Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:19]=[O:20].Cl>C(#N)C>[OH:8][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH:19]=[O:20]
Reactant: C=O
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1ccc(F)cc1O
Temperature: 25 °C
Yield: 72 %

Procedure:
To the mixture of 3-fluorophenol (10 mL, 102 mmol), anhydrous magnesium chloride (28.2g, 744.6 mmol) in 500 mL of anhydrous acetonitrile was added anhydrous triethylamine (67 mL, 382.5 mmol) and paraformaldehyde (22.3g, 744.6 mmol). The mixture was then heated to reflux for five hrs. After cooling to room temperature, 500 mL of 5% aqueous hydrochloric acid was added. The product was extracted with ethyl acetate. The combined organic extracts were washed three times with 5% hydrochloric acid, brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the product was obtained as a light pink solid; 11 g, yield=72%. A small fraction was further purified on silica gel column with EtOAc/hexane mixture for further analytical characterization, it gave a white solid. M.P.=67.5-69.0° C. 1H NMR (CDCl3/300 MHz) 11.40(s, 1H), 9.86(s, 1H), 7.62-7.57(m, 1H ), 6.79-6.67(m, 2H). 13C(CDCl3/30OMH) 195.4, 168.3(d, J=258 Hz), 164.4(d, J=14.9 Hz), 136.3(d, J=12.6 Hz), 118.2(d, J=2.0 Hz), 108.5(d, J=23.3 Hz), 104.9(d, J=24.4 Hz). 19F (CDCl3/400 MHz) −97.9(m). LC-MS couldn't observe the desired peak. HRMS (ES−) m/z calcd for (C7H5FO2) 139.0201 (M−H), found 139.0211(M−H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:44])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:35]([F:36])([F:37])[F:38])[C:31]([F:33])([F:34])[F:32])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 5 h
Yield: 66.8 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.16 mL) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 80-(2); 31.9 mg, 0.0539 mmol) in methanol (1.0 mL), and the mixture was stirred for five hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (8% methanol/dichloromethane) to give the title compound (20.8 mg, 66%).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:17]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][C:14]=1[CH3:16])(=[O:18])=[O:19])[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(CO)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.1 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (2.15 g, 23.6 mmol) in THF (26 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.0 g, 7.85 mmol) and triethylamine (1.2 ml, 8.64 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (1.46 g, 60%) as a light yellow solid. MS (ISP) 308.1 [(M−H)−]; mp 217° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12]COC)#[C:2][CH2:3][CH3:4]>Cl.CC(C)=O.CCOCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])#[C:2][CH2:3][CH3:4]
Reactant: CCC#Cc1ccc(F)cc1OCOC
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCC#Cc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
1-But-1-ynyl-4-fluoro-2-methoxymethoxy-benzene (6.1 g, 29 mmol) is dissolved in 250 mL of a 10% solution of concentrated HCl in acetone. The solution is stirred at room temperature for 5 h. The reaction is diluted with ether and washed with saturated aqueous NaHCO3 and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 5% AcOEt/hexane) to yield 3.52 g (73%) of the title compound as an orange oil. GCMS m/e 164[M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12]C(=O)C)[C:9](=O)[CH3:10].[C:16](#[N:20])[CH2:17][C:18]#[N:19].[OH-].[K+].O>CO>[NH2:19][C:18]1[NH:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:9]([CH3:10])[C:17]=1[C:16]#[N:20]
Reactant: N#CCC#N
Reactant: CC(=O)NC(C(C)=O)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccccc2F)[nH]c(N)c1C#N
Yield: 22.4 %

Procedure:
1-(2-Fluorophenyl)-1-acetamido-2-propanone (3.13 g) and malononitrile (1.49 g) were dissolved in methanol (15 ml) and the solution was stirred under ice-cooling. Then, 55% aqueous solution of potassium hydroxide was added to the above solution to adjust to pH 10. The reaction mixture was then warmed and stirred at 55-60° C. for 0.5 hour. After cooling, the reaction mixture was poured into iced water and the resulting crystals were collected by filtration. This crude crystalline product was recrystallized from methanol-water and, further, from benzene to provide the title compound as colorless crystals (0.72 g). m.p. 117-118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.C([O:29][CH2:30][CH2:31][N:32]1[C:36]([CH:37]([CH3:39])[CH3:38])=[C:35]([CH:40]=[O:41])[C:34]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[N:33]1)(=O)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH2:43]([O:42][C:34]1[C:35]([CH:40]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:41])=[C:36]([CH:37]([CH3:38])[CH3:39])[N:32]([CH2:31][CH2:30][OH:29])[N:33]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: CC(C)c1c(C=O)c(OCc2ccccc2)nn1CCOC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1c(C(O)c2ccccc2OCc2ccccc2)c(OCc2ccccc2)nn1CCO
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a solution of 2-benzyloxybromobenzene (1.66 g) in tetrahydrofuran (50 mL) was added tert-butyllithium (1.6 mol/L pentane solution, 4.33 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added a solution of 1-(2-benzoyloxyethyl)-3-benzyloxy-4-formyl-5-isopropyl-1H-pyrazole (620 mg) in tetrahydrofuran (5 mL), and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1–2/1) to give 2-{3-benzyloxy-4-[(2-benzyloxyphenyl)hydroxymethyl]-5-isopropylpyrazol-1-yl}ethanol (448 mg). To a solution of 2-{3-benzyloxy-4-[(2-benzyloxyphenyl)hydroxymethyl]-5-isopropylpyrazol-1-yl}ethanol (448 mg) in methanol (5 mL) was added 10% palladium-carbon powder (448 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (220 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[O:11][CH2:10]1)(=[O:3])[CH3:2].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.C(OCC)C>[C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])([OH:11])[CH2:10][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(=O)OCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
To a solution of 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (24.0 g, 0.07 mol) in DMF (250 ml), 1,2,4-triazole (16.6 g, 0.24 mol) and potassium carbonate (33.2 g, 0.24 mol) were added, followed by stirring at room temperature for 12 hours and then at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ethyl ether and an insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure. The residue so obtained was recrystallized from isopropyl ether--ethyl acetate, whereby 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (12.2 g, yield: 37.8%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.CCOC(OC(OCC)=O)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Yield: 90 %

Procedure:
A mixture of 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (Example 4, Step 2, 10.00 g, 41.72 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357-60, 15.20 g, 70.93 mmol), DEPC (10.76 mL, 70.93 mmol) and diisopropylethylamine (18.17 mL, 104.4 mmol) in N,N-dimethylformamide (267 mL) was stirred at room temperature for 43 h. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 mL), and extracted with dichloromethane (5×100 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue eluting with dichloromethane/methanol (100:1 to 20:1) afforded 19.08 g (90%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:29][C:30]2([C:35]([O:37]C)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:2]=1.C1COCC1.[Li+].[OH-].Cl>C(Cl)Cl.O.CO>[C:1]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:29][C:30]2([C:35]([OH:37])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:2]=1
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccccc3)c2)CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccccc3)c2)CCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 20 mL vial were added methyl 1-((1-([1,1′-biphenyl]-3-ylmethyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentane-carboxylate (51.4 mg, 0.08 mmol), THF (1 mL) and MeOH (1 mL) followed by with LiOH (1 mL, 1 M). The reaction mixture was capped and heated to 80° C. for 3 h. The mixture was cooled to RT, water (5 mL) was added and the pH was adjusted to ˜4 using 1 M HCl. To the mixture was added DCM (5 mL) and the mixture was stirred for 1 h at RT. The organic layer was separated then concentrated to dryness. The resulting residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C37H33N3O3, 567.25; m/z found, 568.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=8.6, 1H), 8.11 (d, J=8.1, 1H), 7.83 (d, J=8.3, 1H), 7.77-7.71 (m, 1H), 7.69 (d, J=8.6, 1H) 7.58-7.51 (m, 2H), 7.49-7.33 (m, 7H), 7.29 (s, 1H), 7.25-7.22 (m, 1H), 7.11-7.06 (m, 1H), 6.96 (d, J=7.6, 1H), 5.44 (s, 2H), 5.37 (s, 2H), 3.09 (s, 2H), 2.41-2.33 (m, 2H), 1.71-1.63 (m, 2H), 1.47-1.36 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 16 (0.10 g, 0.42 mmol) in THF (5 mL), at 0° C. was added triethylamine (0.064 g, 0.63 mmol) and chloroacetylchloride (0.0715 g, 0.63 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Cl.[OH:2][C:3]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.Cl.OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1CCN(CCCC(C2C=C(C(C)(C)C(OC)=O)C=CC=2)=O)CC1.[OH-].[Na+].[BH4-].[Na+]>CO.C(O)(=O)C.CC(C)=O.O>[CH3:27][C:21]([C:22]([OH:24])=[O:23])([C:18]1[CH:19]=[CH:20][C:15]([CH:13]([OH:14])[CH2:12][CH2:11][CH2:10][N:7]2[CH2:6][CH2:5][CH:4]([C:3]([OH:2])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:9][CH2:8]2)=[CH:16][CH:17]=1)[CH3:26]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: COC(=O)C(C)(C)c1cccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)c1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of a mixture of methyl 4-[4-[4-(hydroxydiphenylmethyl)1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride and methyl 3-[4-[4-(hydroxydiphenylmethyl)1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride (100 g) in methanol (600 ml) is added aqueous sodium hydroxide (36.4 g sodium hydroxide in 132 ml of water). The mixture is heated to reflux for about 2-4 hours. Completion of the reaction is monitored by TLC method and upon completion the reaction mixture is cooled to ambient temperature accompanied by addition of sodium borohydride (6.8 g). The reaction mixture is heated to 50-60° C. and maintained at the same temperature for about 14 hours (completion of the reaction is monitored by TLC method), and subsequently cooled to ambient temperature accompanied by carbon treatment. The clear filtrate obtained after carbon treatment, is stripped of methanol followed by addition of water (300 ml) and acetone (200 ml). The pH of the reaction mixture is then adjusted to ˜6 with acetic acid, stirred for 5 hours and then filtered, followed by water wash (200 ml) to afford crude Fexofenadine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][N:37]1[C:43](=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH2:34][N:40]2[CH2:41][CH2:42][C:43](=[O:44])[N:37]([CH3:36])[CH2:38][CH2:39]2)=[CH:4][N:3]=1
Reactant: CN1CCNCCC1=O
Reactant: COc1cc(-c2csc3c(/C=C\C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(/C=C\CN4CCC(=O)N(C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-(4-{4-amino-7-[(1Z)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl }-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide, 4-methyl-1,4-diazepan-5-one (trifluoroacetic acid salt), and General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.01 (m, 1H), 7.98 (s, 1H), 7.70 (d, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.36 (s, 1H), 7.32 (d, 1H), 7.20 (m, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.69 (d, 1H), 6.21 (m, 1H), 5.65 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H); 3.47 (m, 2H), 3.32 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H), 2.58 (m, 4H); MS: (M−H)− 593.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16](O)[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].B(F)(F)F.CCOCC.CO>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:26]3[C:24](=[O:25])[NH:23][C:21](=[O:22])[N:20]([CH3:19])[CH:27]=3)[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2O
Reactant: Cn1ccc(=O)[nH]c1=O
Agent: FB(F)F
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Temperature: 50 °C

Procedure:
A mixture of the product from step (iii) (0.91 g), and 1-methyluracil (0.44 g) in acetonitrile (40 ml) was treated with boron trifluoride etherate (2.47 g) and heated at 50° C. for 4 h. The solution was treated with methanol (1 ml) and evaporated. Purification was by chromatography on a biotage silica column, using 3% methanol/0.1% 0.880 ammonia in dichloromethane as eluant to give the subtitled product as a cream powder.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.Br[C:14]1C=C(C)C=CC=1OC.[Li]CCCC.COB(OC)OC>>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][C:6]=1[B:8]([OH:10])[OH:9]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1ccc(C)cc1Br
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(C)cc1B(O)O
Yield: 96 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-methylanisole (2.00 g, 9.94 mmol), n-BuLi (2.5M in hexanes; 4.00 mL, 10 mmol), and trimethylborate (3.4 mL, 30 mmol) to afford 1.60 g (96%) of 2-methoxy-5-methylphenylboronic acid which was used without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][CH2:7][OH:8].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.CN(C)C=O>[CH2:13]([O:3][CH2:4][C@@H:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][CH2:7][O:8][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COCO[C@H](CO)CCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COCO[C@@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
A 60% suspension of sodium hydride in oil (1.34 g, 33 mmol) was washed with hexane (2×20 ml) under an atmosphere of dry nitrogen. After decanting the hexane the solid was suspended in dry N,N-dimethylformamide (20 ml) and treated with a solution of (S)-1,4-dihydroxy-2-(methoxymethoxy)butane (2 g, 13 mmol) in N,N-dimethylformamide (5 ml). After stirring at room temperature for 6 hours the mixture was treated with a solution of benzyl bromide (3.9 ml, 33 mmol) in N,N-dimethylformamide (5 ml) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (100 ml) and water (50 ml). The organic phase was washed with water (2×50 ml), dried with MgSO4 and the solvent removed to give an oil which was chromatographed on silica eluting with ethyl acetate-hexane 1:2 to give (S)-1,4-dibenzyloxy-2-(methoxymethoxy)butane (3.6 g, 82%), [α]D25 -16.0° (c 1.6 in ethanol); IR: υmax (film) 3080, 3060, 3030, 2920, 2890, 2860, 1495, 1450, 1360, 1210, 1155, 1100, 1040, 920, 740, 700 cm-1 ; 1H NMR: δH (CDCl3) 1.90 (2H, m, CH2), 3.35 (3H, s, OCH3), 3.60 (4H, m, 2×CH2), 3.90 (1H, m, CH), 4.50 (4H, m, 2×CH2), 4.68 (1H, d, J=7 Hz, CH of CH2), 4.74 (1H, d, J=7 Hz, CH of CH2), 7.30 (10H, m, 2×C6H5); m/z (NH3CI), MH+ 151, MNH4+ 168.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: FC(F)(F)Oc1ccc(-c2ccc(CCl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3ccc(-c4ccc(OC(F)(F)F)cc4)nc3)cc21

Procedure:
In analogy to the procedure described in example 7 a], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 5 b]) was reacted with 5-chloromethyl-2-(4-trifluoromethoxy-phenyl)-pyridine in the presence of cesium carbonate and potassium iodide, using acetonitrile as solvent, to obtain the title compound as colorless crystals.