Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[CH:12][NH:11][N:10]=1.Cl[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([CH2:15][N:11]1[CH:12]=[CH:13][C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:10]1)#[N:17]
Reactant: Fc1cccc(F)c1-c1cc[nH]n1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCn1ccc(-c2c(F)cccc2F)n1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
3.0 g of 3-(2,6-difluorophenyl)pyrazole was dissolved in 20 ml of acetonitrile, and 2.52 g of chloroacetonitrile and 4.61 g of potassium carbonate were added thereto at room temperature, and heated under reflux for 5 hours. After acetonitrile was distilled off under reduced pressure, ethyl acetate was added to the residue, which was then washed with a small amount of water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropylether and diethyl ether to obtain 1.74 g of l-cyanomethyl-3-(2,6-difluorophenyl)pyrazole. 2) A solution of 0.5 g of 1-cyanomethyl-3-(2,6-difluorophenyl)pyrazole dissolved in 10 ml of THF was dropwise added to a suspension of 0.15 g of 55% sodium hydride in 10 ml of THF, at; 50° C. After the resulting product was stirred for 30 minutes, a solution of 0.67 g of 1-(1-methyl-3,5-dichloropyrazole-4-carbonyl)pyrazole dissolved in 10 ml of THF was dropwise added thereto at 50° C. and then stirred overnight at room temperature. The reaction mixture was poured into water, then extracted with ethyl acetate and washed with a small amount of water. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropyl ether/ethyl acetate=3/1 to obtain 0.52 g of 2-(3-(2,6-difluorophenyl)pyrazol-1-yl)-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](O)(=O)[CH2:34]C/C=C\CC=CCC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:33][CH3:34]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O

Procedure:
This compound was prepared as described above for (6) using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid; yield 91 mg (37%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 12H, 6HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][S:43]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)(=[O:45])=[O:44])=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C=CC(NS(=O)(=O)c2ccccc2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.08 M and 0.16 M in dichloromethane, respectively, 500 μL, 0.042 mmol Example 23e and 0.083 mmol N,N-diisopropylethylamine), and benzenesulfonyl chloride (0.40 M in dichloromethane, 239 μL, 0.096 mmol) were mixed and stirred at ambient temperature overnight. The reaction mixture was concentrated, dissolved in methanol (1 mL) and injected on the reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to yield the title compound as an impure mixture.
Reaction SMILES: C([CH2:6][NH:7][NH:8][C:9]([NH:11][CH:12]=O)=[S:10])(OCC)=O.[OH-:14].[K+].S(=O)(=O)(O)O.[CH2:21]([OH:23])C>>[C:21]([CH2:12][N:11]1[CH:6]=[N:7][N:8]=[C:9]1[SH:10])([OH:23])=[O:14]
Reactant: CCO
Reactant: CCOC(=O)CNNC(=S)NC=O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)Cn1cnnc1S

Procedure:
1-Carbethoxymethyl-4-formylthiosemicarbazide (0.50 g., 2.44 mmol.) was dissolved in 5 ml. of ethanol and 5 ml. (2 equivalents) of aqueous potassium hydroxide solution was added. The reaction mixture was refluxed for five hours then cooled, acidified to pH 2.0 with 6N sulfuric acid and evaporated to dryness. The residue was extracted with acetone to give 4-carboxymethyl-1,2,4-triazole-3-thiol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:35]2[CH:47]=[CH:46][C:38]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:35]2[CH:36]=[CH:37][C:38]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:46][CH:47]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (0.30 g, 0.72 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.26 g, 0.865 mmol) and Pd(PPh3)4 (0.042 g, 0.036 mmol) in 1,4-dioxane (6 mL) was purged with argon for 10 min. 2M Na2CO3 solution (0.27 g, 2.54 mmol) was then added before an additional argon purged for 10 min. The reaction mixture was stirred at 80° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give corresponding N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (0.20 g, 55.7%). LCMS: 514.25 (M+1)+; HPLC: 99.71% (@ 254 nm) (Rt; 5.075); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 8.63 (t, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.81 (d, 2H, J=6.8 Hz), 7.43 (d, 2H, J=7.6 Hz), 5.88 (s, 1H), 5.17-5.14 (m, 1H), 4.38 (d, 2H, J=3.2 Hz), 3.59 (m, 4H), 3.52 (s, 2H), 2.38 (m, 4H), 2.21 (s, 3H), 2.12 (s, 3H), 1.49 (d, 6H, J=6.8 Hz).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[F:21][C:22]([F:45])([F:44])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])(=[O:31])=[O:30].Cl.CN(C)CCCN=C=NCC.Cl.Cl.[N:60]1([CH2:65][CH2:66][O:67][C:68]2([C:74]3[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=3)[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)[CH2:64][CH2:63][CH2:62][CH2:61]1>C(Cl)Cl>[N:76]1[CH:77]=[CH:78][CH:79]=[C:74]([C:68]2([O:67][CH2:66][CH2:65][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)[CH2:73][CH2:72][N:71]([C:41](=[O:42])[CH2:40][CH2:39][CH2:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][N:32]3[S:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:21])([F:45])[F:44])(=[O:30])=[O:31])[CH2:70][CH2:69]2)[CH:75]=1
Reactant: O=C(O)CCCC1CCCCN1S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: c1cncc(C2(OCCN3CCCC3)CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCC1CCCCN1S(=O)(=O)c1ccccc1C(F)(F)F)N1CCC(OCCN2CCCC2)(c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-Hydroxybenzotriazole hydrate (HOBT) (0.021 g, 0.158 mmol, 0.3 eq.) and N-ethyl-diisopropylamine (0.269 ml, 1.59 mmol, 3 eq.) were added to a solution of 4-(1-(2-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)butanoic acid (0.251 g, 0.66 mmol, 1.25 eq.) in methylene chloride (7 ml). The mixture was cooled to 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.152 g, 0.792 mmol, 1.5 eq.) was added and the mixture was stirred for approx. 15 min. 3-(4-(2-(Pyrrolidin-1-yl)ethoxy)piperidin-4-yl)pyridine dihydrochloride (0.184 g, 0.528 mmol, 1 eq.) was then added. The reaction mixture was stirred at room temperature for 72 h.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([S:12]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)=[O:13])[NH:9][C:8]=2[CH:25]=1.[Cl-].[Mg+2:27].[Cl-]>O>[OH2:3].[OH2:3].[OH2:3].[OH2:3].[Mg:27].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([S@:12]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)=[O:13])[NH:9][C:8]=2[CH:25]=1
Reactant: [Mg+2]
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Product: [Mg]
Reaction time: 0.08 h

Procedure:
1.65 g of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt was dissolved in 30 mL of water. To the stirring solution was added 0.47 g of magnesium chloride dissolved in 20 mL of water. Immediately upon the addition of the magnesium chloride solution a white powder precipitated. The suspension was allowed to stir for 5 minutes, and then the product was isolated by vacuum filtration. The solids were then placed into a vacuum desiccator overnight to give the desired product as a white powder. A small portion of the powder was dissolved in methanol at about 75 mg/mL, filtered and diluted with a equal volume of water. This solution was partially covered and set aside to slowly evaporate. After approximately 5 days, crystals were isolated, analyzed by single crystal x-ray diffraction and shown to be the desired product.
Reaction SMILES: [NH2-].[Na+].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([CH:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:16]#[N:17])[CH:14]=CC=[CH:11][CH:10]=1.[O:24]1[CH2:29][CH2:28][N:27](CC[Cl:32])[CH2:26][CH2:25]1>C1(C)C(C)=CC=CC=1>[C:3]1([C:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)([CH:9]([CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH3:14])[C:16]#[N:17])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:32]
Reactant: c1ccccc1
Reactant: N#CC(c1ccccc1)c1cccnc1
Reactant: ClCCN1CCOCC1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(CCN1CCOCC1)C(C#N)(c1ccccc1)c1cccnc1
Product: Cl

Procedure:
To a stirred suspension of 7 parts of sodamide in 90 parts of benzene maintained at 30°-35° C there is added a solution of α-phenyl-3-pyridylacetonitrile, described in U.S. Pat. No. 3,225,054 in 70 parts of benzene. The mixture is then refluxed for 1 hour, cooled and treated by portionwise addition with one equivalent of 2-morpholinoethyl chloride (J. Chem. Soc. pp 505, 1949) in 45 parts of xylene at 30°-40° C. The resulting mixture is refluxed for 2 hours, cooled, filtered and extracted with dilute hydrochloric acid. The acid extract is rendered alkaline and extracted with ether. The ether extract is treated with gaseous hydrogen chloride to yield the hydrochloride 2-phenyl-2-(3-pyridyl)-2-morpholinoethylbutyronitrile.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CN(C)[CH:12]=[O:13].P(Cl)(Cl)(Cl)=O.O>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 85 °C
Reaction time: 2 h
Yield: 275.8 %

Procedure:
2,3-Dihydrobenzofuran (100 g, 832 mmol) and N,N-dimethylformamide (134 g, 1830 mmol) were mixed and heated, and phosphorus oxychloride (255 g, 1643 mmol) were added thereto at an inner temperature of 70 to 80° C. over 2 hrs. The reaction mixture was heated at an inner temperature of 80 to 90° C. and stirred for 7.5 hrs. Then, the resulting mixture was added dropwise to water (1000 g) under cooling, and stirred at room temperature for 5 hrs. The resulting mixture was extracted with toluene, and the extract was washed sequentially with water, saturated sodium bicarbonate aqueous solution and water, and the organic layer was concentrated under vacuum to give a toluene solution of the title compound (amount 340 g, apparent yield 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9])[CH3:2].[S:10]([Cl:14])(=O)(=[O:12])[OH:11]>>[CH2:1]([C:3]1[CH:8]=[C:7]([S:10]([Cl:14])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[F:9])[CH3:2]
Reactant: CCc1ccccc1F
Reactant: O=S(=O)(O)Cl
Product: CCc1cc(S(=O)(=O)Cl)ccc1F

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 65a by using 1-ethyl-2-fluorobenzene (2.30 g, 19.0 mmol) and chlorosulfuric acid (4.9 mL, 74.0 mmol), to yield the title compound in a crude form.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[CH2:20]([N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]=O)[CH3:21].[O-:29][CH2:30][CH3:31].[Na+]>C(OCC)(=O)CC>[CH2:20]([N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]1[C:30](=[O:29])[C:31]2[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=2[NH:7][CH:6]1[C:5]1[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: CCn1ccnc1C=O
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1CC)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 7.4 %

Procedure:
A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (765 mg, 3 mmol) and N-ethyl-2-imidazolecarbaldehyde (372 mg, 3 mmol) in ethyl propionate (45 mL) was cooled to 0° C. Then a solution of sodium ethoxide (sodium (276 mg, 12 mmol) in ethanol (45 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 4 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=25:1 to 5:1) to give the title compound (90 mg, yield: 7%). LC-MS (ESI) m/z: 408 (M+1)+.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7](O)([CH3:9])[CH3:8].CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:7]([O:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1)([CH3:9])[CH3:8]
Reactant: OC1C=CCC1
Reactant: CC(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OC1C=CCC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
2-Cyclopentenol (0.30 g), isopropanol (0.40 g), and an aqueous solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water were mixed, and the two-phase system was stirred vigorously at 40° C for 4 hours. Acetone was then added to homogenize the mixture, and it was analyzed by gas chromatography. Peaks corresponding to about a 6% yield of 2-cyclopentenyl isopropyl ether and about a 12% yield of 2-cyclopentenol were observed along with a concomitant peak for the co-product acetic acid. No bis-(2-cyclopentenyl) ether was formed.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccc1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.6 g, 0.020 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.4 g, 0.019 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 5 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of aniline (1.9 g, 0.020 mole) and triethylamine (2.1 g, 0.020 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into ice water (500 ml). The mixture was allowed to precipitate and was filtered. The filter cake was triturated in potassium bicarbonate solution (100 ml), filtered, and the cake washed with water (100 ml). Recrystallization from tetrahydrofuran-isopropyl ether and then isopropyl alcohol-ethanol-tetrahydrofuran give 3.8 g (49%) of an off-white solid, mp 242°-243.5° C.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](O)=[O:4].[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].[CH:15]1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[N:10]([CH3:15])[C:3](=[O:4])[CH:2]([Br:1])[CH3:6]
Reactant: CC(Br)C(=O)O
Reactant: Nc1ccccc1F
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)N(C)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
2-Bromopropionic acid(3.4 g, 0.022 mol) and 2-fluoroaniline(3 g, 0.024 mol) were dissolved in 50 ml of chloroform and cooled to 0° C. A solution of dicyclohexylcarbodiimide(5 g, 0.024 mol) in 10 ml of chloroform was slowly injected through a syringe. A temperature of the reaction mixture was raised to room temperature and it was stirred for 1 hour. Solid remained during the reaction was filtered out and washed twice with 20 ml of chloroform. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent; ethyl acetate/n-hexane=1/3) to afford 5 g of the target product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([CH:17]3[C:18]([CH3:20])([CH3:19])[C:16]3([CH3:24])[CH3:15])=[O:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(Br)ccc23)C1(C)C
Yield: 44 %

Procedure:
A mixture of 6-bromoindole (2.0 g. 10 mmol), ethylmagnesium bromide (1.0 M solution in THF, 12 mL, 12 mmol), zinc chloride (1.0 M solution in Et2O, 12 mL, 12 mmol) and the product of Example 1A (15 mmol) in 50 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.4 g, 4.4 mmol, 44% yield). MS (DCI/NH3) m/z 320, 322 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13].[N+:25]([C:28]1[CH:38]=[CH:37][C:31]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+]>O.O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[C@H:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:34]([O:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:38][CH:37]=2)=[O:35])[CH2:10]1
Reactant: NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Yield: 51.4 %

Procedure:
To a solution of (2S,4R)-2-(2-aminoethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.12 g) in a mixture of water (20 ml) and tetrahydrofuran (40 ml) was added a solution of 4-nitrobenzyloxycarbonyl chloride (0.85 g) in tetrahydrofuran (4 ml) under ice-cooling with stirring, keeping the pH between 8.5-9.5 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 2 hours. The reaction mixture was evaporated under reduced pressure and then ethyl acetate (50 ml) was added thereto. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.88 g).
Reaction SMILES: [NH:1]1[CH2:44][CH2:43][CH2:42][C@@H:2]1[C:3]([NH:5][C@H:6]([C:10]([N:12]([CH3:41])[C@H:13]([C:17]([N:19]1[CH2:40][CH2:39][CH2:38][C@H:20]1[C:21]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH2:46]=[O:47].[CH3:48][OH:49]>[Pd].C>[N:1]1([C:46]([O:49][CH2:48][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:47])[CH2:44][CH2:43][CH2:42][C@@H:2]1[C:3]([NH:5][C@H:6]([C:10]([N:12]([CH3:41])[C@H:13]([C:17]([N:19]1[CH2:40][CH2:39][CH2:38][C@H:20]1[C:21]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: C=O
Reactant: CC(C)[C@H](NC(=O)[C@H]1CCCN1)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C

Procedure:
1.94 g (3 mmol) of D-Pro-Val-MeVal-Pro-Pro-NHBn×HCl was dissolved in 30 ml methanol. To this solution was then added 0.3 g 10% Pd/charcoal and 1.5 ml aqueous formaldehyde solution and the reaction mixture was hydrogenated. Following filtration and evaporation of the solvents, the resulting residue was dissolved in water, adjusted to pH 2 and extracted twice with diethyl ether and several additional times with dichloromethane. The aqueous phase was adjusted to pH 9-10 and extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was crystallized as the hydrochloride salt to give 0.5 g of the desired product which was characterized by fast atom bombardment mass spectrometry ([M+H]+=625).