Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I:9]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:8][C:5]1[N:6]=[C:7]([I:9])[C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-chloropyridine (5.0 g, 0.039 mol) was dissolved in EtOH (25 mL), and silver sulfate (13.3 g, 0.043 mol) and iodine (10.9 g, 0.043 mol) were added. The reaction was stirred at room temperature overnight, and then the mixture was filtered over Celite to remove solids. The filtrate was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: C(=O)=O.[CH3:4][C:5](C)=[O:6].[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[H-].[Na+].C1OC1>O1CCCC1>[OH:6][CH2:5][CH2:4][N:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:20]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CC(C)=O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CO1
Solvent: C1CCOC1
Product: OCCn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A 1-liter three-necked round bottom flask was equipped with a mechanical stirrer, an addition funnel, Dry Ice/acetone reflux condenser and a means for providing nitrogen atmosphere. To the flask were added 67 g (0.4 mole) of carbazole, 11 g (0.44 mole) of sodium hydride and 0.5 liter of dry tetrahydrofuran. After stirring vigorously at 0° C. for about 2.5 hours, 18 g (0.4 mole) of ethylene oxide was added dropwise to the reaction mixture over a period of 1 hour at 0° C. After the addition, stirring was continued for additional 5 hours and the tetrahydrofuran was evaporated. The residue was fully washed with water and then recrystallized from ether to give 80 g of N-(2-hydroxyethyl)carbazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9]C)[CH:5]=[CH:6][C:7]=1[CH3:8].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1ccc(C)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(O)cc1F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a −70° C. solution of 3-fluoro-4-methyl anisole (1.62 g; 11.6 mmol) in CH2Cl2 (10 mL) was added dropwise BBr3 (10 mL; 12 mmol). The reaction mixture was stirred at −70° C. for 10 min, then allowed to warm to 0° C. and stirred at 0° C. for 2 h. The reaction was allowed to warm to RT and concentrated in vacuo and the residue was partitioned between H2O and EtOAc. The organic phase was washed with H2O, dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methyl phenol (1.1 g; 75%) as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1.[H-].[Na+]>CN(C)C=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:14]3[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1[N+](=O)[O-]
Yield: 83.8 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-(imidazol-1-yl)phenol (4.1 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (7.85 g), sodium hydride (55 wt. %, 1.25 g) and anhydrous N,N-dimethylformamide (45 ml) and the reaction mixture was purified to give the title compound (8.8 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>CC(C)=O>[CH3:1][C:2]1[C:6]([O:7][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCCS(=O)(=O)Oc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1C

Procedure:
A mixture of 2.3 g (8 mmol) of di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate, 30 ml of dioxane, 60 ml of acetone, 1.6 g (120 mmol) of anhydrous potassium carbonate and 1.6 g (10 mmol) of butane-sulfonyl chloride was refluxed for about 10 hours. The mixture was then freed from dioxane and acetone by distillation in vacuo and then added with ethylether, washed with water, and dried with anhydrous magnessium sulfate. The solvent was removed by distillation and then recrystallization was effected from methanol to give 2.8 g (86%) of the desired white crystalline compound. m.p. 59°-61° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][N:5]=1
Reactant: Sc1nnc(S)s1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1nnc(S)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a mixture of 3 g of 2,5-dimercapto-1,3,4-thiadiazole, 2.76 g of anhydrous potassium carbonate, and 10 ml of N,N-dimethylformamide was added 1 g of ethyl 4-bromobutyrate and the mixture was stirred overnight at room temperature. After addition of diluted hydrochloric acid to the reaction mixture, the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was applied to silica gel chromatography (using 200 ml of silica gel) and eluted with a mixture of toluene and ethyl acetate (9:1) to provide 0.95 g of ethyl 4-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]butyrate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.S(OC)(O[CH3:17])(=O)=O.C(OCC)(=O)C.[OH-].[Na+]>O1CCOCC1>[Br:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][CH3:17])[CH:3]=2)[CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1ccc2cc(Br)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A solution of 2-amino-6-bromonaphthalene (2.0 g) in 1,4-dioxane (30 ml) was added dropwise with dimethyl sulfate (1300 μl) and stirred at room temperature for 46 hours. The reaction mixture was added with ethyl acetate (90 ml) and then added with 1 N aqueous sodium hydroxide (5 ml). This mixture was extracted with ethyl acetate (150 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=15:1) to obtain the title compound (Intermediate 27, 152 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].[C:39]([O-])([O-])=O.[K+].[K+]>CC(C)=O.CI>[C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:39])[C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2]
Reactant: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccccc1C1CCNc2c(C#N)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (187 mg, 0.36 mmol) in acetone (10 mL) was added K2CO3 (100 mg, 0.72 mmol) and CH3I (15 drops). After stirring at RT for 2 hr, the mixture was filtered. The filtrate was concentrated to afford 192 mg (100%) of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamide as yellow solid. MS (ESI) m/e [M+1]+ 535.8.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])=O.Cl.[CH3:17][O:18][CH2:19][C:20](=[NH:22])[NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:17][O:18][CH2:19][C:20]1[NH:21][C:3]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[CH3:15])[C:8]([O:10][CH3:11])=[O:9])=[CH:2][N:22]=1
Reactant: COC(=O)c1ccc(C)c(C(=O)CBr)c1
Reactant: COCC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCc1ncc(-c2cc(C(=O)OC)ccc2C)[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 18.5 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-bromoacetyl)-4-methylbenzoate (compound 27.2, 281 mg, 1.04 mmol) in ACN (5 mL). 2-Methoxyacetimidamide (compound 4.7, 194 mg, 1.56 mmol) and potassium carbonate (434 mg, 3.14 mmol) were added and the resulting mixture was stirred for 12 hours at 80° C., then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as the eluent to yield 50 mg (19%) of the title compound as a brown solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]([O:33][CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12].[Li+].[OH-].O>CO.C(OCC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([O:33][CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1OCCOc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1OCCOc1ccccc1
Yield: 73.2 %

Procedure:
The title compound 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinic acid (27) was prepared by the following procedure: A mixture of methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinate (27D) (114 mg, 0.20 mmol) and LiOH (18 mg, 0.75 mmol) was stirred in MeOH (3 mL) and water (1 mL) for 20 hours. The mixture was diluted with diethyl ether (2 mL) and the aqueous layer was separated and acidified with 1M HCl. The precipitate was filtered, washed with EtOAc, and dried to provide 83 mg (75%) of the desired product 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-phenoxyethoxy)picolinic acid (27): 1H NMR (300 MHz, DMSO-d6) δ 7.98 (1H, d), 7.77 (2H, d), 7.65 (1H, m), 7.38-7.18 (6H, m), 6.99-6.91 (4H, m), 4.46 (2H, m), 4.31 (2H, m), 3.93 (2H, m), 2.79 (2H, m), 1.90 (2H, m). LC/MS (APCI): m/z 567.2 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:20][CH2:19][CH2:18][N:14]1[C:13]2[CH:28]=[CH:29][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:11][C:12]=2[N:16]=[C:15]1[CH3:17]
Reactant: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCN

Procedure:
5-(Benzoxazol-2-yl)-1-(2-(tert-butoxycarbonylamino)ethyl)-2-methylbenzimidazole (see Working Example 55-2) (100 mg, 0.255 mmol) was added to a 4N hydrochloric acid solution in dioxane (10 mL), and this was heated to reflux for 5 hours. After the reaction was complete, this was concentrated to dryness to yield the title compound (95 mg, quant.) as white crystals.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH:17](=[O:23])/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH3:22]>C(O)C>[C:2]([N:5]1[CH:17]([OH:23])[CH2:18][CH:19]([CH2:20][CH2:21][CH3:22])[C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCC/C=C/C=O
Agent: [Na]
Solvent: CCO
Product: CCCC1CC(O)N(C(C)=O)C1(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Sodium metal (3.48 g, 0.15 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (201.6 g, 0.93 mol) in anhydrous ethanol (1200 mL) at room temperature under nitrogen. The reaction mixture was cooled to 0° C. and trans-2-hexenal (100.0 g, 1.02 mol) was then added dropwise. The resulting mixture was allowed to warm to room temperature. After stirring for 3 hours at 23° C., the reaction was quenched with 24 mL of acetic acid. The solution was concentrated in vacuo and the resulting residue was taken up in ethyl acetate and washed with saturated aqueous NaHCO3 (2×) and brine. Dried over anhydrous magnesium sulfate, concentation and recrystallization of the residue from EtOAc/Hexane gave 271.4 g (93% yield) of the title compound as fine needles, mp 105°-106° C. TLC, Rf =0.43 (9:1 CHCl3 /MeOH). MS(CI) m/e 316 (M+1)+, 298 (MH-H2O)+ . 1H NMR (CD3OD, 300 MHz) δ0.94 (t, J=7.2 Hz, 3H), 1.47-1.11 (m, 9H), 1.90-1.78 (m, 1H), 1.94 (dd, J=12.8, 5.2 Hz, 1H), 2.08 (dd, J=12.8, 6.4 Hz, 1H), 2.21 (s, 3H), 2.83 (m, 1H), 4.10-4.26 (m, 4H), 5.64 (d, J=5.2 Hz, 1H). IR (CDCl3) 3460, 1750, 1665 cm-1. Anal. calcd. for C15H25NO6 : C, 57.13; H, 7.99; N, 4.44. Found: C, 57.28; H, 8.08; N, 4.42.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8](O)=[O:9])[C:4](=[O:11])[O:3]1.B>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Agent: B
Solvent: C1CCOC1
Product: CC1(C)OC(=O)[C@H](CCO)O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
A 500 mL round bottom flask equipped with a nitrogen adapter and a temperature probe was charged with 10.0 g (57 mmol, 1 eq) of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid and 35 mL of anhydrous THF. The solution was cooled to 0° C. using an ice bath and 75 mL (75 mmol, 1.3 eq) of 1.0 M borane in THF was slowly charged. Upon complete addition, the flask was slowly warmed to ambient temperature and consumption of starting material was monitored by TLC. After stirring for 3 hours, starting material was consumed and the flask was cooled to 0° C. and quenched by the slow addition of 50 mL of methanol. The resulting solution was concentrated under reduced pressure at 25° C. The residue was dissolved in 100 mL of methanol and concentrated under reduced pressure at 25° C. The residue was dissolved in 100 mL of EtOAc and concentrated under reduced pressure and the clear oil was dried in vacuo to yield 9.3 g (58 mmol, 100% yield) of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-ethanol as clear colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.58 (dd, J=5.03 and 7.49 Hz, 1H), 3.82–3.88 (m, 2H), 2.13–2.20 (m, 1H), 1.96–2.07(m, 1H), 1.64 (s, 3H), 1.57 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[CH:15]([O:17]CCCC)=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1)(=[O:17])[CH3:16]
Reactant: C[C@@H](NS(C)(=O)=O)c1ccc(Br)cc1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CC(=O)c1ccc([C@@H](C)NS(C)(=O)=O)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
Charge a tube with N-[(1R)-1-(4-bromophenyl)ethyl]methanesulfonamide (29 g, 104 mmol), butyl vinyl ether (34.23 mL, 261 mmol), palladium(II) acetate (14.04 g, 63 mmol), bis-(1,3-diphenylphosphino)propane (52.7 g, 125 mmol) and potassium carbonate (17.3 g, 125 mmol). Degas the tube with nitrogen for 2 minutes, and then add H2O (69.5 mL) and DMF (69.5 mL). Seal the tube and stir at 110° C. for 20 h. Cool the reaction mixture to ambient temperature and add HCl (2N, 60 mL). Stir the mixture at ambient temperature for 10 min. Adjust the pH of the mixture to a pH of 7 using NaOH pellets; dilute with DCM (220 mL); filter through a Celite® pad; and sequentially wash the filtrate with aqueous K2CO3 (2×120 mL), brine (2×100 mL), and H2O (100 mL). Dry the mixture over MgSO4; filter; and concentrate the filtrate under reduced pressure to provide a residue. Purify the residue via flash column chromatography eluting with EtOAc in hexanes (step gradient of 0, 5, 10, 20, 30 and finally 40% EtOAc). Combine the product fractions and remove the solvents under reduced pressure to give the title compound (17.6 g, 70.0%) as a yellow oil. MS (m/z): 242 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:31])[CH2:25]OS(C)(=O)=O)=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:32])[CH2:4][CH3:5])[CH3:2].[CH2:33]([CH2:35][NH2:36])[OH:34]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([OH:31])[CH2:25][NH:36][CH2:35][CH2:33][OH:34])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:32])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)COS(C)(=O)=O)cc3)no2)cc1C
Reactant: NCCO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CNCCO)cc3)no2)cc1C
Yield: 17.3 %

Procedure:
The title compound (16 mg) is prepared starting from rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (100 mg, 208 μmol) and ethanolamine (64 mg, 1.04 mmol) in analogy to Example 168 step b); LC-MS: tR=0.63 min; [M+1]+=445.07; 1H NMR (CDCl3): δ1.10 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 2.53 (s br, 2H), 2.59-2.67 (m, 5H), 2.77-2.90 (m, 5H), 3.69 (t, J=5.0 Hz, 2H), 3.72 (s, 2H), 3.95-4.03 (m, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.66 (s, 1H), 8.08 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26].[Li]CCCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: COc1cc(C)nc(N(C)C)n1
Reactant: COCOCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution containing 933 mg (5.58 mmol) of 4-methoxy-N,N,6-trimethylpyrimidin-2-amine and 1.5 g (5.58 mmol) of 1-Bromo-9-(methoxymethoxy)nonane in 20 mL of anhydrous THF were added 5.23 mL (8.37 mmol) of 1.6 M n-BuLi in hexanes. The reaction mixture was stirred at 23° C. for 20 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and poured into 100 mL of water. The compound was extracted with two 80-mL portions of ethyl acetate. The combined organic layer was washed with one 80-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 9:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 1.41 g (71%); silica gel TLC Rf 0.45 (9:1 hexanes-ethyl acetate); 1H-NMR (CDCl3) δ 1.24-1.32 (br m, 10H), 1.82 (m, 4H), 2.48 (dd, 2H, J=8.0, 8.0 Hz), 3.14 (s, 6H), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.85 (s, 3H), 4.59 (s, 2H) and 5.76 (s, 1H); 13C NMR (CDCl3) δ 26.18, 28.46, 28.66, 29.29, 29.39, 29.45, 29.54, 29.72, 36.77, 37.81, 37.81, 52.74, 55.04, 67.85, 93.03, 96.35, 162.35, 170.25 and 172.03; mass spectrum (APCI+), m/z 354.2766 (M+H) (C19H36N3O3 requires 254.2757).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[NH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][C:39]=1[Cl:46]>CN(C=O)C>[NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[N:4]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[C:39]([Cl:46])[CH:40]=2)[N:3]=1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(N)c32)C1=O
Reactant: Fc1ccc(CBr)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6S)-4-amino-8-ethyl-10-methoxy-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.94 g, 3.23 mmol) in anhydrous DMF (32 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (3.87 mL, 1 M, 3.87 mmol) was added. The mixture was stirred at room temperature for 15 minutes and treated with 4-fluoro-3-chlorobenzyl bromide (0.72 g, 3.23 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-20% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title material.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCC[C@@H](COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@@H](COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
The ester (1 g), dissolved in 20 ml THF/5 ml H2O/5 ml methanol, was treated with 380 mg of lithium hydroxide hydrate. The mixture was stirred at room temperature 4 hours. The mixture was diluted with 50 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 100 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 50 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified recrystalization from acetonitrile/water, yielding 796 mg of product as shining platelets. M.p. 74-76° C., [α]D=−22.2 (c=0.500, in CHCl3).