Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.Cl.[CH:18]([OH:21])([CH3:20])[CH3:19]>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[OH:10][CH:1](/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][C:12](=[O:16])[CH2:13][C:14]([O:21][CH:18]([CH3:20])[CH3:19])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)O
Reactant: O=C/C=C/c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(=O)CC(=O)CC(O)/C=C/c1ccccc1
Temperature: 0 °C

Procedure:
In an atmosphere of argon, 9 ml of dichloromethane and 0.55 ml (5.0 mmol) of titanium tetrachloride were introduced in a schlenk tube, and cooled to 0° C. with stirring. To the dichloromethane solution, 0.68 g (5.2 mmol) of E-cinnamaldehyde and 0.77 ml (10 mmol) of diketene were added, and were vigorously stirred at 0° C. over 30 minutes to obtain a reaction mixture. To the reaction mixture, 2 ml of isopropyl alcohol was added, and vigorously stirred at 0° C. over 30 minutes. The reaction mixture was then added to a mixed solution of 25 ml of 1N HCl and 25 ml of dichloromethane, and vigorously stirred at room temperature over 30 minutes to give a solution. The solution was extracted with three portions of 5 ml of dichloromethane. The dichloromethane portions were combined, and dried by adding anhydrous magnesium sulfate. The solvent of the solution was removed by distillation in vacuo to obtain a concentrated solution. The concentrated solution was placed on a silica gel column and eluted with a mixture of hexane and ethyl acetate (hexane:ethyl acetate=7:3), a fraction corresponding to isopropyl E-5-hydroxy-3-oxo-7-phenyl-6-heptenoate was obtained in the same manner as Example 6. However, the fraction did not show the same peaks of NMR as those corresponding the isopropyl E-5-hydroxy-3-oxo-7-phenyl-6-heptenoate obtained in Example 6.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCCc1ccccc1
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Product: CC(C(=O)NC(=O)OCCCCc1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound, yellow oil, MS: m/e=401.5 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and 4-phenyl-butan-1-ol.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]>OS(O)(=O)=O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
HNO3 (10.35 g, 98.6 mmol) was added dropwise to a stirred solution of 2-(2-chloro-4-fluorophenyl)acetic acid (16.9 g, 89.6 mmol) in conc. H2SO4 (60 mL) at −10° C. After complete addition, the resulting mixture was stirred at 0° C. for 10 min, and was carefully poured into ice water. The off-white solid was collected by filtration and dried to give 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 98.2% yield). 1HNMR (400 Hz, DMSO-d6): δ 12.71 (br s, 1 H), 8.33 (d, J=8.0 Hz, 1 H), 7.92 (d, J=11.2 Hz, 1 H), 3.85 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]#[C:9][CH2:10][OH:11].C(NCC)C.BrC1C=CC=CN=1>[Cu]I.C(OCC)C>[C:2]1([C:8]#[C:9][CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: Brc1ccccn1
Solvent: CCOCC
Solvent: CCNCC
Product: OCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.7 g (1 mmol) of bis-triphenylphosphinepalladium dichloride and 0.38 g (2 mmols) of copper (I) iodide is added, with stirring, to 31.6 g (200 mmols) of bromobenzene, 16.8 g (300 mmols) of 1-propyn-3-ol and 300 ml of diethylamine. The reaction mixture is stirred in an argon atmosphere at room temperature (20°-25° C.), and within one hour the mixture heats up to about 30° C. A precipitate commences to occur, and after a reaction time of 6 hours, no further bromopyridine can be detected according to chromatographic analysis. 200 ml of diethyl ether are added to the reaction mixture and this is then filtered. The filtrate is washed with 200 ml of water, dried over magnesium sulfate, and concentrated by evaporation to leave a solid residue. Recrystallisation from diethyl ether yields 1-(phenyl)-propyn-3-ol. 1H-NMR Spectrum 100 MHz (CDCl3, TMS) δ in ppm: 2.4(s); 4.5(s); 7.2-7.5(m) in the ratio of 1:2:5.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][C:24]([CH:26]([C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)[NH2:27])=[N:23][N:22]=1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:27][CH:26]([C:24]3[O:25][C:21]([CH3:20])=[N:22][N:23]=3)[C:28]3([CH3:32])[CH2:31][O:30][CH2:29]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: Cc1nnc(C(N)C2(C)COC2)o1
Product: Cc1nnc(C(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)C2(C)COC2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and (5-methyl-1,3,4-oxadiazol-2-yl)-(3-methyloxetan-3-yl)methanamine (example 245b) as starting materials and isolated (31 mg, 44%); MS (ESI, m/z): 441.7 (M+H+).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10]C=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][NH2:21].O.OC1C2N=N[NH:31]C=2C=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH3:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][NH:21][C:12]([C:11]1[CH:10]=[N:31][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:16][CH:15]=1)=[O:13]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)CCN
Reactant: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(C(=O)NCCC(C)(C)C)cn1
Reaction time: 8 h
Yield: 89.4 %

Procedure:
A solution of compound 4 (223 mg, 1.0 mmol) in dimethylformamide (2.5 mL) under argon at room temperature was treated with 3,3-dimethylbutyl amine (111 mg, 1.1 mmol), ethyl-3-(3-dimethylamino)-propylcarbodiimide hydrochloride (327 mg, 1.1 mmol) and hydroxybenzotriazole monohydrate (148 mg, 1.1 mmol) and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% citric acid, water, dilute sodium bicarbonate, water and brine, dried (anhydrous mnagnesium sulfate) and concentrated to give an oil. Flash chromatography on silica gel and elution with ethyl acetate/hexanes (1:4) gave an oil (274 mg) that slowly solidified, mp 75-76.5° C. Analysis calculated for C18H30N2O2: C, 70.55; N, 9.87; N, 9.14. Found: C, 70.46; H, 10.06; N, 9.02.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:32](=[CH:36][CH:37]1[CH2:39][CH2:38]1)[C:33](O)=[O:34])#[N:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([C:32](=[CH:36][CH:37]3[CH2:39][CH2:38]3)[C:30]#[N:31])=[O:34])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: N#CC(=CC1CC1)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
To a mixture of (S)-5-(4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.26 mmol, 1.0 eq), 2-cyano-3-cyclopropyl-acrylic acid (45 mg, 0.32 mmol, 1.2 eq) and DIEA (102 mg, 0.78 mmol, 3.0 eq) in 10 ml DCM was added HATU (150 mg, 0.40 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-TLC to give the title compound (71 mg). LCMS: m/z 486.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.[C:24]1([S:30]([N:33]2[C:37]3=[N:38][CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]3[C:35]([CH:43]=[O:44])=[CH:34]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:43]([C:35]2[C:36]3[C:37](=[N:38][CH:39]=[C:40]([Cl:42])[CH:41]=3)[N:33]([S:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:32])=[O:31])[CH:34]=2)[OH:44])=[CH:6][CH:7]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Reactant: Nc1ccc(Br)cn1
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To 2-amino-5-bromopyridine (15, 3.10 g, 17.9 mmol) in tetrahydrofuran (80.0 mL) under an atmosphere of nitrogen at −78° C., a solution n-butyllithium (2.50M in hexane, 7.10 mL) was added slowly. After 30 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (3.90 g dissolved in tetrahydrofuran 20.0 mL, 18.1 mmol) was added to the reaction mixture slowly, and then allowed to warm to room temperature for 1 hour. The reaction was cooled to −78° C. followed by adding a solution of n-butyllithium (2.50M in Hexane, 7.10 mL). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 60 minutes. The reaction mixture was cooled to −78° C., followed by adding a solution of n-butyllithium (2.50M in Hexane, 7.50 mL) slowly. After 60 minutes, 1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (597, 1.90 g in 30 mL tetrahydrofuran, 5.92 mmol) was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound (598, 1.25 g, 50.9%). MS (ESI) [M+H+]+=415.2.
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.[CH2:10]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:29]=1)[CH2:25]O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>ClCCl>[CH2:10]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:29]=1)[CH2:25][Cl:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCC)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Dry dichloromethane (5 mL), DMF (3.04 mL, 39.2 mmol) and a magnetic stir bar were placed into a 250 mL RBF, and the RBF was sealed with a rubber septum. N2 inlet and outlet needles were inserted into the septum. The flask was then cooled to 0° C. in an ice bath. Thionyl chloride (2.86 mL, 39.2 mmol) was added to the RBF via a syringe. The RBF was placed into an ice bath and cooled to 0° C. 3,5-diundecoxybenzyl alcohol (15.0 g, 35.7 mmol) was dissolved in a solution of dichloromethane (60 mL) and pyridine (2.88 mL, 35.7 mmol). This solution was added to the RBF via a syringe cautiously over 20 minutes. The reaction mixture gradually changed from a transparent yellow color to an opaque yellow color. The beaker used to dissolve the 3,5-diundecoxybenzyl alcohol was rinsed with dichloromethane and the rinses were added to the RBF. The RBF was removed from the ice bath and the reaction mixture was stirred overnight. The solution was then concentrated using rotary evaporation. A solution of 50/50 ether/hexanes (100 mL) was added to the RBF, changing the solution color from deep yellow to opaque white. The liquid was decanted leaving behind any solid. The RBF was rinsed in this manner 2 more times, saving the decanted liquid. The decanted liquid was run through a silica gel baseline filtration apparatus. The filtrate was then concentrated using rotary evaporation. The compound solidified after approximately 2 hours under high vacuum. This produced a 14.8 g yield or a 94.5% yield of the derivative. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.9, 6H, CH2CH3), 1.27-1.45 (m, 32H, CH2(CH2)8), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.92 (t, J=6.6, 4H, OCH2), 4.50 (s, 2H, ArCH2Cl), 6.39 (t, J=2.2, 1H, ArH), 6.50 (d, J=2.2, 2H, ArH). 13C NMR (75 MHz, CDCl3): 14.23, 22.79, 26.13, 29.31, 29.45, 29.48, 29.68, 29.71, 32.01, 46.56, 68.19, 101.32, 106.97, 139.38, 160.53.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2cnc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2cnc(N)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of 3.25 g of 2-amino-5-(p-tolyl)-3-nitro-pyridine (compound G3) and 325 mg of Pd/C (10%) in 260 ml of methanol is treated with hydrogen under vigorous stirring at room temperature for 18 h. The suspension is filtered with suction through a celite pad. The colorless filtrate is evaporated to dryness to afford 2.63 g of the pure title compound of m.p. 141° C. MS: 200.3 (MH+).
Reaction SMILES: [N-]=[N+]=[N-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:24]([CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]3=[O:45])=[CH:35][C:34]=2[F:46])[NH:31][CH:32]=1)=[N+]=[N-]>>[NH2:24][CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]3=[O:45])=[CH:35][C:34]=2[F:46])[NH:31][CH:32]=1
Reactant: [N-]=[N+]=NCc1c[nH]c(-c2ccc(-n3ccccc3=O)cc2F)n1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCc1c[nH]c(-c2ccc(-n3ccccc3=O)cc2F)n1

Procedure:
Alternatively as shown in Scheme 4, 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared as above, is treated with 4-hydroxymethylimidazole II-1 in the presence of 8-hydroxyquinoline, and K2CO3 in DMSO. The resulting mixture is degassed before being charged with CuI to give 4-hydroxymethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-1. The compound 4-1 is treated with thionyl chloride to give 4-chloromethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole which is then treated with NaN3 to result in 4-azidomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-2. The azide 4-2 is reduced with Ph3P to give 4-aminomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-3. The compound 4-3 is then treated with 5-chlorothiophene-2-carboxylic acid 1-5 to give the title compound 21.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].COC(SCl)=O.[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(Cl)Cl>[CH:18]1[CH:19]=[C:14]([S:13][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[N:15]=[CH:16][CH:17]=1
Reactant: Sc1ccccn1
Reactant: O=C(O)CCS
Agent: COC(=O)SCl
Solvent: ClCCl
Product: O=C(O)CCSSc1ccccn1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
5.00 g (52.2 mmol) of 3-mercaptopropanoic acid (Aldrich Chemical Co., Milwaukee, Wis.) in 75 ml of dry methylene chloride was added to a solution of 5.96 g (52.2 mmol) of methoxycarbonylsulfenyl chloride (Fluka Chemika, Long Island, N.Y.) in 150 ml of dry methylene chloride. The mixture was stirred at 15-25° C. for 90 minutes and then concentrated. The residue was redissolved in 150 ml of dry methylene chloride and dropwise treated with 5.80 g (52.2 mmol) of 2-mercaptopyridine (Aldrich Chemical Co.) in 75 ml of dry methylene chloride. The mixture was stirred at 15-25° C. for 18 hours and concentrated to afford 11.2 g of the product as a pale yellow oil (99%).
Reaction SMILES: C(O)(=O)CCCCCCCCCCCCCCC.[C:19]([OH:38])(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.C(O)(=O)CCCCCCC/C=C\C/C=C\CCCCC>>[CH3:36][CH2:35]/[CH:34]=[CH:33]\[CH2:32]/[CH:31]=[CH:30]\[CH2:29]/[CH:28]=[CH:27]\[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]([OH:38])=[O:37]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O

Procedure:
Refined, bleached, and deodorized high oleic soybean oil (RBD HOS oil) containing triglycerides of the following fatty acids: palmitic acid (6.5 wt %), stearic acid (4.15 wt %), oleic acid (73.9 wt %), linoleic acid (8.77 wt %), and linolenic acid (2.94 wt %) was obtained according to U.S. Pat. No. 5,981,781. Crude high oleic soybean oil (HOS oil) containing palmitic acid (6.5 wt %), stearic acid (4.1 wt %), oleic acid (74.8 wt %), linoleic acid (7.6 wt %), and linolenic acid (2.8 wt %) was obtained according to U.S. Pat. No. 5,981,781. Commodity Market Pantry™ brand name soybean oil containing triglycerides of the following fatty acids: palmitic acid (10.3 wt %), stearic acid (4.6 wt %), oleic acid (22.7 wt %), linoleic acid (53.5 wt %), and linolenic acid (7.2 wt %) was purchased from a Target store.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]3[C:28]([C:29]([OH:31])=O)=[C:27]([CH3:32])[S:26][C:25]=3[CH:33]=2)[CH:12]=1)=[O:10].[NH2:34][CH2:35][CH2:36][CH2:37][OH:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[OH:38][CH2:37][CH2:36][CH2:35][NH:34][C:29]([C:28]1[C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[CH:12]=[C:11]([C:9]([N:5]5[CH2:6][CH2:7][CH2:8][C@H:4]5[CH2:3][O:2][CH3:1])=[O:10])[S:19][C:18]=34)=[CH:33][C:25]=2[S:26][C:27]=1[CH3:32])=[O:31]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)O)c(C)sc4c3)c2s1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NCCCO)c(C)sc4c3)c2s1
Yield: 87.7 %

Procedure:
This material was prepared by the reaction of 6-[(2-{[(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 121b (45 mg, 0.093 mmole) with 3-amino-1-propanol (21 μL, 0.28 mmole), HBTU (53 mg, 0.14 mmole), and diisopropylethylamine (36 μL, 0.21 mmole) in a manner as previously described for example 117 to give a yellow solid (44 mg, 88%). 1NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.27 Hz), 8.36 (1H, t, J=5.46 Hz), 8.03 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.82 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=1.70, 8.67 Hz), 6.75 (1H, d, J=5.27 Hz), 4.51 (1H, t, J=5.18 Hz), 4.30 (1H, m), 3.85 (2H, m), 3.37 (2H, m), 3.27 (3H, s), 2.60 (3H, s), 2.09-1.83 (4H, m), 1.71 (2H, m).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.Cl.CCOCC>[C:18]([C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:4]=1[CH:3]=[O:2])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=Cc1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1

Procedure:
A solution of crude ketone from Step 1 in acetone (250 mL) and HCl 10% (25 mL) was stirred for 6 hours, diluted with Et2O, washed with a saturated NH4Cl solution, H2O (3×), brine and dried (MgSO4). After evaporation of the solvent, the residue was saturated with hexane and filtered to afford the title compound as pale yellow solid.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3](O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:11]>>[Cl:11][CH2:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cl
Reactant: OCc1ccccc1
Reactant: C=O
Product: ClCOCc1ccccc1
Yield: 33 %

Procedure:
Paraformaldehyde (152 g) power was added to stirred benzyl alcohol (750 g, 6.94 mol), and HCl gas was bubbled into the reaction mixture. The exhaust gas was scrubbed with conc aq NaOH. Reaction progress was monitored by 1H NMR. When the starting material had been consumed, N2 was bubbled through the reaction mixture to remove HCl gas. The mixture was partitioned between water and n-pentane. The organic layer was dried over MgSO4, concentrated, and distilled under vacuum to afford ((chloromethoxy)methyl)benzene boiling at 60-63° C. (350 g, 33%). 1H NMR (400 MHz, CDCl3): 4.76 (s, 2H), 5.54 (s, 2H), 7.36 (m, 5H)
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)N.[Cl:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:13]=[CH:12][N:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]2[NH:1][C:3]3=[N:4][CH:5]=[CH:6][N:7]=[C:8]3[C:17]=2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:13]=[CH:12][N:11]=1
Reactant: NNc1cnccn1
Reactant: O=C(Cc1ccc(F)cc1)c1ccnc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(-c2c(-c3ccnc(Cl)c3)[nH]c3nccnc23)cc1
Reaction time: 2 h
Yield: 26.5 %

Procedure:
Hydrazinopyrazine (6.2 g, 57 mmol) and 1-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)ethanone (14 g, 57 mmol) were suspended in benzene (250 ml) and p-toluenesulfonic acid monohydrate (0.68 g) was added. The reaction mixture was then refluxed with azeotropic removal of water via Dean Stark trap. After 2 h, the benzene was removed in vacuo and di-ethylene glycol was added. The reaction mixture was heated at reflux. After 2 h, the reaction mixture was poured into ether with vigorous stirring. Water was added and the product was extracted into ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Methanol was added and the solid was filtered off to give 6-(2-chloropyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine (4.9 g) as a solid.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1cccnc1
Product: CC(C)N1C(=O)NC(c2cccnc2)c2cc3c(cc21)OCO3
Yield: 36 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (238 mg) and 3-pyridinecarboxaldehyde (100 μL) by the procedure described in example 10 in 36% yield. mp: 172-174° C. 1H NMR (CDCl3): 8.58-8.56 (m, 3H), 7.63 (m, 1H), 7.29 (m, 2H), 6.70 (s, 1H), 6.34 (s, 1H), 5.94 (d, J=1.3, 1H), 5.92 (d, J=1.3, 1H), 5.33 (s, 1H), 5.9 (s, 1H), 4.41 (m, 1H), 1.53 (d, J=6.8, 3H), 1.50 (d, J=6.8, 3H).