Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[F:25][C:26]([F:41])([C:37]([F:40])([F:39])[F:38])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[S:29](F)(=[O:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[O:15][S:29]([C:28]([F:33])([F:34])[C:27]([F:35])([F:36])[C:26]([F:25])([F:41])[C:37]([F:40])([F:39])[F:38])(=[O:31])=[O:30])=[O:5])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)c1sc2cnccc2c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2cnccc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 3-hydroxy-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester-(950 mg, 4.26 mmol) and DMAP (26 mg, 0.21 mmol) in DCM (12 ml) at 0° C. was added DIPEA (1.8 ml, 10.2 mmol) and nonafluorobutylsulfonyl fluoride (0.99 ml, 5.53 mmol). After 10 minutes the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The reaction mixture was diluted with DCM (30 ml) and washed with water (20 ml). The organic phase was dried over sodium sulphate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 90:10 to 65:35) to afford the title compound as a colourless oil which crystallised on standing (678 mg, 31%): LCMS (method B). RT=4.49 min, M+H+=508.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:13](=[O:15])[CH2:12][CH2:11]2
Reactant: COc1ccc(CCC(=O)O)cc1OC
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Further, Patent Document 1 discloses that 300 g of 3-(3,4-dimethoxyphenyl)propionic acid and 1500 g of polyphosphoric acid were reacted at 65° C. for 30 minutes under a nitrogen atmosphere. The reaction mixture was then cooled, to which 2000 mL of deionized water was then gradually added. The mixture was then stirred at room temperature for two hours and then extracted with 600 mL of chloroform six times. The organic layer thus extracted was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, and then filtrated. The filtrate thus obtained was concentrated to dryness under reduced pressure to give 170 g (yield 62%) of 5,6-dimethoxy-1-indanone. However, in this method, a reaction vessel of approximately 3 L or larger is needed to obtain only 170 g of a target compound. Therefore, the volumetric efficiency is low. Also, industrialization of the above method is difficult because chloroform, which is highly toxic to human bodies and the environment, is used as an extraction solvent.
Reaction SMILES: [CH:1](N(C(C)C)CC)([CH3:3])[CH3:2].[CH3:10][O:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]4)[CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13]1.C(Br)C#C>>[CH3:10][O:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]4)[CH:18]=2)[CH2:16][CH2:15][N:14]([CH2:3][C:1]#[CH:2])[CH2:13]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCNC1
Agent: C#CCBr
Product: C#CCN1CCC(OC)(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)C1
Yield: 21 %

Procedure:
Using an analogous procedure to that described in Example 3 except that diisopropylethylamine was used in place of potassium carbonate, 3-methoxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]pyrrolidine was reacted with 2-propynyl bromide to give 3-methoxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-1-(prop-2-ynyl)pyrrolidine as a gum in 21% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCOCC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 47 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and morpholine (0.69 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-41. Mol. Wt.: 483.5152 (C28H25N3O5); Rf: 0.38 (ethyl acetate:n-hexane=1:2); Yield: 47%; Mp.: 225-226° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 483.1794 (C28H25N3O5+). Found, 483.1793. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.39 (br, 4H, —CH2—), 2.45 (s, 3H, —CH3), 3.15 (s, 2H, —CH2N—), 3.22 (br, 4H, —CH2—), 7.45 (d, J=7.8 Hz, 2H, Ar—H), 7.88-7.91 (m, 2H, Ar—H), 8.07-8.12 (m, 3H, Ar—H), 8.27 (d, J=8.7 Hz, 1H, Ar—H), 8.73 (d, J=8.7 Hz, 1H, Ar—H), 9.99 (s, 1H, Ar—NH—), 10.61 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.95, 53.17, 61.94, 65.59, 125.73, 126.37, 126.53, 126.98, 127.82, 128.05, 129.28, 129.46, 130.55, 132.35, 134.16, 134.53, 140.31, 142.66, 166.32 (NCO), 168.97 (NCO), 181.50 (CO), 183.84 (CO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:31](=[O:33])[CH3:32])[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 43 %

Procedure:
A solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine (19.3 mg, 0.044 mmol, 1 eq.) in 1 mL of acetic anhydride and 1 mL of pyridine was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 9 mg (43%) of desired 1(4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidin-1-yl)ethan-1-one. Compound was determined to be 95% pure by 1H NMR. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.52 (m, 2 H) 2.03-2.27 (m, 5 H) 2.81 (t, J=11.49 Hz, 1 H) 3.13-3.33 (m, 1 H) 3.81 (d, J=13.75 Hz, 1 H) 4.41 (br. s., 1 H) 4.55 (d, J=13.66 Hz, 1H) 5.78 (br. s., 1 H) 7.00-7.55 (m, 8 H) 8.37 (s, 1 H), [M+Na]+ 503.8.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].O=[C:10]([CH2:16][CH2:17][C:18](OCC)=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[O:19]=[C:18]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:7]=[C:17]1[CH2:16][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)CCC(=O)C(=O)OCC
Product: CCOC(=O)CCc1nc2ccccc2[nH]c1=O
Yield: 72 %

Procedure:
The title compound was prepared from 1,2-phenylenediamine and diethyl 2-oxopentanedioate using methods as described in the literature for similar compounds (Weygand et al., 1962) in 72% yield.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5].[CH2:11]([O:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([OH:21])=O)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([N:2]([C@@H:3]([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5])[CH3:1])=[O:21])[CH3:12]
Reactant: CCOc1ccsc1C(=O)O
Reactant: C=CC[C@H](NC)C(=O)OC
Product: C=CC[C@@H](C(=O)OC)N(C)C(=O)c1sccc1OCC

Procedure:
Step N (1): (S)-Methyl 2-(methylamino)pent-4-enoate from Step G (1) and 3-ethoxythiophene-2-carboxylic acid were coupled according to the procedure outlined in Step A (1). The product was purified using silica gel column chromatography to provide 80 mg (quantitative yield) of (S)-methyl 2-(3-ethoxy-N-methylthiophene-2-carboxamido)pent-4-enoate. LC-MS (M+H)+=298.29; 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (t, J=6.77 Hz, 3H) 2.48-2.64 (m, 1H) 2.68-2.82 (m, 1H) 3.01 (s, 3H) 3.72 (s, 3H) 4.06 (q, J=6.83 Hz, 2H) 5.00-5.20 (m, 3H) 5.63-5.84 (m, 1H) 6.70 (d, J=5.49 Hz, 1H) 7.29 (d, J=5.49 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)[CH2:6][CH2:7][Cl:8].[OH-].[Na+]>O>[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[CH2:6][CH2:7][Cl:8]
Reactant: COC(=O)CCc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccc(N(CCCl)CCCl)cc1
Yield: 84.6 %

Procedure:
Concentrated hydrochloric acid (10 ml) was added to 1.5 g (4.93 mmol) of methyl 3-[4-[N,N-bis(2-chloroethyl)amino]phenyl]propionate, followed by stirring under heat for 2.5 hours over an oil bath controlled at 90° C. The reaction mixture was diluted with water and was then adjusted to about pH 2 or so with a 5N aqueous solution of sodium hydroxide. The resultant crystals were collected by filtration, whereby 1.21 g (4.17 mmol) of the title compound were obtained as white crystals (yield: 84.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2([NH2:43])[CH2:42][CH2:41]2)[N:35]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:36]6[N:35]=[N:34][CH:39]=[CH:38][CH:37]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2cccnn2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.017 g, 0.092 mmol, 1 eq) and Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by flash column chromatography using 4% MeOH/CHCl3 as eluant. Yield: 0.032 g (63%). 1H NMR (400 MHz, CD3OD): δ 9.15 (s, 1H), 9.00 (d, J=3.8 Hz, 1H), 8.53-8.40 (m, 1H), 8.02-7.95 (m, 2H), 7.84 (dd, J=1.5, 8.5 Hz, 1H), 7.79 (s, 1H), 7.70-7.62 (m, 2H), 7.59 (d, J=1.5 Hz, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.31-7.26 (m, 2H), 7.16 (s, 1H), 4.09 (s, 3H), 2.98-2.95 (m, 3H), 2.38 (s, 3H), 1.89-1.87 (m, 2H), 1.57-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −112.66 LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[O:5][C:6]=1[CH3:7].[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23]CCCCC)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]>>[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23][CH2:8][C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH:3]=2)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: Cc1cc(C=O)oc1C
Product: COC(=O)c1cccc(NCc2cc(C)c(C)o2)c1C(=O)OC
Yield: 75 %

Procedure:
4,5-Dimethyl-furan-2-carbaldehyde (0.98 ml, 8 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 10% ethyl acetate/hexanes) to give 0.95 g (75%) of product as a yellow oil: 1H NMR (CDCl3) δ 7.32 (t, J=8.2 Hz, 1H), 6.97 (bs, 1H), 6.88–6.83 (m, 2H), 5.99 (s, 1H), 4.28 (d, J=5.5 Hz, 2H), 3.86 (s, 3H), 2.17 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:5]([Cl:17])=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>COCCOC.CCO>[Cl:17][C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:1]=2)[C:6]=1[CH2:8][P:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:16]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOP(=O)(Cc1nc(N)ccc1Cl)OCC
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cn2c(CP(=O)(OCC)OCC)c(Cl)ccc2n1
Yield: 13 %

Procedure:
Following the procedure for Example 17, the residue from Example 28 was combined with ethyl bromopyruvate (0.468 g, 2.4 mmol) in DME (25 mL). After the resulting salt was refluxed in abs EtOH (30 mL) for 6 h, workup and puricication produced 0./114 g (13% of title compound).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]([OH:7])=O.[CH2:8]([C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([C@H:15]1[CH2:19][N:18]([C:5](=[O:7])[CH2:4][O:3][CH3:2])[C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 43.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-methoxyacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 122, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-carboxamide (12 mg, 43.2%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.56-7.59 (m, 2H), 7.28-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.94-7.02 (m, 4H), 4.50 (m, 1H), 4.04 (m, 1H), 3.60 (m, 1H), 3.28 (s. 3H), 3.18 (m, 2H), 2.65 (m, 3H), 1.90 (m, 2H). MS (EI) for C27H27FN2O4. found 463.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[C:8](/[OH:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:16]1([C:22](OCC)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CC[O-].[Na+].Cl>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:16]1([CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:22](=[O:23])[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]2[OH:15]
Reactant: CCOC(=O)/C=C(\O)c1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1C(=O)C2(CCOCC2)c2c(Cl)cccc2C1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of (Z)-ethyl 4-(2-chloro-6-(3-ethoxy-1-hydroxy-3-oxoprop-1-enyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (0.38 g, 0.99 mmol) in 5 mL EtOH was treated with NaOEt (freshly made from 0.1 g Na and 5 mL EtOH), and stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and diluted with 100 mL EtOAc, neutralized with 5N HCl to pH 5, washed with water (20 mL), saturated NaCl (20 mL), dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (10-40% EtOAc/hexane) to give 0.27 g yellow solid. MS m/e: (M+H)+ 337.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][NH:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.COC(C)(C)C>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][NH:7][C@H:6]([CH2:4][OH:3])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN[C@H](CO)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.10 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-2-carboxylic acid ethyl ester in 10 ml of tetrahydrofuran are added 17.0 mg of lithium aluminium hydride at 0° C. The reaction mixture is stirred for 1 hour at this temperature, diluted with tert-butyl methyl ether and quenched by addition of 2.0 ml of aqueous saturated sodium sulfate solution. The mixture is allowed to warm to room temperature, filtered and dried over sodium sulfate. The solvent is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[CH3:11][CH2:12][N:13]=[C:14]=NCCCN(C)C.C(NC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:13]([CH2:12][CH3:11])[CH3:14])=[O:10])[N:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1nc(CC(=O)O)cs1
Agent: CCNC
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN(C)C(=O)Cc1csc(N)n1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
This compound was prepared from 2-amino-4-thiazoleacetic acid (3.48 g, 22 mmol), EDCI (4.37 g, 22.8 mmol), DMAP (270 mg, 2.2 mmol) and N-ethylmethylamine (1.99 mL, 23.2 mmol) in DMF (30 mL). The resulting solution was left overnight at room temperature. DMF was removed in vacuo and the residue purified by flash chromatrography on silica gel using 2% and 5% methanol/ethyl acetate as eluent. This procedure yielded 2.09 g (40%) of the title compound: 1H NMR (CDCl3) δ 6.28, 6.30 (1H), 5.06 (bs, 1H), 3.60, 3.61 (2H), 3.41 (m, 2H), 3.0, 2.92 (s, 3H), 1.11 (q, 3H). MS EI m/z 200.2.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:39])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[N:25]([CH:26]=3)[C:24]3[CH:27]=[CH:28][C:29]([O:31][C:32]([C@@H:34]5CCC[NH:35]5)=[O:33])=[CH:30][C:23]=3[S:22]4)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ON1C(=O)[CH2:44][CH2:43][C:42]1=O.C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:39])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[N:25]([CH:26]=3)[C:24]3[CH:27]=[CH:28][C:29]([O:31][C:32](=[O:33])[C@H:34]([NH2:35])[CH:43]([CH3:44])[CH3:42])=[CH:30][C:23]=3[S:22]4)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OC(=O)[C@@H]5CCCN5)ccc34)cc2)no1
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)[C@@H](N)C(=O)Oc1ccc2c(c1)sc1nc(-c3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)cn12

Procedure:
In a manner similar to Step A, (2S)-pyrrolidine-2-carboxylic acid 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl ester was made using Boc-L-proline N-hydroxysuccinimide; LC-MS: ESI 545 (M+H)+. [Compound B6]
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CCCCCC.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:36]/[CH:37]=[CH:38]/[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:34])[C@H:31]([CH2:32][CH3:33])[CH2:36]/[CH:37]=[CH:38]/[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrC/C=C/COCc1ccccc1
Reactant: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@H](C/C=C/COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
164 ml of a solution of sodium bis(trimethylsilyl)amide in n-hexane (1.03 mol/l) (169 mmol) was added to a solution of 35.3 g of (S)-4-benzyl-3-butyryloxazolidin-2-one obtained in Reference Example 5 (141 mmol) in tetrahydrofuran (330 ml) under a nitrogen atmosphere and at −78° C. over 45 minutes, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 35.6 g of [(E)-4-bromobut-2-enyloxymethyl]benzene obtained in Reference Example 4 (148 mmol) in tetrahydrofuran (80 ml) was added to the solution obtained above over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. Thereafter, the mixture was raised to −40° C. and further stirred for four hours. 100 ml of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and diluted with 500 ml of water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=7/1-2/1) to obtain 46.4 g of the title compound (yield: 81%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[O-:13][CH2:14]C.[Na+].C(O)C.[Na].C(OCC)=O>O1CCCC1.O>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2]([CH2:1][CH:14]=[O:13])=[O:3])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC=O
Product: O=CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of 4-nitroacetophenone (8.26 g, 50 mmol) in anhydrous tetrahydrofuran (THF) at 0° C. was slowly added sodium ethoxide in ethanol (prepared from 1.27. g (55 mmol) sodium in 26 ml ethanol) followed by addition of ethyl formate (5.56 g, 75 mmol). The reaction was allowed to slowly warm to room temperature and stir overnight. The reaction was diluted with water (800 ml) and washed with ether. The aqueous layer was acidified (pH 1-2) with concentrated hydrochloric acid (HCl) and the mixture extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent was removed by rotary evaporation to give 4-nitrobenzoylacetaldehyde (2.69 g, 28%) as an orange solid.