Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCOc2ccccc2)cc1C(=O)OC

Procedure:
A mixture of dimethyl 4-hydroxyphthalate (2.1 g; 0.01 mole), 1-bromo-3-phenoxypropane (2.15 g; 0.01 mole) and anhydrous potassium carbonate (1.52 g; 0.015 mole) in dry butanone (30 ml) was stirred at reflux overnight and the cooled mixture filtered. Evaporation in vacuo afforded the title compound in quantitative yield. νmax (film) 1730, 1605 cm-1 ; τ(CDCl3) 7.77 (2H, quintet, J 6.5 Hz); 6.16 (3H, s); 6.11 (3H, s); 5.86 (2H, t, J 6.5 Hz); 5.78 (2H, t, J 6.7 Hz); 3.20-2.55 (7H, m); 2.19 (1H, d, J 8.5 Hz); (Found; C, 65.98; H, 5.89; C19H20O6 requires; C, 66.27; H, 5.85%).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:14]([OH:16])=O)[CH3:2].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[N:22][CH:23]=1>>[C:25]([N:24]([CH3:28])[C:21]1[N:22]=[CH:23][C:18]([NH:17][C:14]([C:4]2[N:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:7][C:3]=2[CH2:1][CH3:2])=[O:16])=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CCc1oc(-c2ccccc2)nc1C(=O)O
Reactant: CC(=O)N(C)c1ccc(N)cn1
Product: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N(C)C(C)=O)nc1

Procedure:
With a procedure similar to example 16 above, 5-ethyl-2-phenyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 5-ethyl-2-phenyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-N-methyl-acetamide. LCMS calcd for C20H20N4O3 (m/e) 364, obsd 365 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:32](OC(C)(C)C)=[O:33]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][N:13]3[N:32]=[O:33])[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)NCC2
Solvent: C1CCOC1
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(N=O)CC2
Reaction time: 2 h

Procedure:
N-[2-({1-[1-(4-Fluorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (92 mg, 0.206 mmol, cf. example 65) was dissolved in tetrahydrofuran (1 mL) under an atmosphere of nitrogen. Tert-butyl nitrite (32 mg, 0.309 mmol) were added and the reaction mixture was stirred under reflux for 3 h. After that time additional tert-butyl nitrite (32 mg, 0.309 mmol) was added and stirring under reflux was continued for 2 h. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:methanol=100:1). Yield: 56 mg (0.118 mmol, 57%).
Reaction SMILES: [F:1][C:2]([F:15])([C:8]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O:5]CC)=[O:4].CO.[OH-].[Na+:19]>C1COCC1>[F:15][C:2]([F:1])([C:8]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O-:5])=[O:4].[Na+:19]
Reactant: CCOC(=O)C(F)(F)c1ncc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])C(F)(F)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To ethyl 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate (470 mg, 2.13 mmol) were added MeOH (4 mL), THF (4 mL) and 1.2; N NaOH (2 mL, 2.4 mmol). The solution was stirred at rt for 30 min and then concentrated to dryness to afford sodium 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate (430 mg, 94%). 1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 2H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([O:39]C)=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:18][C:17]4[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([OH:39])=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:18][C:17]4[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)Cc1cccnc1)Cc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2C1)Cc1cccnc1
Temperature: 60 °C
Yield: 10 %

Procedure:
To a solution of methyl 14-cyclohexyl-6-{2-[methyl(pyridin-3-ylmethyl)amino]ethyl}-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in a mixture of MeOH:THF (4:1; 0.05 M), 10 eq of 1 N NaOH were added. The solution was heated at 60° C. for 3 h. The volatiles were evaporated in vacuo and the crude was then purified by automated prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound in 10% yield (three steps).
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][O:4][C:5]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>O1CCOCC1>[F:1][CH:2]([F:21])[CH2:3][O:4][C:5]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1OCC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNc1cc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared in accordance with Example 72, step (b) using ethyl 2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoate ((950 mg; 3.12 mmol) see Example 59, step (f)), NaOH (3.1 mL; 2 M aq; 6.2 mmol) and 1,4-dioxane (10 mL). Yield: 800 mg (93%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.00 g of (6-bromo-pyridin-2-yl)-methanol was dissolved in 50 mL of dimethylformamide and 2.72 g of imidazole was added thereto. Under cooling with ice, 5.21 g of tert-butyldimethylsilyl chloride was added thereto followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to 1/1) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C3CCCCO3)=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.O>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:30][CH:31]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccc(O)cc1)N(Cc1ccc(O)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide in methanol (20 mL) was added 1N HCl (5 mL). After stirring for 2 hr., water was added and the aqueous solution was washed with methylene chloride (3×). The combined organic solutions were washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated. The residue was purified via radial chromatography using a solvent gradient (methylene chloride to 10% methanol/methylene chloride) to provide the title compound. 1H NMR (CD3OD) δ 7.44 (d, 2H, J=8.0 Hz), 6.96 (d, 2H, J=8.0 Hz), 6.85–6.74 (m, 4H), 6.73 (d, 2H, J=8.0 Hz), 6.58 (d, 2H, J=8.0 Hz), 4.55 (s, 2H), 4.02 (t, 2H, J=5.6 Hz), 2.89 (t, 2H, J=5.6 Hz), 2.67 (bs, 4H), 1.81 (bs, 4H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[F:17].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[F:17]
Reactant: COC(=O)c1cc(-c2c(F)cnn2C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(F)c1-c1cc(C(=O)O)sc1Cl
Yield: 71.7 %

Procedure:
A solution of methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (65 mg, 0.237 mmol) in 6N sodium hydroxide (0.39 ml, 2.37 mmol) and tetrahydrofuran (2 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (54 mg, 0.17 mmol, 72% yield) as a yellow oil; LCMS (ES) m/e 261, 263 (M, M+2)+.
Reaction SMILES: [C:1]([O:10]C(OC(C)(C)C)=O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(O)([C:20]([F:23])([F:22])[F:21])=O>>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:20]([F:23])([F:22])[F:21])=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)c1ccccc1N
Product: Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(trifluoromethyl)aniline (25 g, 0.15 mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET3N (19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried and concentrated. The resulting product was recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol) was dissolved in THF (350 mL) and cooled to −78° C. under nitrogen, then treated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0° C. and held for 1.5 h. The mixture was poured onto excess solid CO2 and stirred overnight at RT. After partitioning against 1 M HCl, the THF layer was evaporated and the residue dissolved in EtOAc, washed with 1 M HCl, then dried and concentrated. The solid product was triturated with hexan to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution/drying process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z (obs, M−H)=204.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)=[O:7].[CH3:17][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:7][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:17]
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)c2nccs2)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](C(C)(O)c2nccs2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,3R)-methyl 3-(thiazole-2-carbonyl)cyclopentanecarboxylate (148 mg, 1.75 mmol) in THF (6 mL) and at −78° C. was added methylmagnesium bromide (582 mL, 1.75 mmol), the solution was stirred at −78° C. for 30 minutes. Saturated aqueous ammonium chloride was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc, organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was absorbed on silica and purified by flash chromatography to afford (1S,3R)-methyl 3-(1-hydroxy-1-(thiazol-2-yl)ethyl)cyclopentanecarboxylate. MS ESI calc'd. for C12H18NO3S [M+H]+ 256. found 256. 1H NMR (500 MHz, DMSO-d6) δ 7.67 (t, J=3.0 Hz, 1H), 7.50 (d, J=3.0 Hz, 1H), 3.58-3.57 (m, 3H), 3.52 (s, 1H), 2.75-2.62 (m, 1H), 2.43-2.35 (m, 1H), 1.97-1.91 (m, 1H), 1.78-1.51 (m, 4H), 1.46-1.44 (m, 3H), 1.25-1.19 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Cl)CC2)cc1
Temperature: 50 °C

Procedure:
To 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (4.07 g, 21.2 mmol) were added thionyl chloride (4.64 mL, 63.5 mmol) and DMF (64 μL). The mixture was heated at 50° C. for 45 minutes. The excess thionyl chloride was evaporated under reduced pressure and the resulting acid chloride was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]1(=[O:24])[CH2:23][CH2:22][CH2:21]1>C1COCC1>[Br:13][C:14]1[C:19]([C:20]2([OH:24])[CH2:23][CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1ccccn1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC1(c2cccnc2Br)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 21.40 mmol) in THF (10 mL) at −78° C. was added n-BuLi (7.6 mL, 17.84 mmol). After 30 min, a solution of 2-bromopyridine (1.1 mL, 11.89 mmol) in THF (30 mL) was added and stirring was continued at −78° C. After 45 min, cyclobutanone (1.0 g, 14.27 mmol) was added and the mixture was stirred at −78° C. for 1.5 h. After warming to room temperature, the mixture was quenched with water (20 mL), diluted with saturated NH4Cl (15 mL), and extracted with Et2O (3×30 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated to afford an orange oil. Purification by flash column chromatography on silica gel using hexanes/EtOAc (2:1) afforded 1-(2-bromo-pyridin-3-yl)-cyclobutanol as an orange oil (1.0 g, 37%). 1H NMR (CDCl3) δ 1.69-1.73 (m, 1H), 2.19-2.22 (m, 1H), 2.49-2.55 (m, 2H), 2.61-2.68 (m, 2H), 3.01 (s, 1H), 7.29 (dd, 1H, J=5.1, 4.8 Hz), 7.68 (dd, 1H, J=7.7, 2.1 Hz), 8.28 (dd, 1H, J=4.7, 1.8 Hz).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[C:28](Br)=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[C:28]([CH:1]2[CH2:3][CH2:2]2)=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)c(C2CCC2)cc1OCc1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(C2CC2)c(C2CCC2)cc1OCc1ccccc1
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
Cyclopropylboronic acid (6.18 g) and sodium carbonate (15.3 g) were added to a mixed solution of methyl 2-(benzyloxy)-5-bromo-4-cyclobutylbenzoate (13.5 g) in toluene (240 mL) and water (60 mL), and the mixture was deaerated for 20 minutes in an argon stream. Then, tris(dibenzylideneacetone)dipalladium(0) (6.25 g) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (2.80 g) were added thereto, and the mixture was further deaerated for 5 minutes. The reaction mixture was stirred at 100 C for 16 hours. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. Combined organic layers were washed with water and saturated saline in this order, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (8.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21]S(C)(=O)=O)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21][C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COS(C)(=O)=O)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Temperature: 40 °C

Procedure:
A mixture of 4-(4-methanesulfonyloxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.5 mmol), 4-methanesulfonyl-phenol (86 mg, 0.5 mmol) and Cs2CO3 (170 mg, 0.52 mmol) in acetonitrile (4 mL) was heated at 40° C. overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.83 (2H, m), 7.23 (1H, s), 7.09 (2H, m), 5.2 (2H, s), 3.64-3.54 (2H, m), 3.3˜3.24 (2H, m), 2.99 (3H, s), 2.2˜2.1 (2H, m), 1.72-1.64 (2H, m), 1.41 (9H, s), 1.36 (3H, s).
Reaction SMILES: [CH2:1]([C:3]1[S:22][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2]>[OH-].[NH4+]>[CH2:1]([C:3]1[S:22][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncnc3sc(CC)cc23)CC1
Agent: [NH4+]
Agent: [OH-]
Product: CCc1cc2c(N3CCC(C(=O)O)CC3)ncnc2s1
Yield: 74.4 %

Procedure:
A solution of ethyl 1-[6-ethylthieno[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylate (1.4 g, 4.38 mmol, 1.00 equiv) in ammonium hydroxide (50 mL) was heated to reflux for 12 hrs. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum and dissolved in 20 ml of aqueous hydrogen chloride (12 N) and concentrated again to give 950 mg (crude) of 1-[6-ethylthieno[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C1CC[CH:15]([N:18]=[C:19]=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CNC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([N:18]([CH3:19])[CH3:15])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(O)c(Cl)c1
Yield: 76.2 %

Procedure:
3-Chloro-4-hydroxy-benzoic acid (800 mg, 4.6 mmol), DCC (856 mg, 5.4 mmol), and HOBt (540 mg, 5.4 mmol) were mixed in DMF (10 mL). N,N-dimethyl amine (2M in THF, 4.6 mL) was added to the mixture at 0° C. The reaction was stirred over night and purified by silica gel chromatography (70%–90% EtOAc/Hexane) to provide the title compound (700 mg, 87.5%). MS (DCI) m/z 200, 202 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[I:10]I.S([O-])([O-])=O.[Na+].[Na+]>CO.O>[I:10][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:9]
Reactant: Cc1ccc(O)cc1C
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(O)c(I)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
3,4-Dimethylphenol (0.68 g) and iodine (1.82 g) were dissolved in methanol/water (10 ml/5 ml), and the mixture was stirred at room temperature overnight. An aqueous sodium sulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using ethyl acetate-hexane to give 2-iodo-4,5-dimethylphenol (833 mg, yield 64%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([C:16]([NH:18][CH2:19][C:20]2[S:21][C:22]([S:25]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[O:17])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:18][CH2:19][C:20]2[S:21][C:22]([S:25]([N:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29]3)(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[O:17])=[CH:34][CH:35]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CC[C@@H](O)C2)s1)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)s2)C1
Yield: 80.2 %

Procedure:
At −80° C. oxalylchloride (36 mg, 0.28 mmol) was dissolved in dry CH2Cl2, while DMSO (50 ul, 0.6 mmol) were added slowly. The solution was stirred under Ar. For 15′. 351a (100 mg, 0.25 mmol) was dissolved in 2 ml CH2Cl2, and this solution was added dropwise to the above reaction mixture at −80° C. The reaction was stirred for 15′ at low temperature, before DIEA (0.21 ml, 1.25 mmol) was added. The reaction was stirred at −80° C. for 30′ and allowed to warm to it during 2 h. A white solid was formed, the reaction was quenched with water and extracted with CH2Cl2 several times. The combined organic layers were dried over MgSO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel using EtOAc/cyclohexane 2:1 as eluent. 351b (80 mg, 80%) was obtained as a colourless solid.: H′ NMR (CDCl3) δ 7.72 (d, J=8.7 Hz, 2H), 7.46 (d, J=3.8 Hz, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.08 (d, J=3.8 Hz, 1H), 6.59 (t, J=5.8, 1H), 4.80 (d, J=6.0 Hz, 2H), 3.58 (t, J=7.5 Hz, 2H), 3.50 (s, 3H), 2.54 (t, J=7.5, 2H), 3.35-3.23 (m, 3H), 2.95 (m, 2H), 1.94 (m, 2H), 1.86 (m, 2H), 1.70-1.50 (m, 5H), 130-1.20 (m, 8H), 0.87 (t, J=6.8, 3H), M/Z APCI-399.0 (M+1), 397.2 (M−1)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([OH:22])[C:5]([CH:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH2:11]O)=[C:6]([CH3:9])[C:7]=1[CH3:8]>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]2[CH:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[CH2:11][O:22][C:4]=2[C:3]=1[CH3:23]
Reactant: Cc1c(C)c(C(CO)c2ccc(C(C)C)cc2)c(O)c(C)c1Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1Br)OCC2c1ccc(C(C)C)cc1
Yield: 57 %

Procedure:
Using 3-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,4,5-trimethylphenol synthesized in Reference Example 234, the title compound was synthesized in the same manner as in Reference Example 13. Yield 57%. Melting point: 56-57° C. (hexane-ethyl acetate).