Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClC(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCc1ccc(CO)o1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1NCc1ccc(CO)o1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 15.9 parts of 4-chloro-3-nitropyridine, 12.7 parts of 5-(aminomethyl)-2-furanmethanol, 13.3 parts of N,N-diethylethanamine and 745 parts of trichloromethane was stirred for 3 hours at reflux temperature. After cooling, the reaction mixture was washed with K2CO3 (aq.), dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 17.76 parts (71.3%) of 5-[[(3-nitro-4-pyridinyl)amino]methyl]-2-furanmethanol; mp. 134.9° C. (interm. 19).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1.O[C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:16]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCOC5)cc4C)c3)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
(R)-(2′,6′-Dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 2c (143 mg, 0.48 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (100 mg, 0.48 mmol) and triphenylphosphine (189 mg, 0.72 mmol) were dissolved in 20 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (146 mg, 0.72 mmol). The reaction solution was warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2d (201 mg, yield 85.9%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:26]=[O+][O-].CSC>ClCCl.C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:22])([CH3:23])[C@@H:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:12]=[O:26])(=[O:6])=[O:7]
Reactant: C=C[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)OCc1ccccc1
Yield: 60 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3S)-2,2-dimethyl-3-(phenylmethoxy)pent-4-enyl (3-chloropropyl]sulfonate (11a) (25.0 g, 69.3 mmol) dissolved in a mixture of 300 mL of dichloromethane (DCM) and 40 mL of ethanol was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 10.6 mL (9.0 g, 138 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:6) as eluent to provide 15.0 g (60% yield) of the title compound (11b) as a colorless oil. Rf=0.22 (EtOAc/Hxn=1:6). 1H NMR (400 MHz, CDCl3): δ=1.10 (s, 6H), 2.26-2.33 (m, 2H), 3.23-3.29 (m, 2H), 3.65 (d, J=2.8 Hz, 1H), 3.63-3.68 (m, 2H), 4.03 (d, J=9.6 Hz, 1H), 4.15 (d, J=8.8 Hz, 1H), 4.50 (d, J=11.2 Hz, 1H), 4.68 (d, J=11.2 Hz, 1H), 7.30-7.39 (m, 5H), 9.73 (d, J=2.8 Hz, 1H) ppm. MS (ESI) m/z 385.03 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[C@@H:12]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C@H:11](O)[CH2:10]2.[CH2:23]([N:25](CC)CC)C.CN>O1CCCC1.C(O)C>[Cl:16][C:15]1[CH:14]=[C:10]2[C:9](=[CH:8][C:7]=1[Cl:6])[C@@H:13]([NH:25][CH3:23])[C@H:12]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:11]2
Reactant: O[C@@H]1Cc2cc(Cl)c(Cl)cc2[C@H]1N1CCCC1
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CN[C@@H]1c2cc(Cl)c(Cl)cc2C[C@H]1N1CCCC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 17 ml of methane sulfonyl chloride in 3 ml of tetrahydrofuran was added dropwise at -20° C. to a mixture of 5 g of the product of Step E, 40 ml of tetrahydrofuran and 4 ml of triethylamine and after stirring for 15 minutes at -20° C., the temperature was raised to 0° C. and 20 ml of methylamine in ethanol were added. The mixture was stirred for 22 hours and was evaporated to dryness. The residue was diluted with water and after the addition of a few drops of sodium hydroxide solution, the mixture was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 5.7 g of residue. The latter was chromatographed on silica and eluted with a 8-1-1 ethyl acetate-methanol-triethylamine mixture and after standing at 4° C., 4.91 g of the desired crystalline product melting at ≈55° C. were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:2]
Reactant: CCc1ccccc1C=CC(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccccc1CCC(=O)O

Procedure:
3-(2-Ethyl-phenyl)-acrylic acid (17.00 g, 96.48 mmol) in THF was mixed with Pd/C (1.50 g) and hydrogenated at 50 psi for 6 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated to give 3-(2-ethyl-phenyl)-propionic acid. The acid was reacted with SOCl2 (5.00 mL, 68.55 mmol) and AlCl3 (6.70 g, 50.25 mmol) according to the protocols as outlined in general procedure C to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=3)=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(F)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 73A in analogy to the synthesis of the compound of Example 1. 28 mg (73% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:9](Cl)=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=2[Cl:14])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:27][NH2:28]>C1COCC1>[Cl:14][C:13]1[N:12]=[C:11]([S:15][CH3:16])[N:10]=[C:9]2[NH:27][N:28]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]=12
Reactant: NN
Reactant: CSc1nc(Cl)c(C(=O)C2CCCC2)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c2c(C3CCCC3)n[nH]c2n1
Temperature: 0 °C
Yield: 119.2 %

Procedure:
Cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanone (2.0 g, 6.868 mmol) was dissolved in 25 mL dry THF and stirred at 0° C. under nitrogen. N,N-diisopropylethylamine (2.392 mL, 13.763 mmol) was added dropwise, and the reaction mixture was stirred for five minutes. Hydrazine (0.205 mL, 6.525 mmol) was added dropwise, and the reaction was stirred for 16 hours, during which time the reaction mixture was allowed to warm to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water, washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give 2.09 g of 4-Chloro-3-cyclopentyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=270.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH3:30])=[CH:24]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]([CH3:30])=[CH:24]4)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ncnc4cc(OCc5ccccc5)ccc34)ccc2[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A solution of 7-benzyloxy-4-chloroquinazoline (2 g, 7.4 mmol), 5-hydroxy-2-methylindole (1.3 g, 8.9 mmol), (prepared as described for the starting material in Example 48), in DMF (20 ml) containing potassium carbonate (1.53 g, 11.1 mmol) was stirred at 80° C. for 3 hours. After cooling, the mixture was poured in portions into ice/water. The precipitate was filtered and washed with water and dried under vacuum. The solid was dissolved in methylene chloride and was purified by column chromatography eluting with ethyl acetate and methylene chloride (1/1) to give 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (2.28 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[C:9]([O:35][CH3:36])=[CH:10][C:11]([CH:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=3)[OH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[C:9]([O:35][CH3:36])=[CH:10][C:11]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)ncc1OCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c[nH]c3ncccc23)ncc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
[5-(4-Chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (75, 60.0 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2.00 mL). Dess-Martin periodinane (55.3 mg, 0.13 mmol) was added to the reaction and it was stirred at room temperature overnight. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica and purified by silica gel chromatography, methanol:dichloromethane, to provide the desired compound (P-2024, 10.7 mg, 25%). 1H-NMR was consistent with the desired compound. MS (ESI) [M+H+]+=394.1, 396.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cu][C:14]#[N:15].CN1CCCC1=O.C(N)CN>S([O-])([O-])(=O)=O.[Cu+2].O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: N#C[Cu]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: NCCN
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1O
Temperature: 25 °C
Yield: 14.7 %

Procedure:
Methyl 5-bromo-2-hydroxybenzoate (25.6 g, 129 mmol), copper(I) cyanide (20.8 g, 257 mmol) and copper sulfate (200 mg) were added to N-methyl-2-pyrrolidone (250 ml) and the mixture was refluxed under heating for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a mixture of water (500 ml) and ethylenediamine (10 ml). After filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=5/1) to give 3.35 g of methyl 5-cyano-2-hydroxybenzoate as a colorless solid (15%). This solid (3.35 g, 18.9 mmol) and potassium carbonate (5.23 g, 37.0 mmol) were added to N,N-dimethylformamide (45 ml), and ethyl bromoacetate (2.21 ml, 19.9 mmol) was gradually added, which was followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with an equivalent mixture of ethyl acetate and n-hexane. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give a crude product of ethyl 4-cyano-2-methoxycarbonylphenoxyacetate. This product (3.39 g, 19.3 mol) was dissolved in ethanol (20 ml) and the obtained solution was gradually added to a solution of metallic sodium (622 mg, 27.1 mmol) dissolved in ethanol (50 ml). The mixture was stirred at room temperature for 45 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure and water (200 ml) was added to the residue. Dilute hydrochloric acid was added to adjust the pH to 2-3. The resulting precipitate was collected by filtration to quantitatively give 2.98 g of ethyl 5-cyano-3-hydroxy-2-benzofurancarboxylate as a colorless solid.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[C:11](=[S:13])=S.[OH-].[Na+].Cl>C(O)C.O>[SH:13][C:11]1[N:3]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]=1
Reactant: S=C=S
Reactant: CNc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(S)nc2ccccc21
Yield: 49.5 %

Procedure:
11.7 g of N-methyl-o-phenylenediamine hydrochloride, 9.1 g of carbon disulfide and an aqueous solution containing 7.2 g of sodium hydroxide and 20 ml of water were added to 150 ml of ethanol and the mixture was heated and refluxed for 4 hours. After cooling, a 3 N hydrochloric acid aqueous solution was added to the reaction mixture to make the reaction solution slightly acidic and, thereby, crystals were precipitated. After filtration, the crystals were recrystallized from a mixture of water and ethanol (70:30 by volume) to obtain 6 g of 2-mercapto-1-methylbenzimidazole (Compound (III-11)) having a melting point of 194° to 195° C. (yield: 67%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[N:12]=[CH:11][NH:10][C:9](=O)[CH:8]=1.P(Cl)(Cl)([Cl:21])=O>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([Cl:21])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(Cc2cccc(C(F)(F)F)c2)nc[nH]1
Product: FC(F)(F)c1cccc(Cc2cc(Cl)ncn2)c1

Procedure:
Under nitrogen atmosphere, 6-(3-trifluoromethylbenzyl)pyrimidin-4-one (7.0 g, 0.027 mol) is dissolved in phosphorus oxychloride (30 ml) and is refluxed for 1.5 hours. After cooling the solution is concentrated under reduced pressure. The solid is then dissolved in ethyl acetate, washed with water, saturated brine, dried and the crude product purified by flash column chromatography to give 6-(3-trifluoromethylbenzyl)-4-chloro-pyrimidine (6.3 g).
Reaction SMILES: O[C:2]1([C:10]2[C:11]([NH:16]C(=O)C(C)(C)C)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C>[CH3:8][C:5]1([CH3:9])[CH2:6][CH2:7][C:2]([C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:3][CH2:4]1
Reactant: CC1(C)CCC(O)(c2cccnc2NC(=O)C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC=C(c2cccnc2N)CC1
Temperature: 100 °C
Yield: 104.5 %

Procedure:
To a solution of N-(3-(1-hydroxy-4,4-dimethylcyclohexyl)pyridin-2-yl)pivalamide (1.034 g, 3.34 mmol) in ethanol (51 mL) was added 2M aqueous sodium hydroxide solution (16.98 mmol, 8.5 mL). The reaction was heated over night at 100° C. The solvent was evaporated under reduced pressure and the residue was partitionated between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to yield the title compound as a white solid (706 mg, quant.). MS ISP (m/e): 203.3 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1>O>[C:1]([OH:13])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 250 °C

Procedure:
Acid Following, U.S. Pat. No. 4,302,595, incorporated herein by reference, a suspension of dimethyl terephthalate in H2O is heated to 250° C. for 4 hour in a Parr pressure reactor resulting in hydrolysis to terephthalic acid.
Reaction SMILES: C([O:5][C@H:6]1[CH2:10][N:9]([C:11](=[O:32])[CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[C:40]([NH:42][CH2:43][C@H:44]2[CH2:49][CH2:48][CH2:47][NH:46][CH2:45]2)=[O:41])=[O:34])[CH2:7]1)(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][C@H:6]1[CH2:10][N:9]([C:11](=[O:32])[CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:8]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[C:40]([NH:42][CH2:43][C@H:44]2[CH2:49][CH2:48][CH2:47][NH:46][CH2:45]2)=[O:41])=[O:34])[CH2:7]1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCNC2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To 1.65 g of (2R)-1-{(2S,4R)-4-tert-butoxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3-piperidylmethyl)pyrrolidine-2-carboxamide, 5 ml of trifluoroacetic acid was added at room temperature, followed by 1 hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, diluted with chloroform, rendered basic with 4N aqueous sodium hydroxide solution, extracted with chloroform and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 1.56 g of the title compound was obtained as a white foamy substance.
Reaction SMILES: [CH3:1][C:2]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:8][C:2]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)OC1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(OC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanoate (0.5 g, 2.31 mmol) in tetrahydrofuran (2 mL) and methanol (6 mL) was added a solution of lithium hydroxide (0.277 g, 11.56 mmol) in water (6 mL). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed under reduced pressure and the resulting aqueous phase was acidified using hydrochloric acid 2N until pH=4. The formed precipitate was extracted with ethyl ether (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to yield the title compound (0.42 g, 96%) as a colourless oil.
Reaction SMILES: [C:1](=[O:13])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[Br-:14].C[SiH](C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1](=[O:13])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3]([Br:14])[CH3:4]
Reactant: CC(Cl)OC(=O)Oc1ccccc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)C
Product: CC(Br)OC(=O)Oc1ccccc1
Temperature: 90 °C

Procedure:
15.4 g (0.077 mol) of 1-chloroethyl phenyl carbonate, 0.44 g (0.0014 mol) of tetrabutylammonium bromide and 13.7 g (0.090 mol) of trimethylsilane bromide are introduced into a distillation apparatus equipped with a 15 cm Vigreux column, a thermometer and a stirrer. The mixture is heated at 90° C. for 24 h and the trimethylsilane chloride released is removed by distillation. The product expected is then distilled. 17.2 g (Yld=91%) are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1B(O)O.[CH2:16]([O:23][CH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH2:32][CH2:33][CH3:34])[C:26]=1I)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:16]([O:23][CH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH2:32][CH2:33][CH3:34])[C:26]=1[C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[O:4][CH2:3][O:2][CH3:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCOc1ncnc(COCc2ccccc2)c1I
Reactant: COCOc1cc(OC)ccc1B(O)O
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCOc1ncnc(COCc2ccccc2)c1-c1ccc(OC)cc1OCOC
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.8 %

Procedure:
To a solution of 2-methoxymethoxy-4-methoxyphenyl boronic acid (2.89 g. 13.65 mmol) in MeOH (8-10 ml) and 6-benzyloxymethyl-5-iodo-4-propoxy-pyrimidine (5 g, 13 mmol) in toluene (75 ml) was added an aqueous solution of 2 M sodium carbonate (14 ml) followed by Tetrakis(triphenylphosphine)palladium (0) (1.25 g, 1.08 mmol). The reaction was allowed to stir at 90-95° for 18 h. The mixture was cooled to room temperature then diluted with ethyl acetate, washed with water, sat'd NH4Cl, 5% NaHCO3 solution, brine and dried (MgSO4). After removing the solvent, flash chromatography of the residue (silica gel, 1:1 t-butyl methyl ether/hexane) provided the title compound as a solid (3.41 g, 62%).