Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([S:14][CH3:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([CH:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([CH:30]([NH:40][C:1]([C:4]2[CH:13]=[C:12]([S:14][CH3:15])[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(SC)c3ccc(Cl)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(3-(3-(3,5-difluorophenyl)-1-oxo-2-(quinolin-3-yl)-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (42 mg, 0.1 mmol) obtained in Step 2 in CH2Cl2 was added trifluoroacetic acid (20 eq, 1.0 mmol). After being stirred for 1 h, the mixture was diluted with CH2Cl2 and basicified to pH 9 with a 3N NaOH solution. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo to provide the title compound, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][CH:3]=1.[CH3:17][C:18]([OH:22])([C:20]#[CH:21])[CH3:19].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:20][C:18]([CH3:19])([OH:22])[CH3:17])=[CH:3][CH:4]=1
Reactant: COCCCCCCOc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCCCCCOc1ccc(C#CC(C)(C)O)cc1

Procedure:
Under a nitrogen atmosphere, to a mixture of 1-bromo-4-(6-methoxyhexyloxy)benzene (3.68 g), 2-methyl-3-butyn-2-ol (1.86 ml) and triethylamine (18 ml) in pyridine (7.4 ml) was added triphenylphosphine (67.2 mg), copper(I) iodide (24.4 mg) and dichlorobis(triphenylphosphine)palladium(II) (18.0 mg), and refluxed overnight. After cooling, insoluble material was filtered off and washed with isopropyl ether. The filtrate was evaporated under reduced pressure. To the residue was added isopropyl ether and the mixture was washed with 0.1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude yellow oil. The crude yellow oil was purified by silica gel chromatography (10:1-2:1 hexane-ethyl acetate) to give 4-[4-(6-methoxyhexyloxy)phenyl]-2-methyl-3-butyn-2-ol (3.17 g) as a yellow powder.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][N:11]=3)[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:26])[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]1([N:4]2[C:12]3=[N:11][CH:10]=[CH:9][N:8]=[C:7]3[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:25])=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:26])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1)N1CCOCC1

Procedure:
The title compound was prepared following the procedure for EXAMPLE 151, using a mixture of 2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxylic acid, EXAMPLE 149, (0.07 g, 0.188 mmol), morpholine (0.025 ml, 0.282 mmol), diisopropylethylamine (0.049 ml, 0.282 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.125 g, 0.282 mmol) to give 1-cyclopropyl-3-(trans-3-((5-(morpholine-4-carbonyl)thiazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.025 g, 0.057 mmol, 30.1% yield). m/z: 442.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.30 (d, J=5.67 Hz, 1 H), 7.81-8.10 (m, 2 H), 7.13 (s, 1 H), 5.13 (t, J=8.31 Hz, 1 H), 4.32 (d, J=4.50 Hz, 1 H), 3.77 (br. s., 2 H), 3.58 (br. s., 6 H), 3.12-3.27 (m, 2 H), 2.85-3.03 (m, 1 H), 2.28-2.46 (m, 2 H), 0.89-1.10 (m, 4 H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].O.[CH3:21][C:22]([CH3:25])([O-:24])[CH3:23].[K+]>CN(C)C=O>[C:22]([O:24][CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4])([CH3:25])([CH3:23])[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 10.6 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), water (0.010 mL, 0.56 mmol), and potassium tert-butoxide (0.10 g, 0.90 mmol) in dimethylformamide (5 mL) provided 2-tert-butoxy-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.015 g) after reverse-phase HPLC purification.MS (ES) m/z 260.1 ([M+H]+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[C:29]([C:32](O)=[O:33])=[N:30][NH:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:11][CH2:12][N:13]([C:32]([C:29]2[C:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:24][C:25]=3[NH:31][N:30]=2)=[O:33])[CH2:14][CH2:15]1
Reactant: Fc1ccc(Cl)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 70 mg, 0.28 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (104 mg, 0.39 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (5.4 mL) was added EDCI (65 mg, 0.34 mmol) and HOBt (45 mg, 0.34 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×20 mL). The combined organic extracts were washed with a saturated brine solution (9×20 mL), H2O (2×20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to provide tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (47) as a white solid (57 mg, 44%): 1H NMR (300 MHz, DMSO-d6) δ 13.16-12.78 (m, 1H), 7.48 (dd, J=9.0, 5.7 Hz, 1H), 7.28 (dd, J=10.5, 3.3 Hz, 1H), 7.17-7.05 (m, 1H), 4.90-4.59 (m, 2H), 4.53-4.40 (m, 2H), 3.62-3.48 (m, 2H), 3.28-3.07 (m, 2H), 2.92-2.73 (m, 1H), 2.64-2.50 (m, 2H, overlaps with solvent), 1.93-1.69 (m, 2H), 1.68-1.49 (m, 2H), 1.42 (S, 9H); ESI MS m/z 463 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[C:24]([NH2:34])[N:23]=3)=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[NH2:34][C:24]1[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=3)=[CH:16][CH:17]=2)[CH:27]=[C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Methanesulfonyl chloride (0.040 mL, 0.52 mmol) was added to a solution of N4-(4-{[2-(aminomethyl)pyridin-4-yl]oxy}phenyl)-6-phenylpyrimidine-2,4-diamine (Example 39, 0.20 g, 0.52 mmol) and DMAP (0.064 g, 0.52 mmol) in pyridine (8.0 mL) at 0° C. The mixture was allowed to warm to rt and was stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in DMF and purified by prep-HPLC to provide 82 mg of an off-white solid (27%). 1H NMR (CD3OD) 8 ppm 8.57 (1H, d, J=6.8 Hz), 8.00 (2H, s), 7.77-7.80 (2H, m), 7.63 (3H, d, J=7.4 Hz), 7.42 (1H, d, J=2.5 Hz), 7.29-7.33 (3H, P m), 6.58 (1H, s), 4.54 (2H, s), 3.04 (3H, s); MS ES 463 (M+H)+, calcd 463, RT=1.17 min.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:25]([C:35]([F:38])([F:37])[F:36])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:29]1([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([CH:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:14][CH2:13]4)=[CH:16][CH:17]=3)=[CH:24][C:25]=2[C:35]([F:38])([F:36])[F:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)CCN1CCC(c2ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCN1CCC(c2ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc2)CC1
Reaction time: 2 h

Procedure:
3-{4-[4-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester is dissolved in DCM and treated with TFA (50% v/v). After 2 h at room temperature, it is concentrated to give a residue which is purified by RP LC-MS to give 3-{4-[4-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-phenyl]-piperidin-1-yl}-propionic acid. 1HNMR (400 MHz, CD3OD) δ 7.83 (1H, s), 7.65 (1H, d), 7.55 (1H, d), 7.20 (4H, m), 5.45 (2H, s), 3.66 (2H, d), 3.44 (2H, m), 3.20 (2H, m), 2.81 (2H, m), 2.68 (2H, m), 1.84 (9H, m), 1.36 (5H, m). MS (ES+): 490.3 (M+1)+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[F:12][CH2:13][C:14]1([CH:18]=[O:19])[CH2:17][O:16][CH2:15]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:12][CH2:13][C:14]1([CH:18]([C:9]2[O:8][C:7]([CH3:6])=[CH:11][CH:10]=2)[OH:19])[CH2:17][O:16][CH2:15]1
Reactant: Cc1ccco1
Reactant: O=CC1(CF)COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C2(CF)COC2)o1
Temperature: -70 °C
Reaction time: 3 h
Yield: 106.3 %

Procedure:
11.0 ml (27 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.25 g (27 mmol, 1.5 eq) of 2-methylfuran in 40 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 3 hours. The reaction medium was cooled to −70° C. and then 2.16 g (18 mmol, 1 eq) of 3-fluoromethyloxetane-3-carbaldehyde were added. The reaction medium was stirred at ambient temperature for two and a half hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 3.83 g of (3-fluoromethyloxetan-3-yl)-(5-methylfuran-2-yl)methanol were obtained in the form of a dark orange oil. Yield=71%. TLC SiO2/CH2Cl2:MeOH (96/4), developing with KMnO4.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH2:7][PH3+].C([Li])CCC.CCCCCC.[Si:27]([O:34][C:35]1[C:42]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>O1CCCC1.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:7]=[CH:37]\[C:36]2[C:35]([O:34][Si:27]([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28])=[C:42]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH:41]=[CH:40][CH:39]=2)[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc(/C=C\c2cccc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A suspension of 3,4,5-trimethoxybenzylphosphonium bromide (1.047 g, 2 mmol) in 12 mL dry tetrahydrofuran was stirred under nitrogen while cooling to −40° C. then adding 1.52 mL of 1.6M butyllithium in hexane (2.44 mmol) dropwise over six minutes below −25° C. The mixture was kept at −15° C. for ten minutes before cooling to −70°. 7 (0.748 g, 2.04 mmol) was added as a solution in 3 mL THF dropwise below −60° C. and the pale orange solution allowed to reach 20° C. over a period of one hour. After stirring for a further three hours the mixture was allowed to stand overnight. Water (8.5 mL) was added slowly and the mixture extracted three times with 8.5 mL t-butyl methyl ether. The organics were washed with brine, dried and evaporated at 30° C. The crude was purified by flash chromatography (cyclohexane:AcOEt 95:5) after removing triphenylphosphine oxide by filtration to give a colourless oil 8 which solidified on standing (0.70 g):
Reaction SMILES: C[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH3:17]O>>[C:3]1([CH3:11])[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:17])=[O:9])[CH:2]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1
Temperature: 65 °C
Reaction time: 17 h

Procedure:
A 3 L reaction flask was charged with methyl m-toluic acid (0.5 kg), anhydrous methanol (2 L), and sulfuric acid (100 g). The mixture was heated to reflux (65° C.) and aged for 14-20 hours, then cooled to an ambient temperature, and the acid was quenched with a two molar equivalent of sodium acetate. Methanol was distilled out of the flask and the mixture was washed with 1 L brine. The crude product was vacuum distilled to give 480 g of methyl m-toluate, which had a boiling point of 113° C. at a pressure of 25 mmHg.
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13](I)=[CH:12][C:11]=2[F:19])[CH:6]=[C:7]([F:9])[CH:8]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.C([Li])CCC.[OH-].[Na+]>C1COCC1>[F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([B:21]([OH:26])[OH:22])=[CH:12][C:11]=2[F:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: COc1cc(-c2cc(F)cc(C(F)F)c2)c(F)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(F)cc(C(F)F)c2)c(F)cc1B(O)O
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A RBF was charged with 3′-(difluoromethyl)-2,5′-difluoro-4-iodo-5-methoxy-1,1′-biphenyl (770 mg, 1.944 mmol), triisopropyl borate (0.580 mL, 2.53 mmol) and THF (9.719 mL). The flask was cooled to 78° C. for 10 min, then n-butyllithium solution, 2.5m in hexanes (1.011 mL, 2.53 mmol) was added drowpise over 1 min. The colorless solution turned green then yellow. After 30 min at 78° C., 2N aq. NaOH (10 mL) was added. The resulting biphasic mixture was stirred for 10 min, and partitioned between water (20 mL) and ether (50 mL). The layers were separated, and the ethereal layer was extracted with water (2×10 mL). The combined aqueous extracts were washed with ether (10 mL), and then were acidified with 6N aq. HCl (10 mL). The resulting aq. mixture was extracted with DCM (3×20 mL). The combined DCM layers were dried over sodium sulfate, filtered, and concentrated to give (3′-(difluoromethyl)-2,5′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (111 mg, 0.353 mmol, 18.18% yield) as white solid. m/z (ESI) 315.0 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CCCCCC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCCCCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 43.8 %

Procedure:
Following the procedure of Example 23, tetrahydro-dibenzofuran-2-ylamine (0.15 g, 0.80 mmol), hexanoyl chloride (0.11 mL, 0.80 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)hexanamide (0.10 g). MS (ESI) m/z286.
Reaction SMILES: C([O:5][C:6]1[N:11]=[C:10]([O:12]C(C)(C)C)[C:9]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:8][N:7]=1)(C)(C)C>O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[C:9]1[C:10](=[O:12])[NH:11][C:6](=[O:5])[NH:7][CH:8]=1
Reactant: Cc1ccsc1-c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Solvent: C1COCCO1
Product: Cc1ccsc1-c1c[nH]c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a solution of 2,4-di-tert-butoxy-5-(3-methyl-thiophen-2-yl)-pyrimidine (Prep 25, 165 mg, 0.52 mmol) in dioxane (5 mL) 4N HClaq in dioxane (1 mL) was added at 0° C. After stirring for 8 hours, the mixture was evaporated to give 110 mg of the title compound as white solid (quantitative yield)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Yield: 78.3 %

Procedure:
A solution of the compound (207 mg, 0.41 mmol) obtained in Example 2-1) and 4 M hydrochloric acid (1,4-dioxane solution, 0.5 mL) in methanol (2 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 30:70, gradient) to obtain the title compound (126 mg, 79%) as a colorless solid.
Reaction SMILES: [OH-].[K+].CS(C)=O.Br.Br.[NH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14](=[NH:16])N.ClC1[N:23]2[CH:24]=[CH:25]N=[C:22]2[CH:21]=[CH:20][CH:19]=1>O>[NH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[N:16]2[CH:25]=[CH:24][N:23]=[C:22]2[CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)SCCCN
Reactant: Clc1cccc2nccn12
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a mixed solution of 10% (w/w) potassium hydroxide (69.3 g, 105 mmoles) and dimethylsulfoxide (50 ml) was added S-(3-aminopropyl)isothiourea dihydrobromide (8.85 g, 39 mmoles) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (3.05 g, 20 mmoles), followed by stirring at room temperature and additionally at 65° C. for 20 hours. Water was added to the reaction mixture, which was extracted with chloroform, washed with 1N sodium hydroxide several times and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain 2.66 g of the desired product (64.3%, pale yellow oily product).