Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2OC=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl>[CH2:7]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:3][C:2]=1[C:1]([Cl:6])=[O:5])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1c(C(=O)O)oc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1c(C(=O)Cl)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl Chloride (3.86 mL, 44.2 mmol) was added under nitrogen at room temperature to a solution of 3-butyl-benzofuran-2-carboxylic acid (1.93 g, 8.84 mmol) in 60 mL of methylene chloride. After the addition a catalytic amount of DMF (10 μL) was added and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. To remove the excess oxalyl chloride the residue was dissolved in benzene and the solvent removed under reduced pressure to give 3-butyl-benzofuran-2-carbonyl chloride, which was immediately used in step 2 without additional purification.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H](C1C=CC=CC=1)O.[NH2:12][C:13]1([CH3:27])[C:17]2([CH2:19][CH2:18]2)[CH2:16][N:15](CC2C=CC=CC=2)[CH2:14]1.[OH-].[Na+].[C:30]1([CH3:36])[CH:35]=CC=C[CH:31]=1>>[C:30]([O:11][C:1]([NH:12][C:13]1([CH3:27])[C:17]2([CH2:18][CH2:19]2)[CH2:16][NH:15][CH2:14]1)=[O:10])([CH3:36])([CH3:35])[CH3:31]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CC1(N)CN(Cc2ccccc2)CC12CC2
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NC1(C)CNCC12CC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
(−)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane D-mandelate (5.99 g) was dissolved in toluene (60 mL). To the solution, 5N Aqueous sodium hydroxide (60 mL) was added, and the mixture was stirred at room temperature, followed by separation of the toluene layer. Toluene was also added to the remaining aqueous layer for extraction. All the toluene layers were combined, and t-butyl dicarbonate (19.0 mL) was added to the combined toluene layer, followed by stirring at room temperature for 2 hours. After completion of reaction, 10% aqueous citric acid was added to the reaction mixture, to thereby extract the aqueous citric acid layer. Separately, 10% aqueous citric acid was added to the remaining toluene layer, to thereby separate another aqueous citric acid layer. Thereafter, all the aqueous layers were combined, and the combined aqueous layer was alkalified with 5N aqueous sodium hydroxide (30 mL). Subsequently, toluene was added to the alkalified aqueous layer so as to extract the organic layer, and the solvent of the organic layer obtained through extraction was evaporated under reduced pressure. Methanol (60.0 mL) was added to the residue, and 5% palladium carbon (0.59 g, water content: 50%) was added to the mixture, followed by stirring at room temperature in a hydrogen atmosphere. After 14 hours, 5% palladium carbon was removed through filtration. The filtrate was concentrated under reduced pressure, to thereby yield the title product (3.576 g, yield: 97%). This product can be purified through recrystallization from a solvent such as hexane, heptane, or acetonitrile, or formation of a crystalline salt with, for example, oxalic acid.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH2:34].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:34][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a suspension of 3.00 g of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 2.01 g of L-histidine methyl ester dihydrochloride in 24 ml of N,N-dimethylformamide were added successively 2.16 ml of diphenylphosphoryl azide and 3.81 ml of triethylamine under ice-cooling, and the mixture was stirred for 16 hours under ice-cooling. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Diethyl ether was added to the residue, the precipitated crystals were collected by filtration to obtain 4.08 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine methyl ester as a white powder. To a solution of 4.00 g of the ester compound obtained in 25 ml of methanol was added 2.75 g of hydrazine monohydrate, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether, and dried under reduced pressure below 40° C. to obtain 3.90 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide as a white powder. In 5 ml of methanol was dissolved 2.20 g of the hydrazide compound obtained with heating at 40° C., and insoluble materials were filtered off. The filtrate was allowed to stand overnight at room temperature, and then precipitated crystals were collected by filtration to obtain 0.70 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide as a white powder.
Reaction SMILES: N#N.[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][OH:19])[O:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[O:16][CH:17]=2)[CH2:11][CH2:12]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)OC1(c2coc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC1(c2coc(COS(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(hydroxymethyl)oxazol-4-yl)cyclopropyl pivalate (288 mg, 1.20 mmol) at 0° C. in CH2Cl2 (12.0 mL) was treated Et3N (0.22 mL, 1.57 mmol) followed by DMAP (15 mg, 0.12 mmol). Methanesulfonyl chloride (0.11 mL, 1.44 mmol) was then added dropwise and the reaction mixture was stirred for 1 h at rt. Water (5 mL) was added, the layers were separated, and the org. phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 06: tR=0.84 min, [M+H]+=318.19.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](O)=[O:20])=[CH:15][N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH2:30])=[O:20])=[CH:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CCC(N)=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.2 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (1.15 g), 1H-1,2,3-benzotriazol-1-ol (0.54 g) and N,N-dimethylformamide (14 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.77 g) at room temperature. The mixture was stirred at room temperature for 1 hr, and 28% aqueous ammonia (1.0 mL) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water and ethyl acetate, and dried to give the title compound (1.46 g, yield 98%) as yellow crystals. melting point 246-247° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[CH:25]=[O:26])[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](#[N:33])[CH:31]=[CH2:32].C1N2CCN(CC2)C1.[O:42]1CCOCC1.O>>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[N:20]=[CH:19][N:18]=2)[CH:23]=1)[C:31](=[CH2:32])[C:30]([NH2:33])=[O:42]
Reactant: O=Cc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Reactant: C1COCCO1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: O
Product: C=C(C(N)=O)C(O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Reaction time: 48 h

Procedure:
To a stirred solution of 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzaldehyde (100 mg, 0.26 mmol) and acrylonitrile (36 mg, 0.52 mmol) in 1,4-dioxane/H2O (0.5 mL/0.5 mL) was added DABCO (29 mg, 0.26 mmol) at rt. Stirring was continued at room temperature for 48 h after which time the reaction mixture was concentrated under reduced pressure. The residue obtained was further purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate, 6/4) to give 2-(hydroxy(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)methyl)acrylamide (I-84) as a white solid. 1H NMR (DMSO-d6) δ ppm: 5.33 (s, 1H), 6.06 (s, 1H), 6.20 (s, 1H), 6.25 (s, 1H), 6.80 (s, 1H), 6.88 (s, 1H), 6.95-7.05 (m, 4H), 7.09-7.13 (m, 2H), 7.16 (bd, J=7.92 Hz, 1H), 7.32-7.39 (m, 5H), 7.47 (s, 1H), 8.31 (s, 1H); LCMS: m/e 436 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:44][C:45]1[S:49][N:48]=[C:47]([CH3:50])[CH:46]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:44][C:45]1[S:49][N:48]=[C:47]([CH3:50])[CH:46]=1)=[O:41]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)sn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)ns4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (43 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 5-amino-3-methylisothiazole hydrochloride (22 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (13.7 mg, yield 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[H][H]>C1C=CC=CC=1.C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[NH2:19]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Yield: 60.1 %

Procedure:
3-Chloro-4-(2-naphthyloxy)nitrobenzene (14.8 g) and platinum dioxide (0.1 g) were suspended in a mixture of benzene and ethanol (1:1) (200 ml), and hydrogenation was carried out until 3.2 liters of hydrogen were absorbed. After removal of the solvent from the reaction mixture by distillation under reduced pressure, the residue was distilled in vacuo to give 3-chloro-4-(2-naphthyloxy)aniline (8 g) as a fraction boiling at 173° to 198° C./0.2 to 0.3 mmHg. M.P., 67°-69° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[O:34])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:37].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH2:34].[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:37])=[O:34])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: O=CCCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O
Product: O=C(O)CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.8 h
Yield: 188 %

Procedure:
To a solution of 3,4,5-triphenyl-lH-pyrazole-1-decanal (2.42 g, 5.4 mmol) in acetone (47 mL maintained at 0° C. was added dropwise 1.75 mL (7 mmol) of 8 N Jones reagent. The ice water was removed and the mixture stirred for 48 minutes before being diluted with acetone, filtered through diatomaceous earth and concentrated. The residual oil was chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate (13:7) as eluent to afford 3,4,5-triphenyl-lH-pyrazole-1-decanoic acid hydrate (2.46 g, 81%) as an oil. MS(CI): m/e =467 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[K+].[K+].CI.ClCCl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 3-fluoro-4-nitro-phenol (25.3 g, 0.16 mol) in acetone (160 ml), potassium carbonate (41.7 g, 0.30 mol) and methyl iodide (20.0 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is stirred at 40 C.° for 3 h. After cooling down to room temperature, dichloromethane is added to the reaction mixture, which is filtrated and evaporated. Dichloromethane is added to the residue and the organic phase is washed with H2O and brine, dried over sodium sulfate and evaporated down to give 2-fluoro-4-methoxy-1-nitro-benzene in 98% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:25][NH:26][CH3:27].O>CS(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([N:26]([CH3:27])[CH3:25])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Reactant: CNC
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CN(C)c1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Temperature: 80 °C
Reaction time: 10 h

Procedure:
In dimethyl sulfoxide (1 ml) was dissolved 60 mg of 1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Example 61). To the mixture was added 50% dimethylamine methanol solution (0.04 ml), followed by heating under stirring at 80° C. for 10 hours. After standing to cool, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by preparative TLC and solidified from isopropyl ether, to give the title compound (17 mg).
Reaction SMILES: C(OC([NH:11][CH:12]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=1)=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl.O>[C:21]([C:16]1[CH:15]=[C:14]([CH2:13][CH:12]([NH2:11])[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:19]=[CH:18][C:17]=1[OH:20])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)c2nccs2)ccc1O
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(CC(N)c2nccs2)ccc1O
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-2-(3-tert-butyl-4-hydroxylphenyl)-1-(thiazol-2-yl)ethylamine (15.28 g, 37.27 mmol) in methylene chloride (1.1 l), thioanisole (8.75 ml, 74.54 mmol) was added. To the mixture, a solution of 1.0M boron tribromide in methylene chloride (186 ml, 186.34 mmol) was added dropwise under cooling with ice and stirred for 1 hour. The reaction mixture was mixed with water and alkalinized by 2N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure, giving the titled compound (9.46 g, 90%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]2[C:21]([CH3:30])=[C:22]([C:26]([F:29])([F:28])[F:27])[C:23]([CH3:25])=[CH:24][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.N1C=CC=CC=1.[CH3:46][O:47][C:48](=[O:52])[C:49](Cl)=[O:50]>ClCCl>[CH3:46][O:47][C:48](=[O:52])[C:49]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]2[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[C:15]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([F:27])([F:28])[F:29])=[C:21]([CH3:30])[C:16]1=2)=[O:50]
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)c(C)c21
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Dissolve (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 148, Step 2) (0.200 g, 0.353 mmol) in dichloromethane (4 mL), cool the solution down with an ice-water bath. Add pyridine (0.143 mL, 1.77 mmol) followed by chloro-oxo-acetic acid methyl ester (0.162 mL, 1.77 mmol) dropwise. Warm up the reaction to room temperature and stir overnight. Dilute the reaction mixture with more dichloromethane (10 mL), and wash with aqueous NaHCO3 (10 mL). Extract back the aqueous layer with dichloromethane (10 mL). Combine the organic layers, dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-30%), to provide the title compound (0.187 g, 81%). MS (ES+): 653 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:60][C:58]2[S:57][C:47]3[C:48]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=3[N:59]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1

Procedure:
From 4-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: N1C=CC=CC=1.[NH:7]([C:14]1[N:19]=[C:18]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH:28]=O)=[N:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:31][OH:32].O>CCO>[NH:7]([C:14]1[N:19]=[C:18]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH:28]=[N:31][OH:32])=[N:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=NO

Procedure:
Pyridine (283 μl, 3.50 mmol) was added to a solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 250 mg, 0.814 mmol) and hydroxylamine.hydrochloride (283 mg, 4.07 mmol) in EtOH (8 ml) and the reaction mixture heated at reflux for 1 hr. The mixture was allowed to cool, water (10 ml) was added and the EtOH was removed by evaporation. Further water (10 ml) was added to the aqueous residue and the precipitated solid was collected by filtration, washed with water and dried to give the title compound as a 9:1 mixture of E and Z isomers (142 mg, 54%) as a white solid. NMR: Major isomer: 1.47 (d, 6H), 5.70 (m, 1H), 6.95 (t, 1H), 7.10 (d, 1H), 7.31 (t, 2H), 7.60 (s,1 H) 7.69 (d, 2H), 8.25 (s, 1H), 8.50 (d, 1H), 9.50 (s, 1H), 11.70 (s, 1 H); Minor isomer: 1.47 (d,6H), 5.70 (m, 1H), 6.95 (t, 1H), 7.19 (d, 1H), 7.31 (t, 2H), 7.69 (d, 2H), 7.78 (s, 1H), 8.10 (s, 1H), 8.52 (d, 1H), 9.57 (s, 1H), 13.89 (s, 1 H); m/z 323.
Reaction SMILES: C1(COC(N[C@H](C(O)=O)CC2N=CN([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=CC=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)C3C=CC=CC=3)C=2)=O)C=CC=CC=1.[C:41]([NH:51][CH2:52][CH2:53][CH2:54][CH2:55][C@@H:56]([C:58]([O:60]C)=[O:59])[NH2:57])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].Cl.N[C@@H:64]([CH2:73][CH:74]([CH3:76])[CH3:75])[CH:65](O)[C:66]([O:68]C(C)C)=O>>[C:36]1([CH2:35][CH:65]([CH2:64][C:73]2[C:74]3[C:75](=[CH:27][CH:28]=[CH:29][CH:76]=3)[CH:32]=[CH:19][CH:26]=2)[C:66]([NH:57][C@H:56]([C:58]([OH:60])=[O:59])[CH2:55][CH2:54][CH2:53][CH2:52][NH:51][C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:42])=[O:68])[C:27]2[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=[CH:32][CH:37]=1
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Agent: Cl
Product: O=C(NCCCC[C@H](NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1

Procedure:
In process analogous to Example H by substituting α-(1-naphthalenylmethyl)-1-naphthalenepropanoic acid (obtained by reacating di-tertiary-butylmalonate (one equivalent) with 1-chloromethylnaphthylene (two equivalents) and sodium hydride (two equivalents) followed by refluxing in acetic acid) for N-[(phenylmethoxy)carbonyl]-1-(triphenylmethyl)-L-histidine and Nε -carbobenzoxy-lysine, methyl ester for (3S)-3-amino-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester, monohydrochloride (mixture of isomers at hydroxy center) one obtains the methyl ester of the title compound which is then hydrolyzed with sodium hydroxide in aqueous methanol to afford the title compound.