Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(F)(C(F)(F)F)C(F)(F)F.ClCl.Cl[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[OH-].[K+]>>[CH:14]([C:15]([C:16]([F:19])([F:18])[F:17])([F:21])[F:20])([F:23])[F:22]
Reactant: FC(F)(F)C(F)(F)C(F)(F)Cl
Agent: ClCl
Agent: FC(C(F)(F)F)C(F)(F)F
Agent: [K+]
Product: FC(F)C(F)(F)C(F)(F)F

Procedure:
A 34 cubic centimeter Inconel™ reactor tube, equipped with a ceramic fiber heater, was packed with Takeda™ brand activated carbon. The activated carbon and reactor were purged with nitrogen between 150° C. and 200° C. The reactor was connected to tubing providing chlorine and the hydrofluorocarbon heptafluoropropane (HFC-227, containing 839 ppm 227ca and the remainder HFC-227ea). The flow of the chlorine and HFC-227 were controlled with gas flowmeters. Tables 1 and 2 below indicate the reaction parameters as well as the results. Fluoromonomer precursor chloroheptafluoropropane (CFC-217) exiting the reactor was first passed through a 10% (wt./wt.) KOH solution and then dried over CaSO4 before being captured for subsequent gas chromatography analysis.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21]Br>C(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH2:21][CH2:20][O:19][CH3:18])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1CCN(CCOC)CC1
Yield: 91.7 %

Procedure:
A solution of ethyl isonipecotate (26 g, 166 mmol) in ethanol (150 ml) was treated with potassium carbonate (41 g, 297 mmol) and 2-bromoethyl methyl ether (25 g, 179 mmol). After heating at reflux for 24 hours, the mixture was filtered and the solid washed with ethanol. The filtrate was concentrated in vacuo to yield the title compound (32.76 g, 92%); 1H NMR (CDCl3) 4.12 (2H, q, J=7.1 Hz), 3.51 (2H, t, J=5.7 Hz), 3.33 (3H, s), 2.92 (2H, m), 2.56 (2H, t, J=5.7 Hz), 2.33-1.71 (7H, m) and 1.25 (3H, t, J7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:3]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)Cc1cccc(NC(C)=O)c1

Procedure:
Methyl (3-aminophenyl)acetate was treated with acetic anhydride to provide methyl[3-(acetylamino)phenyl]acetate. The desired product was prepared by substituting methyl[3-(acetylamino)phenyl]acetate for N-[4-(cyanomethyl)phenyl]acetamide in Example 6A. MS (DCI) m/e 211 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[OH-].[Na+].CC1C=CC=CC=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:22][CH2:21][CH2:20][CH2:19][C:8]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: ClCCCBr
Reactant: N#CC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(CCCCl)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 22.9 parts of 4-fluoro-α-(4-fluorophenyl)benzeneacetonitrile, 23.6 parts of 1-bromo-3-chloropropane and 0.4 parts of N,N,N-triethylbenzenemethanaminium chloride were added dropwise 600 parts of sodium hydroxide solution 50% at a temperature below 30° C. Upon completion, stirring was continued for 3 hours at 50°-60° C. Methylbenzene and water were added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was evaporated once more in vacuo for 30 minutes at 100° C. to remove the last traces of 1-bromo-3-chloropropane, yielding 29 parts (95%) of α-(3-chloropropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetonitrile as a residue (intermediate 14).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:19]([OH:21])=O.C1C=C[C:25]2N(O)N=[N:28][C:26]=2[CH:27]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[Cl:1][CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)[N:6]=[N:5][C:4]=1[C:19]([NH:28][CH:26]1[CH2:27][CH2:25]1)=[O:21]
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 131.1 %

Procedure:
5-(Chloromethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (103 mg, 0.334 mmol) obtained in Example 104b), HOBt (23 mg, 0.167 mmol, 0.5 eq.) and cyclopropylamine (0.031 ml, 0.434 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 1.5 ml), WSC (78.4 mg, 0.401 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. water (10 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (30 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution, washed with 10% aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white powder. This was subjected to column chromatography (elution solvent, ethyl acetate-hexane=2:3-3:2) on silica gel (manufactured by E. Merck, Art.7734, 10 g). The fraction obtained by elution with ethyl acetate-hexane (1:1-3:2) was concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (76 mg, 0.219 mmol, 65.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
A solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et3N (0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a solution of trimethylacetyl chloride (0.04 mmol) in anhydrous THF (0.4 ml) at rt in a sealed reaction vessel. The resulting suspension was stirred at rt for 20 hr, then evaporated to dryness. The product was suspended in a mixture of H2O (0.4 ml) and saturated NaHCO3 solution (0.4 ml), then extracted with CH2Cl2 (3×0.75 ml). The combined extracts were evaporated to dryness to give the crude product. Purification by reverse-phase HPLC, eluting first with gradient. Purification by reverse-phase HPLC on a Primesphere (Phenomenex 2320 West 205th St. Torrance, Calif. 90501) C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:1% TFA/H2O (85:10:5), increasing to H2O:CH3CN:1% TFA/H2O (5:90:5) at 8 min., detected on a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave material which, after evaporation to dryness, was purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give 0.012 g (56% yield) of the pure product. MS 513 m/e (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:22][C:23](O)=[O:24])[NH:21][CH:20]=[CH:19][S:18]2)=[CH:13][CH:12]=1>>[C:4]([C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH:1][C:23](=[O:24])[CH2:22][C:17]1([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[NH:21][CH:20]=[CH:19][S:18]1)#[N:5]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: O=C(O)CC1(c2ccncc2)NC=CS1
Product: N#Cc1cc(Cl)ccc1NC(=O)CC1(c2ccncc2)NC=CS1

Procedure:
This compound was prepared according to the method described in Example 1c by employing 2-amino-5-chlorobenzonitrile (Aldrich) and 2-(4-pyridyl)-thiazole acetic acid (Example 1, Step b). Mp: 164-166° C. MS m/z: 355.0 (M+1). Calc'd for C17H11ClN4OS: 354.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[NH:13][C:12]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][N:44]1[C:48]([CH2:49]O)=[N:47][CH:46]=[N:45]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([O:23][CH2:49][C:48]3[N:44]([CH3:43])[N:45]=[CH:46][N:47]=3)=[N:13][C:12]=12
Reactant: Cn1ncnc1CO
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncnc1COc1nc2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 37.7 %

Procedure:
3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (10 mg, 0.033 mmol), triphenylphosphine (21 mg, 0.08 mmol) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (11 mg, 0.087 mmol) were suspended at room temperature in dry tetrahydrofuran (0.5 ml). Diethyl azodicarboxylate (15 μl, 0.095 mmol) was added at which point a clear yellow solution resulted. The reaction was stirred at room temperature for 64 hours before purification by preparative thin layer chromatography to afford 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[1,5-α]pyrimidine (5 mg, 39%) as a white solid. δH (400 MHz, CDCl3) 3.79 (3H, s, NMe, 5.69 (2H, s, OCH2), 7.24 (1H, td, J=9.2 and 1.2 Hz, ArH), 7.31 (1H, td, J=8.4 and 1.3 Hz, ArH), 7.39-7.43 (1H, m, ArH), 7.48-7.51 (3H, m, ArH), 7.54-7.58 (2H, m, ArH), 7.86 (1H, s, CH-triazole), 8.00 (1H, td, J=8.3 and 2.0 Hz, ArH), 8.80 (1H, s, PhC═CH);m/z (ES+) 402 (M+H+).
Reaction SMILES: C([O-])(=O)C.[OH:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8].C(O[C:53]([CH2:56][CH3:57])([CH3:55])[CH3:54])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH3:54][C:53]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH2:56][CH3:57])[CH3:55]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Reactant: CCC(C)(C)OC(C)=O
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCC(C)(C)O[C@H](C(=O)OC)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Reaction time: 3 h
Yield: 17.9 %

Procedure:
Methyl (2S)-2-[(2-methylbutan-2-yl)oxy 1-24(228)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33), 11, 13, 15 (20),16,18-decaen-3-yl]acetate: To a stirred solution of methyl (2S)-2-hydroxy-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (50 mg, 0.084 mmol) in DCM (2 mL) and tert-pentyl acetate (0.692 mL, 5.85 mmol) at rt was added 70 wt % perchloric acid (0.022 mL, 0.251 mmol). After 3 h, the reaction mixture was diluted with DCM (25 mL), carefully quenched with sat. NaHCO3 (5 mL), organic layer separated and washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatograpgy on silica gel column using (10-50% EtOAc/Hex as eluant) to afford the desired methyl (25)-2-[(2-methylbutan-2-yl)oxy]-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (10 mg, 0.015 mmol, 17.90% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.82-7.76 (m, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.39-7.34 (m, 1H), 7.18 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.90 (s, 1H), 5.90 (s, 1H), 4.66-4.59 (m, 1H), 4.58-4.52 (m, 1H), 3.84-3.79 (m, 1H), 3.77 (s, 3H), 3.50 (td, J=7.7, 3.1 Hz, 1H), 3.44-3.35 (m, 1H), 3.27 (d, J=12.3 Hz, 1H), 2.89 (d, J=11.3 Hz, 1H), 2.61 (s, 3H), 2.36 (s, 3H), 2.07-1.96 (m, 3H), 1.89-1.80 (m, 1H), 1.79-1.70 (m, 3H), 1.63-1.47 (m, 6H), 1.26 (s, 3H), 1.23 (s, 3H), 1.17 (d, J=6.0 Hz, 3H), 1.15 (s, 3H), 0.83 (t, J=7.5 Hz, 3H). LCMS (M+H)=669.4. 35 mg of starting material was also recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26].N1(C2C=CC(NC(=O)C(OC)=O)=CC=2)CCOCC1>>[C:18]([O:17][C:16]([NH:15][CH2:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: COC(=O)C(=O)Cl
Agent: COC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Product: COC(=O)C(=O)Nc1ccc([C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)cc1

Procedure:
Prepared from tert-butyl {[trans-4-(4-aminophenyl)cyclohexyl]methyl}carbamate and methyl chlorooxoacetate by method described for Intermediate 1, method D3.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][CH:18]([OH:27])[CH:19]([OH:26])[CH:20]([OH:25])[CH:21]([OH:24])[CH2:22][OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([N:8]([CH2:17][CH:18]([OH:27])[CH:19]([OH:26])[CH:20]([OH:25])[CH:21]([OH:24])[CH2:22][OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCN(Cc1ccccc1)CC(O)C(O)C(O)C(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCN(Cc1ccccc1)CC(O)C(O)C(O)C(O)CO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
At room temperature, 0.46 g of methyl 5-[benzyl(2,3,4,5,6-pentahydroxyhexyl)-amino]pentanoate is dissolved in a mixture of 5 ml of ethanol and 5 ml of water, 0.4 g of potassium hydroxide is added and the mixture is stirred at 80° C. for 2 h. The cooled reaction mixture is then concentrated under reduced pressure and the residue is taken up in water, neutralized with hydrochloric acid and again concentrated. The crude product is suspended in ethanol, the suspension is filtered and the filtrate is concentrated under reduced pressure. This gives 5-[benzyl-(2,3,4,5,6-pentahydroxyhexyl)amino]pentanoic acid of molecular weight 371.43 (C18H29NO7); MS (ESI): 372.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:14]=1[C:20]([F:23])([F:22])[F:21].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:15]1[C:14]([C:20]([F:23])([F:22])[F:21])=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][CH2:10][C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cccc(F)c2C(F)(F)F)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cccc(NCc3ccccc3)c2C(F)(F)F)c(=O)[nH]1
Temperature: 210 °C
Yield: 31.1 %

Procedure:
A suspension of N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-fluoro-2-(trifluoro methyl)benzamide (0.80 g, 2.34 mmol) in benzylamine (2.6 ml, 23.4 mmol) was heated in a microwave reactor at 210° C. for 4 h. After cooling distilled water (20 ml) was added to the slurry and 2M HCl was added until the suspension was at pH5. and the mixture was extracted using EtOAc (3×50 ml). The combined organics were washed with pH5 HCl solution (2×50 ml), brine (30 ml), dried using Na2SO4 filtered and evaporated. The resultant oil was purified using a 50 g Isolute silica column eluting with a gradient of 0% to 5% MeOH in DCM to afford the title compound as an off-white solid (313 mg, 29%). LC-MS 94%, m/z=430.2, 1H NMR (500 MHz, Acetone-d6) δ 7.41-7.16 (m, 8H), 6.69 (d, J=8.5 Hz, 1H), 6.50 (d, J=7.4 Hz, 1H), 5.87 (s, 1H), 5.84 (s, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.35 (d, J=5.6 Hz, 2H), 2.28, (d, J=4.0 Hz, 3H), 2.21 (s, 3H).
Reaction SMILES: C1(S([CH:10]([CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=O)=O)C=CC=CC=1>CO.C(OCC)(=O)C.CCCCCC.[Na].[Hg]>[C:21]([OH:23])(=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCC(=O)O)S(=O)(=O)c1ccccc1
Agent: [Hg]
Agent: [Na]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 50.4 %

Procedure:
To a solution of (17Z,20Z,23Z,26Z)-12-(phenylsulfonyl)dotriaconta-17,20,23,26-tetraenoic acid (0.0643 g, 0.105 mmol) in methanol (8 mL) was added Na2HPO4 (0.074 g, 0.525 mmol) and 10% sodium amalgam (5.16 g, 2.308 mmol) and the resulting reaction mixture was stirred under nitrogen at room temperature for 40 h. The solvent was decanted and acidified (pH 4) with 1M HCl. The aqueous phase was extracted with DCM (3×10 mL), washed with brine (2×10 mL), dried over MgSO4, filtered and evaporated. The product from the crude was isolated by flash chromatography using 25% ethyl acetate/hexane as eluent to afford the title product as a light yellow oil (0.025 g, 51%). 1H NMR (CDCl3): δ 5.36 (m, 8H), 2.79 (m, 6H), 2.28 (t, 2H, J=6.7 Hz), 1.99 (m, 4H), 1.61 (m, 2H), 1.51-1.18 (m, 30H), 0.97 (t, 3H, J=6.8 Hz). m/z (APCI) 473.62 (M++1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](N(OC)C)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Li].Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:16])[CH3:21])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Cis-4-(benzyloxy)-N-methoxy-N-methylcyclohexanecarboxamide (1.3 g, 4.7 mmol) was dissolved in THF (10 mL). CH3Li (3.0 M solution in diethoxymethane, 8.0 mL, 14.1 mmol, 3.0 eq.) was added to the solution dropwise at −70° C. The mixture was stirred at −70° C. under nitrogen atmosphere for 1 h. then 1 M HCl solution was added to the mixture until pH=6. The mixture was extracted with ethyl acetate and the organic layer was concentrated and purified by silica gel column chromatography using petroleum ether/ethyl acetate (3/1) as eluent to give product as a slight yellow oil (720 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 5H), 4.49 (s, 2H), 3.62-3.60 (m, 1H), 2.40-2.25 (m, 1H), 2.13 (s, 3H), 1.97-1.93 (m, 2H), 1.86-1.80 (m, 2H), 1.67-1.54 (m, 2H), 1.53-1.47 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[C:25]2[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][CH2:34][OH:35])=[C:27]([CH3:36])[CH:26]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[OH:35][CH2:34][CH2:33][O:32][C:28]1[C:27]([CH3:36])=[CH:26][C:25]([C:15]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:9][CH:10]=3)[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:30][C:29]=1[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(NC(=O)C(C)C)cc2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
TEA (0.07 mL, 0.50 mmol) and isobutyryl chloride (0.25 mmol) were added to a solution of 3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.100 g, 0.25 mmol) in CH2Cl2 (5 mL), stirred at room temperature for 2 hours, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH in CH2Cl2, afforded the title compound as a white solid in 78% yield. 1H-NMR (300 MHz, DMSO-d6): δ 9.90 (s, 1H), 8.17 (dd, J=6.8, 1.2 Hz, 1H), 7.85-7.91 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.53-7.65 (m, 3H), 7.20 (d, J=8.9 Hz, 2H), 7.04 (s, 2H), 4.83 (t, J=5.4 Hz, 1H), 3.61-3.72 (m, 4H), 2.56-2.63 (m, 1H), 2.10 (s, 6H), 1.08 (d, J=6.9 Hz, 6H). MS (APCI) m/z: 472 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-methoxyphenylboronic acid: MS (m/z) 407.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([O:11]CC)=[O:10])[C:4](=[O:18])[CH:3]=1.[OH-].[Li+]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([OH:11])=[O:10])[C:4](=[O:18])[CH:3]=1
Reactant: CCOC(=O)C(CC1CC1)n1ccc(Br)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C(CC1CC1)n1ccc(Br)cc1=O

Procedure:
350 mg (1.1 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 290 mg (purity 94%, 86% of theory)