Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](=O)[C:11]=3[CH:23]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].O.C(N(CC)CC)C>C1COCC1.CO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]=3[CH:23]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCOc2ccc(N3CCOCC3)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(N3CCOCC3)ccc2OCC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
In THF (10 ml) was dissolved ethyl 7-morpholino-5-oxo-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate (924 mg, 2.89 mmol), and to the mixture was added at -30° C. a solution of sodium boro hydride (164 mg, 4.34 mmol) in methanol (3 ml). The mixture was stirred at -20° C. to -15° C. for 30 minutes, and the mixture was cooled to -50° C., to which was added water (15 ml). The mixture was extracted with ethylacetate (15 ml×3), and the organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and to the mixture were added at 0° C. triethylamine (2.02 ml, 14.5 mmol) andmethanesulfonylchloride (0.336 ml, 4.34 mmol). The mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. To the residue was added water (15 ml), and the mixture was extracted with ethyl acetate (20 ml×3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 30 g, ethyl acetate/ hexane=1/5), and the desired fraction was concentrated under reduced pressure to give ethyl 7-morpholino-2,3-dihydro-1-benzoxepine-4-carboxylate (691 mg, 2.28 mmol, 79%).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C@@H:10]([C@H:18]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([O:13]C(C)(C)C)=[O:12].CO>C(Cl)Cl>[OH:8][CH2:9][CH:10]([CH:18]([S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)(=[O:30])=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@H](CO)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(CO)C(=O)O)cc1
Yield: 51.4 %

Procedure:
Trifluoroacetic acid (5 mL) is added to a solution of (±)-t-butyl (2R*,3R*)-2-hydroxymethyl-3-(4-methoxybenzenesulfonyl)-7-phenylheptanoate (3.1 g, 6.7 mmol) in CH2Cl2 (20 mL). The reaction is monitored by TLC analysis (5% MeOH in CH2Cl2) and before all of the ester is consumed the reaction is concentrated and azeotroped with CHCl3 (3×15 mL). The crude product is purified by column chromatography (silica, 5% MeOH in CH2Cl2) to yield pure (±)-(2R*, 3R*)-2-Hydroxymethyl-3-(4-methoxybenzenesulfonyl)-7-phenylheptanoic acid (1.4 g, 51%): 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=7.0 Hz, 2H), 7.25-7.11 (m, 3H), 7.07-6.93 (m, 4H), 6.5-5.7 (bs, 1H), 4.34-4.26 (bm, 1H), 3.95-3.89 (bm, 1H), 3.82 (s, 3H), 3.81-3.69 (bm, 1H), 3.13-3.06 (bm, 1H), 2.46-2.37 (bm, 2H), 1.75-1.67 (bm, 2H), 1.48-1.30 (bm, 3H), 1.22-1.09 (bm, 1H); MS (FAB) m/e 406 (M+H)+.
Reaction SMILES: [H-].[Na+].O[C:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:25][O:6][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:9][CH:8]=2)[CH2:5][O:6][CH2:4][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(O)(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCC(OCc2ccccc2)c2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reaction time: 18 h

Procedure:
At 0° C., 50% NaH in oil (37 mg) was added portionwise to a solution of 1-hydroxy-1-(4-2(-quinolinylmethoxy)phenyl)ethanol (Step 1) (104 mg) and benzyl bromide (92 mg). Stirring was continued for 18 h and the reaction was quenched with 25% aqueous NH4OAc. The product was extracted with EtOAc, dried over MgSO4 and purified by flash chromatography on silica gel using EtOAc:hexane (1:4) to give the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:19]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 95.2 %

Procedure:
To a solution of (S)-proline (25 g:0.22 mole) and sodium hydroxide (8.7 g:0.22 mole) in 150 ml of water was slowly added a solution of benzylchloroformate (43.5 g:0.26 mole) and sodium hydroxide (11.6 g:0.29 mole) in 75 ml of water with stirring under cooling on ice over 30 minutes, followed by continuing the stirring at the same temperature for 15 minutes. From the reaction mixture, excess benzylchloroformate was removed by extraction with 150 ml of chloroform. The aqueous layer was acidified with 5N hydrochloric acid, and the resulting oily product was extracted with chloroform. After drying the chloroform layer over magnesium sulfate, chloroform was removed by evaporation to give 52.2 g of (S)-1-carbobenzoxypyrrolidine-2-carboxylic acid as oil. Yield: 96%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(N(C(C)C)CC)(C)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:27](=[O:28])[CH2:26][Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCNCc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N(CCC(O)(c1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
To the stirred solution of 15.6 g of N-benzyl-3-hydroxy-3,3-diphenylpropylamine in 7.0 g of di-isopropylethylamine and 150 ml of methylene chloride, that of 5.88 g of chloroacetyl chloride in 50 ml of methylene chloride is added dropwise while stirring and cooling with an ice-bath. Thereupon the solution is stirred for 15 minutes at 0°-5° and washed successively with N hydrochloric acid, 10% aqueous sodium bicarbonate and finally with saturated aqueous sodium chloride. The organic layer is separated, dried, filtered and evaporated, to yield the N-benzyl-N-chloroacetyl-3-hydroxy-3,3-diphenylpropylamine showing in the I.R. spectrum a strong band at 1640 cm-1.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@@H:30]1[CH2:34][CH2:33][C@@H:32]([CH2:35][C:36](OC)=[O:37])[CH2:31]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][C@@H:32]5[CH2:33][CH2:34][C@@H:30]([O:29][CH3:28])[CH2:31]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)C[C@@H]1CC[C@@H](OC)C1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CO[C@@H]1CC[C@@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)C1

Procedure:
The title compound, white solid (14 mg, 42%), MS (ISP) m/z=472.6 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and methyl 2-((1R,3R)-3-methoxycyclopentyl)acetate
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:9]=[C:10]([C:29]#[C:30][Si](C)(C)C)[C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][CH:13]=1>CN(C=O)C.CCOC(C)=O.O>[Br:7][C:8]1[CH:9]=[C:10]([C:29]#[CH:30])[C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1cc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
2M aqueous Na2CO3 (639.0 μL, 1.278 mmol) was added to a stirred solution of tert-butyl N-[5-bromo-3-(2-trimethylsilylethynyl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (500 mg, 1.065 mmol) in DMF (1.5 mL) and the resulting suspension stirred at ambient temperature for 18 hours. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts washed with water (×3), brine (×2), dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as an off-white solid (424 mg, 100% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.34 (s, 18H), 4.78 (s, 1H), 8.38 (d, J=2.4 Hz, 1H) and 8.66 (d, J=2.4 Hz, 1H) ppm; MS (ES+) 399.1.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1.O>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:14])=[O:4])=[CH:7][CH:8]=1)#[CH:13]
Reactant: C#Cc1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
LiOH (95.97 mg, 2.2 mmol) was added to a stirred solution of 4-ethynyl-benzoic acid methyl ester (305 mg, 1.9 mmol) in MeOH:H2O (1:1, 6 mL), and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added, acidified it with conc.HCl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 226 mg (81.9% yield) of 4-ethynyl-benzoic acid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[O:1][CH2:2][CH2:3]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C1CCOc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCCCNC1CCOc2cccnc21
Yield: 71.8 %

Procedure:
Reaction of 2,3-Dihydro-pyrano[3,2-b]pyridin-4-one (277 mg, 1.85 mmol) with (4-Amino-butyl)-carbamic acid tert-butyl ester (269 mg, 1.43 mmol) using general procedure B for reductive amination with NaBH(OAc)3 (605 mg, 2.86 mmol), followed by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 97:2:1 followed by 95:4:1) afforded [4-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino)-butyl]-carbamic acid tert-butyl ester (330 mg, 72%) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[OH:9][CH:10]1[CH2:15][O:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[O:12][CH2:11]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[CH2:23]([O:9][CH:10]1[CH2:11][O:12][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[O:14][CH2:15]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(C2OCC(O)CO2)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: Cc1cccc(C2OCC(OCc3ccccc3)CO2)c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A slurry of sodium hydride (2.1 g. 0.08 mole in 100 ml of xylene and 100 ml of benzene was stirred at ambient temperature while 5-hydroxy-2-(3-methylphenyl)-1,3-dioxane (15.9 g, 0.08 mole) was added dropwise during 1 hour. Stirring was continued for one hour and to the mixture was added benzyl chloride (10.4 g, 0.08 mole) during 0.5 hour. This mixture was heated under reflux for 22 hours, cooled, filtered and the filtrate washed with water (2 × 250 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure to give 20.9 g of oil which distilled at 2 × 10-4 mm. to give three fractions distilling respectively at 102°-133° C (cut 1); 133°-141° C (cut 2); and 141° C (cut 3). Analysis of the various cuts indicated that cut 3 was essentially pure cis-5 -benzyloxy-2-(3-methylphenyl)-1,3-dioxane, 2.1 g, m.p. 68°-70° C and this cut was used in further studies.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)[C:5]([F:25])=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:28]=1[NH2:29]>>[Cl:26][C:27]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:28]=1[NH:29][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)[C:5]([F:25])=[CH:4][N:3]=1
Reactant: Cc1cc(N)c(Cl)cc1O
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OCCCN2CCOCC2)cc1
Product: Cc1cc(Nc2ncc(F)c(Nc3ccc(OCCCN4CCOCC4)cc3)n2)c(Cl)cc1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineamine with 2-chloro-4-hydroxy-5-methylaniline gave N2-(2-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine. LCMS: retn, time: 15.19 min.; purity: 94%; MS (m/e): 488 (MH+); 1H NMR (CDCl3): δ 7.89 (1H, d, J=3.3 Hz), 7.52 (1H, d, J=2.5 Hz), 7.44 (2H, d, 8.7 Hz), 6.97 (1H, d, J=2.5 Hz), 6.91 (2H, d, 9 Hz), 6.71 (1H, s), 6.64 (1H, 2.5 Hz), 4.03 (2H, t, J=6.03 Hz), 3.74 (4H, t, J=4.65 Hz), 2.60-2.43 (6H, m), 2.23 (3H, s), 1.49 (2H, m).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C.ClCCl>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[O:6][C:5]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=3[C:3]=2[C:13](=[O:26])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:30][CH2:29]1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(Br)oc2c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(N3CCN(C)CC3)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (20 mg, 0.047 mmol) in a mixture of acetonitrile/dichloromethane; 1:1 (2 mL) was added N-methylpiperazine (50 μL, excess) and the reaction mixture was stirred at room temperature for 1 hour. After this time the solvent was removed by distillation under vacuum and the product was purified by PTLC (eluent=hexane/ethyl acetate; 4:6+1% triethylamine) to give the title compound as a green yellow paste which was crystallized by freeze drying in t-butanol to give a yellow solid; (8 mg, 43%); 1H NMR (300 MHz, CDCl3) δ 7.07(s, 2H, benzoyl Hs), 6.93(d, 1H, J=8.60 Hz), 6.84(d, 1H, J=2.25 Hz), 6.65(dd, 1H, J=8.64, 2.30 Hz), 3.92(s, 3H, OMe), 3.83(s, 6H, 2×OMe), 3.78(s, 3H, OMe), 3.66-3.64(bm, 4H), 2.65-2.63(bm, 4H), 2.40(s, 3H, N-Me); 13C NMR (75 MHz, CDCl3) δ 188.76(CO), 162.24, 155.88, 152.72, 149.06, 141.09, 135.36, 121.68, 119.64, 110.42, 106.11, 155.88, 95.63, 60.64, 55.88, 55.44, 53.88, 47.06, 45.29.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].CO[CH:7]=[C:8]([C:13](=[O:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10]>>[C:1]([NH:4][CH:7]=[C:8]([C:13](=[O:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: COC=C(C(C)=O)C(=O)OC
Product: COC(=O)C(=CNC(C)=O)C(C)=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Acetamide (10.0 g) and methyl 2-methoxymethylene-3-oxobutanoate (30.0 ml) were heated with stirring at 100° C. for 4 hours. On cooling the product was flash chromatographed on Merck silica 9385 using a 50/50 mixture of ether/hexane to give the title compound (18.5 g) m.p. 60°-62° C. (hexane/ether).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CCN(CC)CC.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.[Cu]I>[CH3:14][C:8]1([CH3:13])[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=2)[O:9]1
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)O2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylchroman-4-one (Compound 262, 2.60 g, 13.0 mmol) and ethyl 4-iodobenzoate (3.6 g, 13.0 mmol) in 50.0 mL Et3N was purged with argon for 15 minutes. To this solution was added bis(triphenylphosphine)-palladium(II) chloride (1.82 g, 2.6 mmol) and copper(I) iodide (496 mg, 2.6 mmol). After sparging for an additional 10 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography (2-5% EtOAc-hexanes) of the residual solid afforded 2.28 g (50%) the title compound as an orange solid. 1H NMR (300 MHz, CDCl3) δ: 8.06 (1H, d, J=2.2 Hz), 8.02 (2H, d, J=8.5 Hz), 2.61 (1H, dd, J=2.2, 8.6 Hz), 7.55 (2H, d, J=8.5 Hz), 6.93 (1H, d, J=8.6 Hz), 4.39 (2H, q, J=7.1 Hz), 2.75 (3H, s), 1.48 (6H, s), 1.41 (t, J=7.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[O:32]CC3C=CC=CC=3)[C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC2C(C3C=C(Cl)C(OCC4C=CC=CC=4)=CC=3OCC3C=CC=CC=3)=NNC=2C1)=O)(C)(C)C>C(O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[CH:19][C:18]=3[OH:32])[C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)c21
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CCc2c(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)n[nH]c2C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3cc(Cl)c(O)cc3O)c21
Reaction time: 10 h
Yield: 48 %

Procedure:
A mixture of 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1,5,6,7-tetrahydro-pyrazolo[4,3-b]pyridine-4-carboxylic acid tert-butyl ester (e) and 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester (f) (7 g, 13 mmol) was dissolved in a mixture of ethanol (50 mL) and glacial acetic acid (10 mL) at room temperature before the addition of 10% Pd/C (1 g). The reaction mixture was stirred under hydrogen atmosphere (20 psi) for 10 h. The suspension was filtered through celite and the filtrate was concentrate to small volume and ethylacetate (200 mL) was added. The solution was washed with 1 M NaHCO3 solution, then with brine and dried. The solvent was removed and the crude reaction mixture was carefully chromatographed on silica gel eluting with ethylacetate/methanol 6/1 to provide 3-(5-chloro-2,4-dihydroxy-phenyl)-1,5,6,7-tetrahydro-pyrazolo[4,3-b]pyridine-4-carboxylic acid tert-butyl ester (g) (2.3 g, 48% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.[Br:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C(O[Na])(C)(C)C>CS(C)=O>[Br:17][C:18]1[C:19]([O:16][CH:13]2[CH2:14][CH2:15][CH:10]([C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH2:11][CH2:12]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: Clc1ncccc1Br
Agent: CC(C)(C)O[Na]
Solvent: CS(C)=O
Product: Brc1cccnc1OC1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 60 °C
Yield: 24.1 %

Procedure:
The mixture of 4-(1H-benzoimidazol-2-yl)-cyclohexanol (0.36 g, 1.67 mmol), 3-bromo-2-chloro-pyridine (0.64 g, 3.34 mmol), t-BuONa (0.37 g, 3.34 mmol) and DMSO (5 mL) was heated at 60° C. for 2 days under N2 atmosphere. Then the mixture was concentrated under vacuum and the obtained residue was purified by silica gel chromatograph (DCM:MeOH=10:1) to give 2-[4-(3-bromo-pyridin-2-yloxy)-cyclohexyl]-1H-benzoimidazole (0.15 g, 0.403 mmol, 36% yield) as white solid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[CH3:12][O-:13].[Na+].Cl>>[CH3:12][O:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: C[O-]
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: Cl
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C

Procedure:
4-fluoro-2-chloro-benzoic acid (10 g) was combined with sodium methoxide (393 mL, 4.37 M in methanol) and heated at 75 C for 46 h. The reaction was cooled to room temp and acidified with 1 N HCl. The mixture was extracted with EtOAc (3×). The combined extracts were then dried (MgSO4) and concentrated to give 8.5 g of 4-methoxy-2-chloro-benzoic acid as a white solid.
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=1)(=O)C.[ClH:39]>>[ClH:39].[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:16][CH2:15]1
Reactant: CCOC(=O)CCCCn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)nn1
Agent: Cl
Product: CCOC(=O)CCCCn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Yield: 92 %

Procedure:
In a similar manner to that described in Example 133, (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[4-(ethoxycarbonyl)butyl]-1H-1,2,3-triazol-4-yl}methylidene)piperidine (1.32 g) was treated with hydrogen chloride. The crude product was purified by chromatography on silica gel using a mixture of methanol and dichloromethane (1:99 to 10:90) as the eluent to afford the title compound as a pale yellow amorphous solid (1.44 g, yield: 92%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:4]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:21]2[SH:22])=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: NCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2cnc(S)n2-c2ccc(Cl)cc2)cc1
Temperature: 90 °C
Yield: 99.2 %

Procedure:
A mixture of 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (5.0 g, 26.5 mmol), 4-chlorophenyl isothiocyanate (4.49 g, 26.5 mmol) and sodium hydrogencarbonate (3.3 g, 39.7 mmol) in ethanol (100 mL) was heated at 90° C. for 2 hours. The solvent was removed under reduce pressure. The resulting residue was re-suspended in aqueous 1N sodium hydroxide (50 mL) and heated at 100° C. overnight. The hot mixture was filtered, cooled and carefully acidifed with aqueous 6N HCl. The resulting mixture was filtered to give 1-(4-chloro-phenyl)-5-(4-fluoro-phenyl)-1H-imidazole-2-thiol (8.0 g, 26.3 mmol) as a yellow solid after drying.