Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[O:10][C:9](=[O:17])[CH:8]=[CH:7]2)[CH:2]=[CH2:3].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:18]([O:14][C:13]1[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:17])[O:10]2)=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])(=[O:20])[CH3:19]
Reactant: C=CCc1cc2ccc(=O)oc2c(OC)c1O
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=CCc1cc2ccc(=O)oc2c(OC)c1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 2.32g. (0.010 mole) of 6-allyl-7-hydroxy-8-methoxycoumarin in 8 ml. of chloroform was treated with 4.5 ml. of acetic anhydride/pyridine, 1:2. The reactants were stirred at 25° for 2.0 hours and then partitioned between 1N HCl/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, and evaporated to afford pure 7-acetoxy-6-allyl-8-methoxycoumarin as a white solid, mp 101°-102°. Recrystallization from ethanol afforded an analytical sample, mp 102°-103°.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10]1>CS(C)=O>[O:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:4]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)NC[C@@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CCO4)CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A mixture of 60% sodium hydride (6.0 mmol), trimethyloxo sulfonium iodide (6.1 mmol) was stirred for 30 minutes and (R)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (4.80 mmol) in DMSO (20 ml) was stirred for 75 hour at the room temperature. The reaction mixture was poured on ice water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuum to provide crude compound. The crude compound was purified over silica gel column to provide title compound in 20% yield.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][CH:7]=[C:6]([Cl:14])[C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][O:12][CH3:13])=[C:2]([Cl:1])[C:3]=1[CH2:4][O:5][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(Cl)c(CO)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-dichloro-3-(methoxymethoxy)benzyl alcohol (1.1 g) and triethylamine (563 mg) in dichloromethane was added a solution of methanesulfonyl chloride (585 mg) in dichloromethane at <20° C. over 5 minutes under nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes and under ice-cooling for 30 minutes. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 1,3-dichloro-2-methanesulfonyloxymethyl-4-(methoxymethoxy)benzene.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([NH2:15])=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5](=[O:16])[NH:4][CH2:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:17])[C:11]2[CH:10]=[C:9]3[NH:12][C:10]([C:11]4[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=4)=[N:15][C:8]3=[CH:7][C:6]=2[C:5](=[O:16])[NH:4][CH2:3]1
Reactant: CC1(C)CNC(=O)c2cc(N)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CNC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21
Reaction time: 1 h

Procedure:
5 g. (20.4 mmole) 4,4-dimethyl-6-nitro-7-amino-1,2,3,4-tetrahydroisoquinolin-1-one were hydrogenated in 120 ml. methanol in the presence of 0.5 g. 10% palladium on charcoal. After separating off the catalyst, the evaporation residue (4.3 g.) was acylated in 150 ml. methylene chloride and 8.4 ml. triethylamine with 5.4 g. isonicotinic acid chloride hydrochloride. After 1 hour, the evaporation residue is worked up with water and filtered off with suction. The moist residue was subsequently boiled in 100 ml. ethanol and 20 ml. concentrated hydrochloric acid for 24 hours, evaporated, mixed with water and neutralised. After column chromatography (silica gel, elution agent: methylene chloride/methanol saturated with ammonia; 15:1 v/v) and boiling up, there were obtained 2.3 g. (41% of theory) of the title compound; m.p. above 300° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([N:17]=[C:18]=[O:19])=[N:14][C:13]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][CH2:22][CH2:23][OH:24]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18]([NH:21][CH2:22][CH2:23][OH:24])=[O:19])=[N:14][C:13]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1nc(N=C=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: NCCO
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NCCO)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 80 °C

Procedure:
5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole (88a) (0.58 mmol, 0.183 g) is dissolved in dioxane (5 ml) and treated with 2-aminoethanol (0.64 mmol, 0.039 ml) under argon. The reaction mixture is stirred and heated to 80° C. for 1 hour. The solvent is then removed and the residue dissolved in EtOAc and washed with water (2×20 ml) followed by brine (20 ml) and dried over MgSO4. After filtration, the solvent is removed in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate-methanol (9:1) to give the title compound.
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC([C:27]1[N:28]=[CH:29][C:30]2[C:31](=[O:45])[N:32]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=[CH:34][C:35]=2[C:36]=1[OH:37])=O>C(Cl)Cl.CCOC(C)=O>[CH3:14][S:11]([NH:10][CH2:9][CH2:8][NH:7][C:6]([C:27]1[N:28]=[CH:29][C:30]2[C:31](=[O:45])[N:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:33]=[CH:34][C:35]=2[C:36]=1[OH:37])=[O:15])(=[O:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
(2-Methanesulfonylamino-ethyl)-carbamic acid tert-butyl ester (77 mg, 0.32 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed by evaporation, and the residue was taken up in EtOH (2 mL). NaOMe was added with vigorous stirring until pH about 8. The resulting cloudy solution was transferred to a microwave vial containing 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), and the mixture was heated at 140° C. for 6 h in a microwave reactor. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 20 mg of the title compound as an off-white solid. MS: (+) m/z 417.30 (M+1).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.C1(CC(O)=O)CCCCC1>>[CH:5]1([CH2:13][C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:4]1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: O=C(O)CC1CCCCC1
Product: CC(C)c1ccc(C(=O)CC2CCCCC2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with cyclohexylacetic acid; 1H NMR (CDCl3): δ 8.35 (s, 1H), 7.1-7.3 (m, 3H), 3.3-3.45 (m, 2H), 2.35 (d, 2H), 1.55-1.95 (m, 8H), 1.22 (d, 12H) , 0.9-1.1 (m, 2H), ppm.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=O.[CH3:15][C:16]1[C:20](=[O:21])[O:19][CH2:18][C:17]=1[N:22]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23]1=[O:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:12][CH2:13][N:29]2[CH2:30][CH2:31][C:24]3([C:23](=[O:32])[N:22]([C:17]4[CH2:18][O:19][C:20](=[O:21])[C:16]=4[CH3:15])[CH2:26][CH2:25]3)[CH2:27][CH2:28]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(N2CCC3(CCN(CCc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (I-3) (100 mg, crude) and 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-16) (145 mg, 0.58 mmol) in THF (5 mL) was stirred at rt for 2 hours and then NaBH(OAc)3 (167 mg, 0.79 mmol) was added to the mixture, which was further stirred at 50° C. for 3 hours. After quenching with saturated NH4Cl aq, the mixture was extracted with EtOAc and organic layer was dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by prep-TLC (EtOAc/MeOH:1/1) and prep-HPLC to give the title product. MS (ESI) m/z: 425 (M+H+); 1H NMR (400 MHz, MeOD): δ 7.69 (d, J=7.6 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 5.38 (s, 2H), 5.27-5.25 (m, 2H), 4.20-4.14 (m, 2H), 3.83-3.80 (m, 1H), 3.68-3.66 (m, 1H), 3.42-3.38 (m, 2H), 3.33-3.23 (m, 4H), 2.41 (s, 3H), 2.39-2.30 (m, 2H), 2.24-2.17 (m, 2H), 2.10-2.03 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:37])=[N:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)=[CH:20][C:21]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][C:9]=1[CH3:38])[CH3:6])C.[Li+].[OH-]>>[CH3:39][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:37])=[N:18][C:19]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=3)=[CH:20][C:21]=2[C:22]([F:23])([F:24])[F:25])=[CH:10][C:9]=1[CH3:38])([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2C)cc1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 26C], 2-methyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was treated with LiOH to obtain the title compound as colorless solid.
Reaction SMILES: [C:1]([C:5]([OH:16])([CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH3:15])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]>N1C=CC=CC=1.[Pd]>[C:1]([C:5]([OH:16])([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH3:15])[C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC#CCC(O)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: c1ccncc1
Product: CCC/C=C\CC(O)(C(C)(C)C)C(C)(C)C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
50 mg of a catalyst of 5% palladium on barium sulfate were added at once to a stirred solution of 500 mg (2.23 mmol) 3-tert-butyl-2,2-dimethylnon-5-in-3-ol in 5 ml pyridine. The mixture obtained was degassed three times, exposed to a hydrogen atmosphere and stirred overnight. Subsequently, it was diluted with 100 ml pentane and filtered over silica gel. The silica gel was washed with 100 ml Et2O. The combined organic phases were washed with a copper sulfate solution (5×100 ml), with H2O (100 ml) and with salt solution (50 ml), dried and concentrated under reduced pressure. There were obtained 503 mg (99%) (Z)-3-tert-butyl-2,2-dimethylnon-5-en-3-ol
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]([CH3:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.25 g, 0.00078 mole) in DMF (5 mL) was added K2CO3 (0.225 g, 0.00163 mole) followed by methyl iodide (0.116 g, 0.00081 mole) and at the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then quenched with iced water and the resulting precipitate was isolated by filtration. The solid was recrystallized from ethyl acetate to afford 0.251 g (96%) of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 337.15 (M+1)+, 90.13%. To a stirred solution of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.251 g, 0.00075 mole) in methanol (40 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite and the celite was washed with methanol. The combined filtrate was concentrated under reduced pressure to afford 0.169 g (92%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 247.1 (M+1)+, 99%. To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.169 g, 0.00069 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL), was added LiOH.H2O (0.087 g, 0.00206 mol) at ambient temperature and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and acidified with 10% HCl. The product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.13 g (87%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS: 219.07 (M+1)+, 81.5%
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[NH:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:17][CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[C:14](=[O:19])[NH:15]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(CC3NC(=O)NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(CC4NC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-imidazolidine-2,4-dione (which was obtained in Example 44) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >105° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-2.00 (m, 2H), 2.50-2.75 (m, 5H), 2.86 (d, J=4.8 Hz, 2H), 2.93 (s, 3H), 3.50-3.65 (m, 2H), 4.24 (t, J=4.8 Hz, 1H), 4.51 (dd, J=8.2, 4.0 Hz, 1H), 6.81 (d, J=6.3 Hz, 1H), 6.84 (d, J=5.7 Hz, 2H), 7.18 (d, J=1.8 Hz, 1H), 7.85 (brs, 1H); MS (ES) m/z: 518.0 (MH+); HRMS Calcd. for C24H32N5O6S(MH+): 518.2073. Found: 518.2056.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][CH:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1.Cl>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][CH:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CCC(Cc1ccc(O)cc1)NC(=O)CCCCCCc1ccccc1
Yield: 98 %

Procedure:
(RS)-5-(4-Benzyloxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester 78 (872 mg, 1.74 mmol) was hydrogenated over 10% Pd—C in THF (20 mL) containing HCl solution (1 M, 2.5 mL). The solution was filtered (Celite™) and approximately two thirds of the solvent removed under reduced pressure. The solution was diluted with water and extracted into EtOAc. The combined extracts were washed with water, brine and dried with MgSO4. Evaporation of the solvent in vacuo afforded the title compound (702 mg, 98%). ESMS 412 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CO.[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>O>[S:7]([N:1]=[N+:2]=[N-:3])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1

Procedure:
In a 250 ml round bottom flask was added 60 ml of deionized (DI) water and 21 g (0.32 mole) of sodium azide. It was mixed at room temperature for 15 minutes until all the sodium azide was in solution. In a 1 liter round bottom flask was added 300 ml of methanol and 50.1 g (0.26 moles) of toluenesulfonyl chloride(tosyl chloride). The solution was mixed at room temperature until all of the tosyl chloride was dissolved. The sodium azide solution was added to the tosyl chloride solution and mixed for 1 hour. The solution darkened and a second phase formed. After the 1 hour hold the reaction was poured into 1200 ml of 20° C. DI water. Two phases formed and the bottom layer was kept. The bottom layer was washed twice with 100 ml of DI water. The yield was 32.4 grams.
Reaction SMILES: C([SiH2]Cl)(C)(C)C.[Br:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([N+:16]([O-])=O)[C:9]=1[OH:19].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.[Cl-].[Cr+2].[Cl-].[Mn]>[Br:7][C:8]1[C:9]2[O:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:16][C:10]=2[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=Cc1ccccc1
Agent: [Cr+2]
Agent: [Mn]
Agent: CC(C)(C)[SiH2]Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)c2oc(-c3ccccc3)nc2c1
Reaction time: 0.07 h

Procedure:
tert-Butyl-chloro-silane (0.25 ml) was added to a mixture of 2-bromo-4-methoxy-6-nitro-phenol (0.124 g), chromium (II) chloride (0.012 g) and manganese (0) powder (0.137 g) in dimethylformamide (3 mL). The mixture was subjected to microwaves for 4 min at 150° C. Benzaldehyde (0.06 mL) was added and the reaction was subjected to microwaves for 6 min at 150° C. Water (0.5 mL) was added, then after 30 min the mixture was filtered through a pad of celite. The above procedure was repeated three more times. The combined filtrate was partitioned between dilute aq. HCl (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered through celite and concentrated. Chromatography on silica gel (eluant: gradient 0 to 30% ethyl acetate:hexane) afforded 7-bromo-5-methoxy-2-phenyl-benzooxazole (0.13 g). MS: 304 (95%), 306.4 (100%) (MH+); HPLC tR: 2.79 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@H:33]([OH:40])[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:32][C@H:33]([OH:40])[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([O:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)COc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 99.2 %

Procedure:
To a solution of methyl 4′-[2-[[tert-butoxycarbonyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutoxy-4-biphenylcarboxylate (511 mg) in methanol (5.11 ml) and tetrahydrofuran (1.53 ml) was added 1N sodium hydroxide (2.79 ml) and the mixture was stirred at room temperature for 36 hours. Methanol and tetrahydrofuran were removed by evaporation under reduced pressure and the pH was adjusted to 5.9 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice) and the extract was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave 4′-[2-[[tert-butoxycarbonyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutoxy-4-biphenylcarboxylic acid (494 mg) as a brown solid (foam).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([N:18]([CH2:19][CH3:20])[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1)[CH3:17]
Reactant: CCNCC
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1oc(N(CC)CC)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a reaction vessel containing a stirred mixture of 3.15 g (13 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate in 25 ml of toluene, there was added 3 ml (29 mmol) of diethylamine. The reactionmixture was stirred at ambient temperature for 4 hours and then suction filtered. The filtrate was washed with 5% hydrochloric acid, then with saturated brine, then dried over sodium sulfate and concentrated under reduced pressure to yield 3.3 g of a pale yellow oil. This oil was subjected to Kugelrohr distillation (60° C. @ 3 mm Hg) to remove trace amounts of starting material. Further Kugelrohr distillation provided 2.9 g of colorless oil (b.p. 110° C. @ 3 mm Hg) identified in Table I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:20][C:21]([C:23]2[C:31]3[CH:30]=[C:29]([C:32]4[C:37]([CH3:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=4)[S:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:34]2[N:33]=[C:32]([C:29]3[S:28][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:21](=[O:22])[NH:20][CH:17]5[CH2:19][CH2:18]5)[C:31]=4[CH:30]=3)[C:37]([CH3:38])=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cnc(NCCC2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
4-(2-Aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.22 g, 5.35 mmol) is added to a stirred suspension of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.736 g, 2.14 mmol) and diisopropylethylamine (1.12 mL, 6.42 mmol) in anhydrous 1,4-dioxane (8 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 97° C. for 48 hours. At room temperature the mixture is concentrated and chromatographed on silica gel, eluting with CH3OH in dichloromethane: 0-4%, to give 4-{2-[4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-5-methyl-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid.