Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][C:3]=1[C:22](=O)[CH3:23]>C(O)(=O)C.CO.[Pd]>[CH2:22]([C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][C:2]=1[OH:1])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCc1ccc(CC)c(O)c1
Reaction time: 18 h

Procedure:
A 15.6 g portion of 1-(2-hydroxy-4-tetradecylphenyl)-ethanone was heated in a mixture of 120 ml of acetic acid and 30 ml of methanol until solution was complete. A 4 g portion of 5% palladium on carbon was added and the mixture was hydrogenated in a Parr apparatus for 18 hours. The mixture was then filtered through diatomaceous earth and the solvents removed under reduced pressure, giving 14.5 g of the desired compound, mp 59°-60° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:11][C:12](=[O:41])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=3Br)[CH:23]=2)=[CH:17][C:16]=1[CH3:40]>>[CH3:40][C:16]1[CH:17]=[C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:23]=2)[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:12]([OH:11])=[O:41]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using phenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 74 mg (49%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H23O4F3 492, found 493 (M+1, 100%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]1[CH:19]=[C:20]([CH2:26][CH:27]([O:31][CH:32]([CH3:34])[CH3:33])[C:28]([O-:30])=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH:32]([O:31][CH:27]([CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([CH2:17][O:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[CH:19]=1)[C:28]([OH:30])=[O:29])([CH3:33])[CH3:34]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: OCc1ccc(Oc2ccccc2)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(Oc2ccccc2)cc1

Procedure:
Using (4-phenoxyphenyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(4-phenoxybenzyl)oxy]methylphenyl)propanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+].ClCCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23][NH:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1ccc(C=O)cc1Cl
Reactant: CCOC(=O)c1sc(N2CCCC2CO)nc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1sc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-amino-5-ethoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolodinyl)thiazole (prepared in the above (2)) 177 mg, 3-chloro-4-methoxybenzaldehyde 111 mg, acetic acid 78 mg and 1,2-dichloroethane 8 ml is added sodium triacetoxyborohydride 415 mg, and the mixture is stirred at room temperature for 6 hours. Further 3-chloro-2 5 4-methoxybenzaldehyde 111 mg and sodium triacetoxyborohydride 415 mg are added thereto, and the mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and the organic layer is washed, dried and concentrated in vacuo. The residue is separated with reversed phase column chromatography and preparative thin-layer chromatography, and then triturated with ether to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolodinyl)thiazole as crystals, 171 mg. mp 103.5-104.5° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[NH2:28][C:26]([C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[CH:23][CH:24]=1)=[O:27]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Product: NC(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminobenzamide (Aldrich), the title compound was obtained as a brown solid in 85% yield after trituration in DCM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(C#CCCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCCO)cc1
Yield: 93.2 %

Procedure:
A solution of 16 (7.1 g, 37 mmol) in 150 dry ethanol (150 mL) was placed in a 0.5 L Parr flask and palladium on carbon (0.92 g, 5% wet. Pd/C) was added as a suspension in ethanol (25 mL). The reaction mixture was shaken at 50 psi of hydrogen pressure at room temperature for 24 hours. After this time, the mixture was filtered through a silica gel pad and the solvent was removed at reduced pressure. The residue was purified by flash chromatography (silica gel, 1:3 ethyl acetate/hexanes) to provide 17 (6.7 g, 92%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.48 (m, 2H), 1.60 (m, 4H), 2.58 (m, 2H), 3.63 (m, 2H) 3.80 (s, 3H), 6.83 (d, 2H), 7.10 (d, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:21][C:22]1[CH:23]=[C:24]([NH:29][NH2:30])[CH:25]=[CH:26][C:27]=1[Cl:28].O>C(O)(=O)C>[Cl:28][C:27]1[CH:26]=[CH:25][C:24]([N:29]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][C:13]([C:14]([F:17])([F:16])[F:15])=[N:30]2)=[CH:23][C:22]=1[CH3:21]
Reactant: CS(=O)(=O)c1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: Cc1cc(NN)ccc1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1Cl
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]-4,4,4-trifluorobutane-1,3-dione (620 mg) and (3-methyl-4-chlorophenyl)hydrazine hydrochloride (425 mg) in acetic acid (2 ml) was refluxed for 1 hour. After cooling, the solvent was poured into water (50 ml) and stirred for 30 minutes. The resulting precipitates were collected by filtration and washed with water and dried in vacuo. The residue was recrystallized from ethanol to afford 1-(4-chloro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (569 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][C@@H:5]1[C@@H:9]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6]1.NN>C(O)C>[CH3:1][O:2][C:3](=[O:28])[NH:4][C@@H:5]1[C@@H:9]([NH2:10])[CH2:8][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6]1
Reactant: COC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: COC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of the product from Step 2 (3.60 g, 9.49 mmol) and anhydrous hydrazine (0.61 g, 19.0 mmol) in ethanol (36 mL) was heated at reflux temperature for 2 h. The reaction was cooled to room temperature and the precipitate was removed by filtration and washed with ethanol. The filtrate was concentrated to dryness and the residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated to an oil that solidified upon standing to afford 2.20 g (93%) of the product as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.22 (m, 5H), 5.12-5.00 (br s, 1H), 3.74-3.57 (m, 1H), 3.64 (s, 3H), 3.63-3.54 (m, 2H), 3.34-3.25 (m, 1H), 3.14-3.02 (m, 1H), 2.88-2.53 (m, 1H), 2.54-2.42 (m, 1H), 2.17-2.10 (m, 1H) 2.00-1.60 (br s, 2H). MS 250.3 (AP+, 100).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([CH3:26])[O:15][C:14](=[O:27])[C@H:13]([NH:28]C(=O)OC(C)(C)C)[CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36].O1CCOCC1>C(Cl)Cl>[ClH:36].[NH2:28][C@@H:13]1[CH2:12][O:11][CH2:10][C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([CH3:26])[O:15][C:14]1=[O:27]
Reactant: C[C@H]1OC(=O)[C@H](NC(=O)OC(C)(C)C)COC[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1OC(=O)[C@H](N)COC[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of tert-butyl ((3R,7S,8S,9R)-7,8-bis(benzyloxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (104.0 mg, 0.214 mmol) in DCM (1.20 mL) was added a 4.0 M solution of HCl in dioxane (1.07 mL, 4.28 mmol) and the reaction was stirred at room temperature for 2 h. The solvent was removed under vacuum and the residue was dried under high vacuum to yield the title compound as an off-white oil (85.0 mg, 94%): IR (neat) 3365, 1636, 1235, 1063 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.76 (bs, 2H), 7.35-7.20 (m, 10H), 5.30 (s, 1H), 4.69-4.45 (m, 5H), 4.20 (d, J=9.1 Hz, 2H), 3.89-3.75 (m, 2H), 3.59 (d, J=11.1 Hz, 1H), 3.47 (d, J=7.1 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H); HRMS-ESI (m/z) [M]+ calcd for C22H27NO5, 385.1889; found, 385.1890.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Br-].O=[C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[N+]1CCCC1>CO.C(#N)C>[C:7]([C:6]1[CH:10]=[C:2]([N:1]2[C:17]3[CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[CH:15]=[C:14]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=[CH:4][C:5]=1[OH:11])([OH:9])=[O:8]
Reactant: O=C(CC1C(=[N+]2CCCC2)CCc2ccccc21)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: [Br-]
Solvent: CO
Solvent: CC#N
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A mixture of 1.92 g of 5-aminosalicylic acid and 5.0 g of tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide (Example 1a), in 75 ml of methanol is refluxed under nitrogen for 9 hours. The solution is allowed to reach ambient temperature before being filtered. The methanol is removed under a vacuum to give a viscous oil which is dissolved in acetonitrile. This solution immediately crystallizes to give a yellow crystalline solid which is collected by filtration and washed with acetonitrile to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[Si:7]([CH3:14])([CH3:13])[O:8][Si:9](Cl)([CH3:11])[CH3:10]>CCOCC>[CH2:1]([N:3]([Si:7]([CH3:14])([CH3:13])[O:8][Si:9]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])([CH3:11])[CH3:10])[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: C[Si](C)(Cl)O[Si](C)(C)Cl
Solvent: CCOCC
Product: CCN(CC)[Si](C)(C)O[Si](C)(C)N(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylamine, 184 g. (2.50 mole) of 400 ml. of anhydrous ether were added to a one-liter multi-necked round bottom flask equipped with reflux condenser, pressure equalizing addition funnel, thermometer and stirrer, which was maintained under a positive pressure of argon. The solution was chilled with an ice water bath to 5°-10° C. during the dropwise addition of 100 g. (0.50 mole) of 1,3-dichloro-1,1,3,3,-tetramethyldisiloxane. After addition was completed the mixture was stirred overnight at room temperature (20°-25° C.). The mixture was then filtered and the filtrate was concentrated by rotary evaporation. The resulting residue was distilled at reduced pressure and yielded 81 g. (0.29 mole; 60% theoretical) of V (b.p. 75°-80° C., 2 mm. Hg.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]([CH3:35])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([O:30][C@@H:24]([C:15]1[C:14]([CH3:35])=[CH:13][C:11]2[N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:40]4[CH:41]=[N:36][CH:37]=[N:38][CH:39]=4)[CH:3]=3)[S:9][C:10]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH3:34])([CH3:33])[CH3:32]
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(Br)c3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4cncnc4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
The reaction mixture of (S)-ethyl 2-(2-(3-bromophenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (12 mg, 0.025 mmol), 5-pyrimidineboronic acid (5 mg, 0.0375 mmol), 2N K2CO3 (60 μL), Pd(PPh3)4 (3 mg, 0.0025 mmol) in dioxane (1 mL) was heated at 120° C. in sealed tube. After the reaction was finished, the reaction was washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C32H30ClN3O3S: 572.2 (M+H+); Found: 572.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:17]([O:35][CH3:36])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:36][O:35][C:17]1[CH:16]=[C:15]([CH:34]=[CH:33][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:14][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: CCOC(=O)c1cn(C)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (1.93 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (3.89 g), potassium carbonate (3.15 g) and N,N-dimethylformamide (30 mL) was stirred overnight at 60° C. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylate (5.23 g, yield 97%). The crystals were recrystallized from acetone-hexane. melting point: 134-135° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[N:27]=[C:26]([CH:39]([CH3:41])[CH3:40])[C:25]=2/[CH:42]=[CH:43]/[CH:44]=[O:45])=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[N:27]=[C:26]([CH:39]([CH3:41])[CH3:40])[C:25]=2/[CH:42]=[CH:43]/[CH:44]([OH:45])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:19]=1
Reactant: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1/C=C/C=O
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2ccc3ccccc3n2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirred suspension of hexane washed NaH (0.77 g, 19.1 mmoles) in 30 mL THF at 0° C. under a nitrogen atmosphere, was added dropwise a solution of ethyl acetoacetate (2.27 mL, 17.9 mmoles) in 30 mL THF. The mixture was stirred for 15 minutes before a 2.2 M solution of n-BuLi (8.2 mL, 17.9 mmoles) in THF was added dropwise via syringe. The resulting orange solution was stirred at 0° C. for 15 minutes and then cooled to -7S° C. A solution of trans-3-[5-(4-fluorophenyl)-3-(l-methylethyl)-1-(2-quinolinyl)-1H-pyrazol-4-yl]-2-propenal (4.61 g, 12.0 mmoles) in 50 mL THF was added dropwise and after 2 hours at -78° C. the reaction was quenched by adding 6 mL glacial HOAc and removing the cooling bath. The reaction was partitioned between 5% K2CO3 and Et2O. The organic layer was dried over MgSO4, filtered, and evaporated to give an orange oil. Chromatography (SiO2, 20% EtOAc/hexanes) gave 5.57 g (90%) of the title compound as a yellow solid, mp 47°-53° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:51])([F:50])[O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[CH3:21][CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[O:30])=[CH:13][CH:12]=1)[S:22][C:23]1[CH:24]=[CH:25][C:26]([C:44]2[CH:43]=[CH:42][C:41]([O:40][C:39]([F:51])([F:50])[F:38])=[CH:46][CH:45]=2)=[CH:27][CH:28]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCCCC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC(C)CC(Sc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Yield: 50.6 %

Procedure:
3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-propionic acid methyl ester (100 mg, 0.2 mmol), potassium carbonate (83 mg, 0.6 mmol), 3-trifluoromethoxylphenyl boronic acid (76 mg, 0.4 mmol) and tetrakis-(triphenylphosphine)palladium (23 mg, 0.02 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, concentrated, diluted with ethyl acetate, acidified with 1 N HCl (0.6 mL), extracted with ethyl acetate. The organic layers are dried and purified with reverse phase HPLC to afford the title compound (58 mg). MS (ES): 544.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH2:9][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[CH3:8])[NH2:6]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](N)C(C)CCc1ccc(-c2ccccc2C#N)cc1

Procedure:
L-valine methyl ester hydrochloride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester thus formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester is treated with tributyltin azide to give valsartan methyl ester, which is then hydrolyzed under alkaline condition to give finally valsartan.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[SH:13].Cl[Sn:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:13][Sn:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1c(S)nc2ccccc2c1=O
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(S[Sn](c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccccc2c1=O
Yield: 61.6 %

Procedure:
A mixture of 11.6 g (0.06 mole) 3-methyl-2-mercapto-4(3H)-quinazolinone, 23.2 g (0.06 mole) chlorotriphenyl tin and 6.1 g (0.06 mole) triethylamine in methylene chloride (about 200 ml) were stirred together, then refluxed for four hours and stirred overnight. The reaction mixture was washed with water, dried and stripped. After trituration with ether, 20.0 g of the above-identified product as a white solid, melting point 155°-157° C. was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[C:14]2=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[CH2:14]2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)c1ccc2c(c1)C(=O)c1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(c1)Cc1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2

Procedure:
0.3 g of (3S,5S)-5-[(7-amidino-9-keto-2-fluorenyl)oxymethyl]-3-carboxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone are dissolved in 7 ml of glacial acetic acid, 0.05 g of 10% palladium charcoal are added and the mixture is hydrogenated for 6 hours at 70° C. under 3 bar of hydrogen pressure. The catalyst is filtered off, the filtrate is evaporated down and the product is purified by chromatography on silica gel (eluent: tetrahydrofuran/2N acetic acid=10:1)