Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.[CH:22]1([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[SH:37])[CH2:26][CH2:25][CH2:24][CH2:23]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:22]1([N:27]2[C:28](=[O:38])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[S:37]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C(=O)NC2CCCC2)c(S)c1
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C3CCCC3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of bis(trifluoroacetoxy)iodobenzene (PIFA) (0.645 g, 1.5 mmol) in CH2Cl2 was added to a solution of N-cyclopentyl-2-mercapto-4-methoxybenzamide (0.251 g, 1 mmol) and trifluoroacetic acid (TFA) (0.23 mL, 3 mmol) in CH2Cl2 at 0° C. The resulting mixture was gradually warmed to room temperature. After 1 h, the solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography using dichloromethane to afford 2-cyclopentyl-6-methoxybenzo[d]isothiazol-3(2H)-one as a white solid (84%, 0.210 g). 1H NMR (300 MHz, CDCl3): δ 7.87 (d, 1H, J=8.5 Hz), 6.93 (s, 1H), 6.92 (d, 1H, J=8.2 Hz), 5.50-5.01 (m, 1H), 3.86 (s, 3H), 2.13-2.12 (m, 2H), 1.83-1.67 (m, 6H). LC-MS (ESI) Calcd for C13H15NO2S [M+H]+: 250.08. Found: 249.95.
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[H-].[Na+]>CS(C)=O>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C)cc2)cc1

Procedure:
(4-methoxy-phenyl)-acetic acid methyl ester Compound 22a was reacted with p-toluidine and sodium hydride in DMSO at room temperature to provide 2-(4-methoxy-phenyl)-N-p-tolyl-acetamide Compound 22b.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:19][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[O:17][N:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br-].[CH3:27][C:28]1[CH:29]=[CH:30][C:31]([Zn+])=[N:32][CH:33]=1.[K+].[K+].[K+].C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.ClCCl>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]3[CH2:19][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[O:17][N:16]=3)[CH:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[N:32][CH:33]=1
Reactant: Cc1ccc([Zn+])nc1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C2=NO[C@H](c3ccccn3)C2)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)[O-]
Agent: [Br-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl 3-bromo-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoate (19.95 g, 49.5 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.76 g, 1.48 mmol) in dioxane (247 mL) was added 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 198 mL, 99 mmol). The reaction mixture was heated to 75° C. After 1 h, the reaction was cooled to ambient temperature. Aqueous ethylenediaminetetraacetic acid tripotassium salt (0.4 M, 200 mL) and dichloromethane (200 mL) were added. The mixture was stirred for 15 min and the organic solvent was evaporated. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% ethyl acetate 98% ethyl acetate/methanol) gave the title compound (18.6 g). MS 416.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[CH:22]=[C:23]2[C:28]([CH:27]=[CH:26][CH:25]=[CH:24]2)=[N:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1cc2ccccc2n1

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and indazole (0.56 g, 4.74 mmol) gives the title compound.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].II.C(Cl)=C.[CH2:10]([CH:12]1[O:17][CH:16]([OH:18])[CH2:15][CH2:14][CH2:13]1)[CH3:11].[Cl-].[NH4+]>O1CCCC1>[OH:17][CH:12]([CH2:13][CH2:14][CH2:15][CH:16]([OH:18])[CH2:2][CH3:3])[CH:10]=[CH2:11]
Reactant: CCC1CCCC(O)O1
Reactant: CCBr
Agent: C=CCl
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC(O)CCCC(O)CC
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To 7.6 grams of magnesium in 7 milliliters of anhydrous tetrahydrofuran containing a few drops of ethyl bromide and a few milligrams of iodine maintained at 45°-48°C. was added, over a 4-hour period, 120 milliliters of a 20.8 weight per cent solution of vinyl chloride in tetrahydrofuran. The resulting reaction mixture was cooled to 30°C. and a solution of 13 grams of 6-ethyl-2-hydroxytetrahydropyran in 40 milliliters of tetrahydrofuran was added. After standing overnight, there was added ice and ammonium chloride. Extraction of the resulting mixture with three 250-milliliter portions of ether, washing with three 100-milliliter portions of sodium chloride, drying over sodium sulfate, and evaporation gave 16 grams of 3,7-dihydroxy-1-nonene.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH3:20]O>>[CH3:20][O:2][C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:8]=1[C:9]([NH2:11])=[O:10])=[O:3]
Reactant: Cc1cc(C)cc(-n2ncc(C(=O)O)c2C(N)=O)c1
Reactant: CO
Product: COC(=O)c1cnn(-c2cc(C)cc(C)c2)c1C(N)=O

Procedure:
A 1.1 g portion of the compound of Example 1 was suspended in 20 ml of methanol and hydrogen chloride gas was bubbled through the mixture for 1 minute. The mixture was then heated under reflux for 2 hours, and was poured into 50 ml of ice-water. The aqueous mixture was made basic with sodium hydroxide and was filtered, and the solids were dried under vacuum and recrystallized from toluene to obtain 0.14 g of the desired product, m.p. 179°-180°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1Br)=[O:4]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH:11]=[CH:10][CH2:9][CH2:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:5][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2ccccc2c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1
Reaction time: 2 h

Procedure:
530 mg g 1-bromo-naphthalene-2-carboxylic acid methyl ester and 9 mg tris(dibenzylideneacetone)dipalladium(0) were placed in a reaction vial, which was evacuated and backfilled with argon three times. Via septum 125 μl tri-tert.butylphosphine (10% in hexane), 291 mg 4-phenyl-1-butene, 470 μl N,N-dicyclohexylmethylamine and 1.8 ml dioxane were added. After 2 h at 80° C., the reaction mixture was cooled and filtrated over silica with diethyl ether. After concentration of the organic phase the resulting residue was purified by chromatography on silica (ethyl acetate/heptane) to yield 175 mg of a mixture of the (E)- and (Z)-isomers of 1-(4-phenyl-but-1-enyl)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][CH:14]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)#[N:4].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH:27]=O)[CH3:22].C(N(C(C)C)C(C)C)C.C([BH3-])#N.[Na+]>C(O)(C)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:3]([C:5]1([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][CH:14]=2)[CH2:10][CH2:9][N:8]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=2)[CH2:7][CH2:6]1)#[N:4]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: Cc1cncc(C(=O)NC2(C#N)CCNCC2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOc1cc(CN2CCC(C#N)(NC(=O)c3cncc(C)c3)CC2)ccc1C
Reaction time: 1 h

Procedure:
To a solution of N-(4-cyano-piperidin-4-yl)-5-methyl-nicotinamide dihydrochloride (171.0 mg, 0.54 mmol, 1.0 equiv) in isopropanol (5 mL) was added 3-ethoxy-4-methyl-benzaldehyde (88.7 mg, 0.54 mmol, 1.0 equiv; intermediate B10), titanium tetra-isopropoxide (766.5 mg, 2.70 mmol, 5.0 equiv) and N-ethyl diisopropylamine (209.5 mg, 1.62 mmol, 3.0 equiv), followed by sodium cyanoborohydride (67.4 mg, 1.08 mmol, 2.0 equiv) after stirring for 1 h. The reaction mixture was allowed to react overnight and then poured directly onto a silica column eluting with ethyl acetate. The isolated crude product was purified by a second silica column eluting with dichloromethane/methanol (93:7) delivered finally 22.0 mg (24%) of the title compound as colorless oil. MS (ISP): 393.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15](C)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22](F)=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1.FC(F)(F)C1C=C(C2N=C(C3CCNCC3)NC=2)C=CC=1>>[Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Agent: FC(F)(F)c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Product: Nc1ncnc(N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)c1Br

Procedure:
The title compound was prepared in an analogous manner as 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=467, obsd.=467).
Reaction SMILES: Cl.C(OC1C=CC(C(N)=N)=CC=1)CCCCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:36]([C:38]1[C:39](O)=[N:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:46][CH:45]=2)=[N:42][CH:43]=1)#[N:37].P(Cl)(Cl)([Cl:60])=O>C(O)C>[Cl:60][C:39]1[C:38]([C:36]#[N:37])=[CH:43][N:42]=[C:41]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:46][CH:45]=2)[N:40]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCOc1ccc(-c2ncc(C#N)c(O)n2)cc1
Agent: CCCCCCOc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-hexyloxybenzamidine hydrochloride with α -ethoxymethylene-α -cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-hexyloxyphenyl)-pyrimidine (melting point 193.0° C; smectic up to 226.0° (clearing point)) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-hexyloxyphenyl)-pyrimidine having a melting point of 132.7°-133.1° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[C:7]([Br:23])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Br[C:34]1C=C(CC(OC)=O)C=C(Br)[C:39]=1OC1C=CC(N)=C(N)C=1.Cl.C(CC(=O)C)(=O)C>CO>[Br:23][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:24])[CH:10]=[C:9]([Br:11])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]=[C:34]([CH3:39])[NH:20][C:15]=2[CH:14]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c([N+](=O)[O-])c2)c(Br)c1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c(N)c2)c(Br)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: COC(=O)Cc1cc(Br)c(Oc2ccc3nc(C)[nH]c3c2)c(Br)c1
Yield: 5 %

Procedure:
Methyl[3,5-dibromo-4-(4-amino-3-nitrophenoxy)phenyl]acetate (1.1 g, Example 2(b)) was treated with sodium dithionite as described in Example 2(c). The formed methyl [3,5-dibromo-4-(3,4-diaminophenoxy)phenyl]acetate was dissolved in methanol (36 mL). An aqueous solution of hydrochloric acid (35%, 2.1 mL) was added, followed by acetylacetone (0.48 g). The reaction mixture was refluxed for 5.5 hours, cooled down and the formed yellow precipitate was filtered off. After recrystallisation from ethanol, 80 mg (5%) of methyl [3,5-dibromo-4-(2-methyl-5-benzoimidazolyloxy)phenyl]acetate was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:29]([O:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[OH:45])=[O:37])[CH3:30]>CC(=O)CC>[CH2:29]([O:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[O:45][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4])=[O:37])[CH3:30]
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Reactant: CCOC(=O)CCCC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 60 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
To a solution of (2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.10 g, 0.35 mmol) in 2-butanone (1 mL) was added potassium carbonate (0.13 g, 0.90 mmol), potassium iodide (0.065 g, 0.39 mmol) and 5-(5-chloro-2-hydroxy-phenyl)-5-oxo-pentanoic acid ethyl ester (0.11 g, 0.39 mmol). The reaction was stirred at 60° C. for 12 hours, then cooled and concentrated. Chromatography on silica gel gave the title compound (0.089 g).
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH:5][CH2:6][C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1C=CC=CC=1>[Cl:3][C:1]([O:5][CH2:6][C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C#CCO
Solvent: c1ccccc1
Product: CCOC(=O)C#CCOC(=O)Cl
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To 40 ml of a benzene solution of phosgene (containing 6.2 g (62.5 millimoles) of phosgene), 6.4 g (50 millimoles) of ethyl 4-hydroxy-2-butynoate was rapidly added under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. The reaction mixture was returned to room temperature and left to stand for one night. Then, the reaction mixture was concentrated under reduced pressure to distil off benzene, whereby 8.1 g (yield: 85%) of oily ethyl 4-(chlorocarbonyloxy)-2-butynoate was obtained as the residue.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15]C)[CH:7]=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1-n1cnc2cc(N)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc2c(c1)ncn2-c1ccccc1O
Yield: 77.5 %

Procedure:
A solution of 5-amino-1-(2-methoxyphenyl)benzimidazole (3) (829 mg, 3.46 mmol), 1.0 M boron tribromide (10 mmol) in dichloromethane (10 mL), and dichloromethane (35 mL) is stirred under argon for 4 h, quenched with sat. NaHCO3 (55 mL), and extracted with ethyl acetate (150 mL, 100 mL, and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the crude material is washed (dichloromethane) to give 604 mg (78%) of 4 as a brown solid, mp 202-203° C. IR 3346, 2956, 1512, 1256 cm−1; 1H NMR (DMSO-d6) δ 5.18 (bs, 2H, NH2), 6.65 (d, J=8.4 Hz, 1H, 6-BenzimidH), 6.90 (s, 1H, 4-BenzimidH), 6.99 (d, J=8.4 Hz, 1H, 7-BenzimidH), 7.02 (d, J=7.8 Hz, 1H, 3-PhH), 7.13 (d, J=7.8 Hz, 1H, 5-ArH), 7.32 (d, J=7.8 Hz, 1H, 4-PhH), 7.38 (d, J=7.8 Hz, 1H, 6-PhH), 8.13 (s, 1H, 2-BenzimidH), 10.15 ppm (s, 1H, OH). HRMS calcd C13H11N3O [M+H]+ 226.0975. found 226.0975.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[C:8]([NH:37][C:34]2[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol) in methylene chloride (2.9 mL) at 0° C. was treated with oxalyl chloride (0.03 mL, 0.34 mmol) followed by N,N-dimethylformamide (5 drops). The resulting solution was stirred at 0° C. for 30 min. At this time, the solution was warmed to room temperature and stirred for 30 min. The reaction was then concentrated in vacuo. The residue was re-suspended in methylene chloride (2×5 mL) and then concentrated in vacuo. The residue was then dissolved in methylene chloride (1 mL) and was added to a pre-cooled solution of 1-methyl-1H-pyrazol-3-ylamine (Matrix, 30 mg, 1.05 mmol) and 2,6-lutidine (0.05 mL, 0.47 mmol) in methylene chloride (3 mL) at 0° C. The reaction was allowed to gradually warm to room temperature and was stirred at room temperature overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×100 mL) and water (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (50-75% ethyl acetate/hexanes) afforded (S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 77%) as a white solid; ES+-HRMS m/e calcd for C21H23N4O2F3 (M+H)+ 421.1846 found 421.1844. 1H-NMR (300 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.01 (t, J=8.6 Hz, 2H), 7.68-7.81 (m, 1H), 7.54 (d, J=1.9 Hz, 1H), 6.39 (d, J=1.9 Hz, 1H), 5.02-5.15 (m, 1H), 5.03 (d, J=18.5 Hz, 1H), 4.71 (d, J=18.5 Hz, 1H), 3.73 (s, 3H), 0.98-2.12 (m, 11H).
Reaction SMILES: BrCC(O)=O.BrC(CC)C(O)=O.BrC(CCC)C(O)=O.[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH:32](C)[C:33]([Cl:35])=[O:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([Cl:35])=[O:34])=[CH:29][CH:28]=2)=[CH:39][CH:40]=1
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Cl
Agent: CCC(Br)C(=O)O
Agent: CCCC(Br)C(=O)O
Agent: O=C(O)CBr
Product: O=C(Cl)COc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
2-bromoacetic acid, (b) 2-bromobutyric acid, and (c) 2-bromovaleric acid in the above (A), were used to obtain (a'), 4-(4-chlorophenoxy)phenoxyacetic acid chloride, (b') 2-(4-(4-chlorophenoxy)phenoxybutyric acid chloride, (c') 2-(4-(4-chlorophenoxy)phenoxy)valeric acid chloride, respectively. Also, by using (d) 4-bromonitrobenzene instead of 4-bromochlorobenzene in the above (a), (d') 2-(4-(4-nitrophenoxy)phenoxy)propionic acid chloride was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc2cccnc2c(Br)n1
Reactant: C1COCCN1
Solvent: CO
Product: Nc1cc2cccnc2c(N2CCOCC2)n1
Yield: 60.8 %

Procedure:
To a mixture of 800 mg of 6-amino-8-bromo-1,7-naphthyridine and 3.12 g of morpholine, 40 ml of methanol was added. The resultant mixture was refluxed for 13 hours. After the reaction, methanol was distilled off under reduced pressure and chloroform was added to the residue. After washing the chloroform solution with water, it was dried with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure and a small amount of acetone was added to the residue to dissolve same. Hexane was then added to the residue, followed by removal of insoluble matter by filtration. The filtrate was concentrated and the residue was recrystallized from a mixed solvent of chloroform and hexane, thereby obtaining 500 mg of 6-amino-8-morpholino-1,7-naphthyridine (Compound No. 3) as yellowish crystals (yield: 60.9%).
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([P:34](=[O:37])([OH:36])[OH:35])[CH3:33])=[O:30])[CH3:28])=[O:25])[CH2:21][CH2:22][CH3:23])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([P:34](=[O:35])([OH:37])[OH:36])[CH3:33])=[O:30])[CH3:28])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A)(iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-norvalyl-L-alanyl)amino]-ethyl-phosphonic acid there was obtained (1R)-1-(L-norvalyl-L-alanylamino)ethylphosphonic acid of melting point 260°-261° C. (decomposition); [α]D20 =-46.5°; [α]36520 =-168° (c=0.51% in water).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][SH:6].[H-].[Na+].Cl[C:10]1[N:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1>C1COCC1>[CH3:2][NH:3][CH2:4][CH2:5][S:6][C:10]1[N:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: CNCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(SCCNC)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a stirred solution of 2-(methylamino)ethanethiol hydrochloride (217 mg, 10 eq) in 20 mL anhydrous THF was added NaH (120 mg, 12 eq) at 0° C. After the mixture was stirred at rt for 1 h, (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)-phenol (80 mg, 1.0 eq, made from example 1) was added. The reaction mixture was heated under reflux for 48 h, cooled, quenched with sat. NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (75 mg, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=2.4 Hz, 0.8 Hz, 1H), 7.13-7.21 (m, 3H), 7.05-7.10 (m, 4H), 6.95 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 3.23 (t, J=6.4 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J=7.2 Hz, 3H); m/z=391[M+1]+.