Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:19][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH2:16])[O:3][CH2:2]1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]1[O:3][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH:16][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[CH:33][CH:32]=2)[O:19][CH2:1]1
Reactant: CCC1(Cc2cccc(C(=O)OC)c2N)OCCO1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1(Cc2cccc(C(=O)OC)c2NCc2ccc(-c3ccccc3C#N)cc2)OCCO1
Yield: 43.2 %

Procedure:
A mixture of 1-(2-amino-3-methoxycarbonylphenyl)butan-2-one ethylene ketal (T) (0.7 g) (prepared, e.g., as described in Preparation 14), 2'-(cyano)biphenyl-4-yl-methylbromide (0.826 g) and potassium carbonate (0.41 g) in dimethylformamide (20 ml) was heated at 80°-90° C. for 16 hours under an inert atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was diluted with ethyl acetate (100 ml), washed twice with cold water, and then brine. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel, eluting with 20% ethyl acetate/hexane, to give 1-[2-(2"-cyanobiphenyl-4'-ylmethylamino)-3-methoxycarbonylphenyl]butan-2-one ethylene ketal (0.52 g), a compound of Formula (U), as an oil.
Reaction SMILES: [C:1]1([C:7]([CH3:14])([CH3:13])[CH:8]([SH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=1>CC(C)=O.O>[C:1]1([C:7]([CH3:14])([CH3:13])[CH:8]([S:12][C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: CC(C)(c1ccccc1)C(S)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(OC)nc(SC(C(=O)O)C(C)(C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
1.9 g of 3-phenyl-3-methyl-2-mercaptobutyric acid was dissolved in 50 ml of acetone, and 1.2 g of potassium hydroxide dissolved in 5 ml of water was added thereto under cooling with ice. 1.5 g of 2-chloro-4,6-dimethoxy-S-triazine dissolved in 20 ml of acetone was added thereto. The mixture was stirred for 30 minutes. Then, the reaction solution was poured into water and extracted with 50 ml of ethyl acetate. The aqueous layer was acidified with a citric acid aqueous solution and extracted with 100 ml of chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 2.2 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=[O:13].[OH-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:12]([OH:13])[C:11]([OH:15])=[O:14])[CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2]
Reactant: CCOc1ccccc1O
Reactant: O=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(C(O)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
2-Ethoxyphenol (56.6, 0.401 mol, 1 eq.), glyoxylic acid (50% aqueous solution) (41.0 mL, 0.396 mol, 0.99 eq.), and distilled water (110 mL) were combined. The mixture was cooled in an ice bath, and a solution of 10% NaOH (32.2 g NaOH in 300 mL distilled water, 0.805 mol, 2 eq.) was slowly added via addition funnel. The reaction was allowed to slowly warm to room temperature, and after ˜18 hours, the solution was washed with ethyl acetate (4×250 mL), then acidified with 6N HCl until pH ˜3. NaCl was added and the product was then extracted into ethyl acetate (4×200 mL). The organic phase was washed with brine, dried over magnesium sulfate, and solvent was removed under vacuum, giving 51.8 g of intermediate 2 as a light pink solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCCN4)cc3)oc12
Yield: 7.3 %

Procedure:
2-(4-(Pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, 0.3 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by pre-HPLC. 7 mg of 2-(4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 7%. 1H-NMR (400 MHz, DMSO-d6) δ 1.23 (s, 1H), 1.56-1.70 (m, 4H), 1.87 (brs, 2H), 2.88-2.91 (m, 1H), 4.02-4.04 (m, 1H); 7.48-7.52 (m, 1H); 7.72-7.74 (m, 2H); 7.82-7.98 (m, 4H); 8.30-8.32 (d, J=7.2 Hz, 2H); LC-MS (m/z) 316 (M+1)+.
Reaction SMILES: COC1C=C([C:11](=O)[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3CCC[C@H:18]3[CH2:17]2)=O)C=CC=1OC.C(OC(N1CCCC[C@H]1C(O)=O)=O)(C)(C)C.[F:42][C:43]1[CH:44]=[C:45]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[C:46]([CH2:48][CH2:49][C:50]([OH:52])=O)=[O:47]>>[F:42][C:43]1[CH:44]=[C:45]([C:46](=[O:47])[CH2:48][CH2:49][C:50]([N:19]2[CH2:20][CH2:21][N:16]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:17]3[CH2:18]2)=[O:52])[CH:53]=[CH:54][C:55]=1[O:56][CH3:57]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Agent: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCCC[C@H]3C2)cc1F

Procedure:
380 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using (S)-1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(3-fluoro-4-methoxybenzoyl)propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 12 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 12 (1.42 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0°. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 24.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([CH3:10])[CH:3]=1.S(Cl)([Cl:13])=O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ccc1CO
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) in dichloromethane (50 mL) was added thionyl chloride (3.8 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 4-bromo-2-methylbenzyl chloride (9.8 g). To a suspension of sodium hydride (60%, 2.1 g) in tetrahydrofuran (90 mL) was added ethyl 4-methyl-3-oxopentanoate (7.5 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 1 hour. 4-Bromo-2-methylbenzyl chloride (9.8 g) was added to the reaction mixture, and the resulting mixture was stirred at 70° C. for 3 days. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a solution of the residue in toluene (20 mL) was added hydrazine monohydrate (5.4 mL), and the mixture was stirred at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was treated with n-hexane-diethyl ether (10/1) to crystallize. The crystals were collected by filtration and washed with n-hexane, water and n-hexane successively, and dried under reduced pressure to give the title compound (12.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[CH:55]=[N:56][C:57]2[C:62]([CH:63]=1)=[CH:61][CH:60]=[CH:59][CH:58]=2>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[NH:53][C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc21
Reactant: Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21

Procedure:
A solution of 2,3-dihydro-indole-1,5-dicarboxylic acid 1-tert-butyl ester (1.5 g, 5.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.37 g, 6.27 mmol), N,N-diisopropylethylamine (2.41 mL, 13.8 mmol) and 3-aminoquinoline (0.904 g, 6.27 mmol) in acetonitrile was heated to reflux for 20 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was separated, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluted with ethyl acetate/hexane to give the product, 1.43 g (64%). MS: m/z 390 (MH+). 1H NMR (DMSO-d6): δ 1.54 (s, 9 H), 3.16 (t, 2 H), 4.00 (t, 2 H), 7.57-7.83 (m, 3 H), 7.88-8.00 (m, 4 H), 8.84 (d, 1 H), 9.15 (d, 1 H) and 10.53 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].CN(C(O[N:34]1N=N[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC(C(O)=O)=NC=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[CH3:9][N:8]1[C:36]([C:37]2[CH:38]=[CH:39][N:40]=[CH:35][N:34]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:14][CH2:15]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccncn1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-c2ccncn2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 150 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of 1-(1-(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (50 mg, 0.14 mmol) in anhydrous DMA (5 mL) and diisopropylethylamine (0.5 mL) were added HATU (150 mg, 0.39 mmol), and pyrimidine-4-carboxylic acid (100 mg, 0.8 mmol). The reaction mixture was stirred for 1 h, and concentrated under reduced pressure. The resulting oil was dissolved in 10 mL of dichloromethane, and the solution was washed with 5 mL of water. The organic layer was dried over MgSO4, concentrated under reduced pressure, and the residue was dissolved in Acetic acid (2 mL). The reaction mixture was heated in a microwave reactor to 150° C. for 20 min, and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 3 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.34 (s, 1H), 8.96 (d, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 7.21-7.14 (m, 1H), 6.93 (d, 3H), 4.64-4.52 (m, 1H), 4.18 (s, 3H), 2.37 (dd, 2H), 1.85 (t, 2H); MS (EI) for C23H21N9O: 428.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28]C)=[O:27].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COCCOCOc1c(C/C=C(\C)CCC(=O)OC)c(OC)c(C)c2c1C(=O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCOc1c(CC=C(C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To methyl (E) 6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (76.0 g) in methanol (300 ml) was added 1N aqueous sodium hydroxide (300 ml). After 11/2 hours the solution was diluted with water, washed twice with ether, then acidified with dilute hydrochloric acid. The acidified solution was extracted with ether, and the extract was dried and evaporated to give (E) 6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 77°-82° C. (etherhexane).
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:71]([NH2:73])=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:71]([NH2:73])=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 46 %

Procedure:
Condensation of BocPro-DTrp-PheOH (0.88 g.) and HDLys(Boc)-Leu-MetNH2 (0.68 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DLys(Boc)-Leu-MetNH2 in 46% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DLys(Boc)-Leu-MetNH2 (560 mg.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DLys-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) acetate (1:3) salt in 26% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@H:23]3[C:24]([OH:26])=[O:25])=[O:21])=[CH:11][CH:10]=2)=[C:4]([CH:33]=O)[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:41][OH:42].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@H:23]3[C:24]([OH:26])=[O:25])=[O:21])=[CH:11][CH:10]=2)=[C:4]([CH:33]=[N:41][OH:42])[CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)N3CCC[C@H]3C(=O)O)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3C=NO)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
The compound (20 mg, 0.043 mmol) of Example 43 was dissolved in acetic acid (5 mL), and sodium acetate (45 mg, 0.56 mmol) and hydroxylamine hydrochloride (14 mg, 0.21 mmol) were added thereto, and stirred at 60° C. for 2 hours. After that, acetic anhydride (0.026 mL, 0.28 mmol) was added thereto, and stirred at 100° C. for 2 hours. After cooling, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@@H:26]([OH:29])[CH2:27][NH2:28]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][CH2:27][C@H:26]([OH:29])[CH3:25])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[C@@H](O)CN
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NC[C@@H](C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 116 μL of R-(−)-1-amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide. MS (Q1) 397.4 (M)+.
Reaction SMILES: [N:1]1([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:8][C:7](=[O:9])[CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CCCCC(C(C)=O)n1ccnc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCC(C(=O)C=Cc1ccc(Cl)c(Cl)c1)n1ccnc1

Procedure:
2.7 g of 3-(imidazole-1-yl)-2-heptanone and 3.0 g of 3,4-dichlorobenzaldehyde were dissolved in 50 ml of methanol. While stirring this solution under cooling with ice (0°-5° C.), 2.1 g of potassium carbonate was added. Then, the mixture was stirred at the same temperature for 7 hours. The reaction mixture was poured into water and extracted with chloroform. The extraction solution was treated by a usual method, and the obtained oily product was purified by chromatography, whereby 1-(3',4'-dichlorophenyl)-4-(imidazole-1-yl)-1-octene-3-one was obtained as an oily product.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:25])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:26]>ClCCl.C(O)(=O)C>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][CH3:25])[O:22][C@@H:5]1[Br:26])(=[O:10])[CH3:9]
Reactant: Br
Reactant: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC[C@H]1O[C@H](Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-6-O-methyl-β-D-mannopyranose (2.8 g) in dry dichloromethane (2 ml) at 0°-5° C. is treated with 30% hydrobromic acid in glacial acetic acid (25 ml) for 2 hours. The reaction mixture is worked-up in the normal manner to give 2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl bromide (2.8 g), which is reacted with thiourea (0.76 g) in dry acetone (5 ml) at reflux temperature for 2 hours. The solution is evaporated in vacuo to a syrup, which is partitioned between ethyl ether (25 ml) and water (25 ml). The aqueous layer is extracted three times with ethyl ether. A solution of cinnamyl bromide (1.44 g) in acetone (30 ml) is added to the aqueous solution containing 2-S-(2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl)-2-thiopseudourea hydrobromide. This is followed by the addition of potassium carbonate (1.26 g) and potassium metabisulfite (1.77 g) and the reaction mixture is stirred vigorously for 2 hours at room temperature. Acetone is evaporated in vacuo and the product is extracted with chloroform and washed twice with water. The solution is dried and evaporated to an oil, which is put on a column of silica gel and eluted with CHCl3 --EtOAc (98:2, v/v). The desired fractions are combined and evaporated in vacuo to give 19 as an oil (1.15 g, 33% overall yield): [α]D27 +147° (C 2.08, chloroform).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>[OH-].C[N+](C)(C)C.C(Cl)Cl>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)=[O:16]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: ClCCl
Product: C=Cc1ccc(OC(=O)C(Cl)(Cl)Cl)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
About 10.0 gs (6.17×10-2 moles of 4-acetoxystyrene was dissolved in 42.5 mL of 25 wt % tetramethylammonium hydroxide with stirring. The solution was cooled to 5° C. and to it was added 12.63 gs (6.95×10-2 moles) of trichloracetyl chloride dissolved in 150 mL of methylene chloride. The addition was done slowly with stirring while cooling with an ice bath so as to avoid heating the reaction mixture above 15° C. After 15 mins. of reaction, workup was done by separating the methylene chloride layer, washing it with 3×40 mL of 6 wt % tetramethylammonium hydroxide and several 40 mL aliquots of distilled water. The washed organic layer was dried over magnesium sulphate, filtered over silica gel, and the solvent removed under vacuum. The residue was recrystallized from pet ether to give 10.2 gs (62% yield) of 4-trichloroacetoxystyrene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), ethyl 4-piperidinecarboxylate (38 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was quenched with water, partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with brine, dried over sodium sulphate and evaporated to afford the crude product ethyl 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-4-piperidinecarboxylate (D91) (60 mg). MS (ES): C30H35ClN4O4 requires 550; found 551.3 (M+H+).