Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)([CH3:8])[O:5][C:4]1=[O:19].C1CCN2C(=NCCC2)CC1>C(OC(C)C)(C)C>[CH2:2]=[C:3]1[O:7][C:6]([C:9]23[CH2:16][CH:15]4[CH2:17][CH:11]([CH2:12][CH:13]([CH2:14]4)[CH2:18]2)[CH2:10]3)([CH3:8])[O:5][C:4]1=[O:19]
Reactant: CC1(C23CC4CC(CC(C4)C2)C3)OC(=O)C(CBr)O1
Solvent: CC(C)OC(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
A mixture obtained by dissolving 16.4 g of 5-bromomethyl-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one in 80 ml of isopropyl ether was placed in a flask equipped with an agitator, a thermometer, a condenser and a dropping funnel. While cooling in an ice bath, 9.1 g (0.06 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene diluted with 20 ml of isopropyl ether was added by drops into the solution over 1 hour, followed by stirring at room temperature for 2 hours. After completion of the stirring, the reaction solution was analyzed. As a result, it was found that the reaction solution contained only 1.8 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (yield: 15%) and that 81% of the raw materials was decomposed into adamantyl methyl ketone.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[OH-].[Na+].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([CH2:15][CH2:16][CH:17]=[O:18])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>CO>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[C:16]([CH:17]=[O:18])[CH2:15][C:14]1[CH:19]=[CH:20][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: CC(C)(C)CC=O
Reactant: O=CCCc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CC=C(C=O)Cc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
79 g (0.79 mol) of 3,3-dimethylbutyraldehyde are added to a solution of 10.5 g of 50% strength by weight aqueous NaOH in 500 ml of methanol, after which 123 g (0.73 mol) of p-chlorodihydrocinnamaldehyde are added dropwise at 34° C. The mixture is stirred for one hour and then neutralized with dilute sulfuric acid, the solution is evaporated down and the residue is then subjected to fractional distillation.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=4)=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.2 %

Procedure:
To a solution of 3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzooxazol-6-yl}oxy)benzoic acid (221 mg, 653 μmol) produced in Example B1(vi) in pyridine (5 mL) were added 3-(trifluoromethyl)aniline (298 mg, 1.85 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg, 1.71 mmol) and N,N-dimethylpyridine-4-amine (21.6 mmol, 177 μmol), and the mixture was stirred at room temperature for 14 hr. The mixture was concentrated under reduced pressure, and the obtained residue was dissolved in methanol (1 mL) and ethyl acetate (50 mL). This solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98→80/20), and triturated with diisopropyl ether to give the title compound (57.3 mg, 18%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][CH:28]([F:30])[F:29])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][CH:28]([F:30])[F:29])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:31])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4-difluoro-butyramide (180 mg, 0.35 mmol), methanol (5 mL) and p-toluenesulfonic acid hydrate (20 mg). The mixture was stirred at 25° C. for 16 h and then diluted with dichloromethane and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire, 40 g column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4,4-difluoro-butyramide (109 mg, 66%) as a white foam: HR-ES-MS m/z calculated for C20H21N4O5ClF2 [M+Na]+ 493.1061, observed 493.1057; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.43 (m, 2H), 3.19-3.31 (m, 2H), 3.76 (br. s., 1H), 3.85 (dd, J=13.3, 7.8 Hz, 1H), 4.08 (dd, J=13.3, 3.8 Hz, 1H), 4.35 (d, J=18.4 Hz, 1H), 4.45 (d, J=18.4 Hz, 1H), 4.70 (t, J=5.6 Hz, 1H), 4.81 (s, 1H), 4.93 (d, J=5.1 Hz, 1H), 4.94-5.02 (m, 1H), 6.10 (tt, J=56.1, 4.2 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.31-7.39 (m, 1H), 7.41-7.52 (m, 2H), 7.53 (d, J=2.1 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][NH:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:24][CH2:25][CH:26]([N:31]([CH3:32])[CH3:30])[CH2:27][CH2:28]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: CNC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(=O)CC3)c2C)c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(N(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
To a stirred solution of 5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-((4-oxocyclohexyl)thio)benzamide (0.45 g, 1.03 mmol) and dimethylamine (0.14 g, 3.11 mmol) in dichloroethane (5 mL) was added acetic acid (0.37 g, 6.16 mmol) and the mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.66 g, 3.11 mmol) was added at 0° C. and the mixture stirred overnight at room temperature. On completion of the reaction, the solvent was removed under reduced pressure. Water was added to the residue and extraction was performed using 5% MeOH/DCM. The combined organic layers were dried and concentrated to afford crude material which was purified by column chromatography to afford the title compound (0.016 g, 3.3%). Analytical Data: LCMS: 462.35 (M+1)+; HPLC: 89.00% (@ 210-370 nm) (Rt; 4.949; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 7.44 (s, 1H), 7.16 (s, 1H), 6.10 (s, 1H), 4.44 (s, 2H), 3.63 (m, 1H), 3.13 (m, 1H), 2.38 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.75-2.08 (m, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.C[Si](CCOCCl)(C)C.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[N:32]=[CH:31][N:30]=1.CN1C=CN=C1>CC#N>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([NH:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[N:32]=[CH:31][N:30]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)CCOCCl
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of pyrimidin-4-amine (0.029 g, 0.300 mmol) in 3 mL of MeCN was treated with SEM-Cl (0.053 ml, 0.300 mmol), and the reaction mixture was allowed to stir for one hour. 4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline-7-sulfonyl chloride (Intermediate DDDD; 0.110 g, 0.273 mmol) was added as a solution in 3 mL of MeCN, followed by 1-methylimidazole (0.054 ml, 0.546 mmol). After stirring at room temperature for an additional hour, the reaction mixture was concentrated and then dissolved in 1 mL of THF. 4N HCl dioxanes (1.024 ml, 4.10 mmol) was added, and the reaction mixture was heated to 110° C. for one hour. The reaction mixture was concentrated and purification of the crude residue by reverse phase column chromatography [C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielded 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide. 1H NMR (acetonitrile-d3) δ ppm: 9.44 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.18 (br. s., 1H), 8.03 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.43-7.51 (m, 2H), 7.07 (br. s., 1H), 3.75 (s, 3H). m/z (ESI) 462.0 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[C:17](OCC)=[O:18])[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a solution of ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (289 mg, 0.886 mmol) in THF (4 mL) at 0° C. was slowly added diisobutylaluminum hydride (1.5M in toluene, 1.24 mL, 1.86 mmol). The solution was allowed to warm slowly to ambient temperature. After approximately 4 hours of stirring, the solution was re-cooled to 0° C. and an additional 1 mL of diisobutylaluminum hydride was added. After approximately 1.5 hours of stirring the mixture was re-cooled to 0° C., quenched with some aqueous Rochelle's salt and allowed to stir overnight while warming to ambient temperature. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed once with Rochelle's Salt, dried over magnesium sulfate and concentrated to afford [5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (242 mg, 96%). 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.93 (t, J=5 Hz, 1H), 4.19 (d, J=5 Hz, 2H), 2.31-2.27 (m, 1H), 1.11-1.04 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Na+].C(O)(=O)C>CO.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:26][CH:27]=1)=[C:8]2[CH3:33]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
A solution of [8-chloro-2-difluoromethoxy-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.38 g) in methanol (7.0 mL) and water (0.7 mL) was treated with 5.0M aqueous sodium hydroxide solution (0.32 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified by the addition of glacial acetic acid, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by trituration with methanol, followed by column chromatography on silica gel to afford title compound as a white solid (0.036 g).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7](O)[CH2:8][OH:9].S(=O)(=O)(O)O>ClCCl>[C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: OCCO
Reactant: CC(C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C(=O)OCCO
Temperature: 80 °C

Procedure:
To a suspension of isobutyric acid (5 g, 0.056 mol) and ethylene glycol (15.8 g, 0.283 mol.) was added dropwise Sulfuric acid (cat. 0.4 mL). The resulting mixture was heated at 80° C. for 4 hrs. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was then cooled down to rt, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 2-hydroxyethyl isobutyrate isolated as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([O:10][C:11]1[C:16]2[CH:17]=[C:18]([CH3:27])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]=2[CH:14]=[CH:13][N:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34](=[O:54])[CH2:35]OC1C2C=C(C)N(CC3C=CC=CC=3)C=2C=CN=1)(C)(C)C.ICC>O1CCCC1>[C:1]([O:5][C:6](=[O:28])[CH:7]([O:10][C:11]1[C:16]2[CH:17]=[C:18]([CH3:27])[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]=2[CH:14]=[CH:13][N:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:2])[CH3:3].[CH3:29][O:33][C:34](=[O:54])[CH3:35]
Reactant: Cc1cc2c(OCC(=O)OC(C)(C)C)nccc2n1Cc1ccccc1
Agent: CCC(Oc1nccc2c1cc(C)n2Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: COC(C)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-(1-Benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)-butyric acid tert-butyl ester, 15: (1-Benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)-acetic acid tert-butyl ester, 14 (200 mg, 0.568 mmol) was dissolved in a dry tetrahydrofuran (10 mL) and then cooled to −78° C. To the mixture the tetrahydrofuran solution (1.0 M) of LiN(Si(CH3)3)2 (1.70 mL) was added dropwise at −78° C. The reaction mixture was stirred from −78° C. to −5° C. for 1 h and then the tetrahydrofuran solution (5 mL) of iodoethane (0.15 mL, 1.84 mmol) was added dropwise at −50° C. The mixture was stirred for 4 h from −50° C. to room temperature. The mixture was concentrated and the residue was purified by silica gel chromatography (hexane to hexane:ethyl acetate, 4:1) to afford 2-(1-benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)-butyric acid tert-butyl ester, 15 Yield: 50 mg, (23%)
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([CH:23]([CH3:25])[CH3:24])[N:3]=1.[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([CH:23]([CH3:24])[CH3:25])[N:3]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)c1nc(Cl)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c(Nc3ccc(Br)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 130 °C
Yield: 80.4 %

Procedure:
Step E A mixture of 4-chloro-2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (50 mg, 0.14 mmol), 4-bromoaniline (35 mg, 0.36 mmol), and p-toluenesulfonic acid (51 mg, 0.27 mmol) in toluene (2 mL) was heated in a sealed tube at 130° C. for 18 h. The mixture was cooled, diluted with satd. aq. NaHCO3, and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The residue was purified (FCC) to give the title compound (57 mg, 77%). MS (ESI): mass calcd. for C23H23BrF3N5, 505.11; m/z found, 506.1 [M+H]+. 1H NMR (CDCl3): 8.41-8.39 (m, 1H), 7.90-7.87 (m, 1H), 7.61-7.56 (m, 2H), 7.48-7.43 (m, 2H), 6.99-6.95 (m, 1H), 6.49 (s, 1H), 3.68-3.65 (m, 2H), 3.63-3.60 (m, 2H), 3.25-3.21 (m, 2H), 3.08-2.99 (m, 1H), 2.98-2.94 (m, 2H), 1.32 (d, J=6.9 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:25])=[N:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[CH:17]=3)=[N:9][N:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:25])=[N:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[CH:17]=3)=[N:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCNCC4)o3)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCN(C)CC4)o3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-piperidin-4-yl-[1,3,4]oxadiazol-2-yl)-5-p-tolyl-pyridin-2-ylamine (250 mg, 0.746 mmol) in THF (25 mL) was added NaH (55%) (48.8 mg, 1.119 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then MeI (95 mg, 0.671 mmol) was added at 0° C., and the reaction mixture was stirred at 0° C. for a further 3 h. The reaction mixture was then poured into ice-water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound. Crude compound was purified by preparative HPLC to afford the title compound as a pale yellow solid.
Reaction SMILES: C([O:4][C:5](OC(=O)C)(OC(=O)C)[C@H:6]([OH:16])[C@H:7]([OH:15])[C@@H:8]([OH:14])[C@@H:9]([OH:13])[C:10](Br)=O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(N(CC)CC)C>ClCCl.O1CCCC1.CO>[CH3:10][C@H:9]([OH:13])[C@H:8]([OH:14])[C@@H:7]([OH:15])[C@@H:6]([OH:16])[CH:5]=[O:4]
Reactant: CC(=O)OC(OC(C)=O)(OC(C)=O)[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(=O)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
To a stirred solution of 20β-t-butyldimethylsilyloxy-3β, 14-dihydroxy-5β,14β-pregnane (see FIG. 6) (420 mg) in dichloromethane (60 ml) was added Fetizons reagent (10 g) and, over 10 minutes, a solution of triacetoxybromorhamnose (2.55 g) in dichloromethane (30 ml). After 3 hours the reaction mixture was washed thoroughly with sodium hydrogen carbonate, water, dried over sodium sulfate and evaporated to give a residue which was dissolved in tetrahydrofuran (50 ml) and treated with tetra-n-butlyammonium fluoride (352 mg) for 16 hours, water was added and the mixture extracted with ether to give a product which was dissolved in methanol (20 ml), triethylamine (20 ml) and water (2 ml) and allowed to stand at room temperature for 72 hours under argon. The reaction mixture was evaporated to dryness and the residue dissolved in methanol and placed on silica gel (20 g) and the solvent allowed to evaporate. The silica gel was washed with petroleum ether (30/60) and dichloromethane. Elution with 8- 10% methanoldichloromethane gave fractions of the α-L-rhamnoside (FIG. 6) (170 mg) recrystallized from methanol-water to give (81 mg) mp 243°-246° C. 1H nmr (CDCl3 :CD3OD, 1:1) δ:0.95,(19CH3), 0.97, S(18CH3), 1.27, DD, J=6.2Hz(6'CH3), 2.27,S(21CH3), 2.96,dd, J=4.1,9.3Hz(17αH), 3.40,t, J=9.5Hz(4'H), 3.64-3.76, m(3'H and 5'H), 3.82,dd,j=1.7, 3.3 Hz (2'H), 3.95, s, w1/2 7 Hz (3H), 4.30, s(ROH), 4.80, d, J=1.5 Hz (1'H)ppm; 13C nmr (CDCl3 :CD3OD,1:1) δ:31.0a (1), 27.0b (2), 72.6c (3), 30.3a (4), 37.5(5), 27.2b (6), 22.1d (7), 40.6(8), 35.7(9), 35.8 (10), 21.3d (11), 39.7(12), --(13), 86.2(14) 34.3(15), 25.4(16), 63.0(17), 15.5(18), 24.1(19), 219.4(20), 33.1(21), 98.8(1'), 72.0c (2'), 72.0c (3'), 73.4c (4'), 69.0(5'), 17.7(6') ppm. Anal. C 65.87; H, 9.63 C27H46O7.1/2H2O requires C, 65.96; H, 9.64.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[K].[SH:13][C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2>CC(C)=O>[N:22]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[S:13][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2cccnc2s1
Agent: [K]
Solvent: CC(C)=O
Product: O=C(O)C(Sc1nc2cccnc2s1)c1ccccc1

Procedure:
6.5 g. (0.03 moles) α-bromophenylacetic acid and 6.2 g. (0.03 moles) potassium salt of 2-mercaptothiazolo[5,4-b]pyridine are suspended in 200 ml. acetone and the mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate concentrated to dryness. The resulting compound is an oil and is not isolated.
Reaction SMILES: [C:1]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-])=[O:5].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].OS([O-])(=O)=O.[K+]>CO>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11]
Reactant: O=C([O-])c1ccccc1C(=O)OCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: CO
Product: O=C(OCCc1ccccc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
25.2 g (93 mmol) monophenylethyl (−)-phthalate was heated at reflux in 50 ml oxalyl chloride (3 eq.) for 2 h. The excess oxalyl chloride was distilled under vacuum. The crude acid chloride was then diluted in 100 ml THF cooled to 0° under argon, and 7.4 g (2 eq.) NaBH4 was added. The reaction mixture was maintained under stirring at ambient temperature for 1 h, then cooled to 0° and 20 ml of methanol was added. After leaving the reaction mixture under stirring at ambient temperature for 1 h it was poured over cold 5% KHSO4 then extracted using diethyl ether. Chromatography of the crude product over silica gel (9:1 toluene/ether) yielded 12.1 g (47%) 2-phenylethyl 2-hydroxymethylbenzoate containing about 9% phthalide in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17]>C(O)C>[C:16]([NH:19][NH:20][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])(=[O:18])[CH3:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CC(=O)NN
Solvent: CCO
Product: CC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 77.5 %

Procedure:
6-Cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (5.0 g) and 4.0 g of acetohydrazide were dissolved in 20 ml of ethanol and the solution was heated under reflux for 9 hours. After the reaction, the ethanol was distilled off under reduced pressure and the residue was crushed by adding ice water and filtered to obtain crystals. The crystals were dried and recrystallized from ethyl acetate-ethanol (7:1) to give 5.3 g of trans-4-(2-acetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H 1-benzopyran-3-ol as white crystals, m.p. 209°-210° C.