C:3](=[CH2:7])[CH:4]([OH:6])[CH3:5].[C:11](O)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:5][CH:4]([O:6][C:11](=[O:15])[CH:12]=[CH:13][CH3:14])[C:3](=[CH2:7])[CH:2]([CH3:1])[CH:8]([CH3:10])[CH3:9]
Reactant: C=C(C(C)O)C(C)C(C)C
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C(C)OC(=O)C=CC)C(C)C(C)C
Temperature: 125 °C
Yield: 70 %

Procedure:
The obtained 4,5-dimethyl-3-methylene-hexan-2-ol (280 g), crotonic acid (188 g,), PTSA (2.5 g), and toluene (250 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 4-5 hours until no more water evolved. The reaction was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further fractional distilled to provide but-2-enoic acid 1,3,4-trimethyl-2-methylene-pentyl ester (290 g) with a boiling point of 114° C. at 11 mmHg.