Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:28]=4[N:29]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO.[Cl-].[NH4+]>[N:29]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[O:22][C:21]=1[N:18]1[CH2:17][CH2:16][N:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=2)[CH2:20][CH2:19]1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4ccncc4o3)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C[C@@H](O)c1nccc(N2CCN(c3nc4ccncc4o3)CC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
To a solution of (R)-1-[4-(4-oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 2, Step A, 1.2 g, 3.0 mmol) in methanol (30 mL) was added potassium carbonate (823 mg, 6.0 mmol). This mixture was stirred at room temperature for 5 h, diluted with saturated aqueous ammonium chloride, concentrated, and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (6% methanol/chloroform) to give 915 mg (94%) of the title compound as a white solid after tritration with hexanes. mp: 181-183° C.; 1H NMR (CDCl3, 300 MHz) δ 8.54 (d, 1H), 8.35 (d, 1H), 8.25 (d, 1H), 7.27 (dd, 1H), 6.44 (d, 1H), 4.71 (q, 1H), 4.25 (br s, 1H), 3.86-3.83 (c, 8H), 1.50 (d, 3H); MS (APCI) 327 (MH+); [αD+15.3 (c, 0.5, MeOH).
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:31])[CH:10]([N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([CH3:31])[CH:10]([N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:11]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)NC(=O)OC(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)N)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of diethyl 1-{3-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (6.00 g, 13.8 mmol) in CH2Cl2 (20 mL) is added TFA (10 mL). The mixture is stirred at room temperature for 16 h. The mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The resulting white solid was collected by filtration and dried in vacuo to afford the title compound (3.83 g, 83%). LCMS: 334.80 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2ncccc2C(F)(F)F)cc1
Yield: 82.5 %

Procedure:
2-Chloro-3-trifluoromethylpyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (838.3 mg) and potassium carbonate (2.28 g) were suspended in acetonitrile (10 mL), and heated under reflux for 27 hours, and then 2-chloro-3-trifluoromethylpyridine (1.0 g) was added thereto and further heated under reflux for 24 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate and evaporated under reduced pressure to obtain a pale yellow oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=8/2) to obtain the entitled compound (1.35 g) as a pale yellow oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:20])[C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:15][CH:14]=3)([CH3:12])[CH3:11])=[CH:6][CH:5]=2)=[O:3])=[CH:30][CH:29]=1
Reactant: Fc1ccccc1
Reactant: CC(C)(c1ccc(C(=O)Cl)cc1)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(c1ccc(C(=O)c2ccc(F)cc2)cc1)c1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
A 250-ml, round-bottom flask was purged with argon and filled with 15.8653 g (0.0494 mol) of 2,2-bis-(4-chloroformylphenyl)propane (6HDAC) and 100 mL of fluorobenzene. To this solution was added with stirring 18.5 grams of anhydrous aluminum chloride in small portions over a 5-minute period. A small amount of heat was given off as evidenced by a slight rise in the temperature of the solution. The yellow reaction mixture was heated to 50-60° C. for 1.5 hours. The reaction progress was monitored by observing the HCl gas adsorption in a water trap. The reaction mixture was allowed to cool and then poured slowly into 700 ml of stirred, ice-cold 1M HCl. The lower organic layer was collected and concentrated to a light-red solid under reduced pressure. The solid was digested in 100 mL of ethanol for 12 hours and the resulting white solid was collected by filtration. Recrystallization from isopropyl alcohol yielded 15.8 g(73%) of 2,2-Bis-[4-(4-fluorobenzoyl)phenyl]propane (6HBFP), m.p. 167-168° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([NH2:43])=[O:42])=[C:39]([F:46])[CH:38]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:41]([C:40]1[CH:44]=[CH:45][C:37]([NH:36][C:11](=[O:13])[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=2)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:38][C:39]=1[F:46])(=[O:42])[NH2:43]
Reactant: NC(=O)c1ccc(N)cc1F
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc(C(N)=O)c(F)c2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid in pyridine was added EDC, DMAP, and 4-amino-2-fluorobenzamide (E336), and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-6% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propylcarbamate (E337).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:13][CH:14]([F:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH2:15][CH:14]([F:17])[F:13]
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: NCC(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)CNc1nc2ccncc2nc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (50 mg, 0.250 mmol) in dioxane (250 μL) was treated with 2,2-difluoroethanamine (21.0 μL, 0.275 mmol) and DIPEA (131 μL, 0.750 mmol). The resulting reaction mixture was stirred at 70° C. for 1 h then purified by flash silica gel chromatography using a gradient of 0% to 60% EtOAc in hexanes to give the title compound (52 mg, 85%) as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:11][NH:12][C:13]([C:15]1[CH:33]=[CH:32][C:18]2[O:19][CH2:20][CH:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:22][C:17]=2[C:16]=1[CH3:34])=[O:14])([CH3:10])([CH3:9])[CH3:8].[CH3:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([CH3:45])[CH:44]=1)[C:39](Cl)=[O:40].CCOCC.CCCCCC>C(OCC)(=O)C>[C:7]([N:11]([C:39](=[O:40])[C:38]1[CH:42]=[C:43]([CH3:45])[CH:44]=[C:36]([CH3:35])[CH:37]=1)[NH:12][C:13]([C:15]1[CH:33]=[CH:32][C:18]2[O:19][CH2:20][CH:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:22][C:17]=2[C:16]=1[CH3:34])=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: Cc1c(C(=O)NNC(C)(C)C)ccc2c1OC(CO[Si](C)(C)C(C)(C)C)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(CO[Si](C)(C)C(C)(C)C)CO3)C(C)(C)C)c1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a round bottom flask equipped with magnetic stirring was added ethyl acetate (7 mL), 25 wt % aqueous potassium carbonate solution (2.03 g, 3.67 mmol), and 3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid N′-tert-butyl hydrazide (0.50 g, 1.22 mmol). To this was added 3,5-dimethylbenzoyl chloride (0.31 g, 1.84 mmol). Stirring was continued for 18 hours. The reaction was diluted with ethyl acetate and the phases separated. The organic phase was washed once with water, once with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was flash chromatographed on silica gel eluting with 20% ether/hexane, then 50% ether/hexane to give a white solid, 3,5-dimethylbenzoic acid N-tert-butyl-N′-[3-(tert-butyldimethylsiloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carbonyl]-hydrazide, (0.50 g, 0.92 mmol) in 76% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 0.10 (s, 6H), 0.90 (s, 9H), 1.59 (s, 9H), 1.89 (s, 3H), 2.25 (s, 6H), 3.92 (m, 2H), 4.05 (m, 1H), 4.22 (m, 1H), 4.34 (m, 1H), 6.33 (d, 1H), 6.56 (d, 1H), 7.02 (s, 1H), 7.13 (s, 2H), 9.49 (s, 1H); TLC: Rf=0.30 (1:1 ether/hexane).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([C:22](OCC)=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].O>O1CCCC1>[CH:27]([C:6]1[C:7]([CH2:22][OH:23])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
257 ml (0.9 mol) of a 3.5 molar solution of sodium-bis-(2-methoxy-ethoxy)dihydroaluminate is steadily added by drops under nitrogen to a solution of 120 g (0.3 mol) of the compound from Example VIII in 800 ml of dried tetrahydrofuran at room temperature, and the mixture is subsequently stirred for 5 h. After cooling to 0° C., 500 ml of water is carefully added by drops, the phases are separated, and the aqueous phase is extracted three times with 250 ml ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. The residue is mixed with petroleum ether, drawn off by suction, and dried in a desiccator.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[F:29])[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:29][C:28]1[CH:27]=[CH:26][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(N)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(Nc2ncnc3cc(OC)c(OC)cc23)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
Ethyl chloroformate (0.058 ml) was added to a suspension of 4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline (159 mg) and triethylamine (0.14 ml) in dry methylene chloride (3.5 ml) and the resulting mixture was stirred at ambient temperature for 18 hours. Methylene chloride (100 ml) was added and the mixture was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by silica column chromatography, eluting with 2% methanol in methylene chloride to yield the title compound as a solid (38 mg, 19%); NMR: 1.23 (t, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 4.12 (m, 2H), 7.16 (s, 1H), 7.21 (m, 1H), 7.57 (m, 1H), 7.83 (s, 1H), 8.0 (m, 1H), 8.42 (s, 1H), 9.28 (s, 1H), 9.49 (s, 1H); m/s: M+H+ 387.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[Cl:14][C:15]1[CH:16]=[C:17](N)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:14][C:15]1[CH:16]=[C:17]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)c(Cl)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 3-chloro-4-trifluoromethyl-phenylamine.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:37][CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41].C[O-].[Na+]>CCO>[F:29][C:27]1[CH:28]=[C:23]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:9]=3)[C:14]([OH:15])=[C:5]([C:3]([NH:37][CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41])=[O:4])[N:6]=2)[CH:24]=[N:25][CH:26]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A mixture of 1-(5-fluoro-pyridin-3-yl)-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (51 mg, 0.13 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (121 mg, 0.52 mmol) and NaOMe (56 mg, 1.05 mmol) in EtOH (3 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (20 mL) and EtOAc (20 mL). 1 M HCl was added with vigorous stirring until pH was ˜3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-35% EtOAc/hexanes+2% AcOH) to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 476.14 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C1C=CN=CC=1)C.ClCCCl>[C:16]([O:12][C:11]1[C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[CH:2]([CH3:1])[CH3:3])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(=O)Oc1c(C(C)C)cc(C=O)cc1C(C)C

Procedure:
3,5-bis(1-methylethyl)-4-hydroxybenzaldehyde is acetylated with acetic anhydride in refluxing 1,2-dichloroethane, in the presence of DMAP, to provide 4-acetoxy-3,5-Bis(1-methylethyl)benzaldehyde. This material is converted by the method of example 2 into the title compound, obtained as a white solid, mp 95°-97° after recrystallization from hexane.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25][C:26]\3=C)/[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H](C(C)C)C.[BH4-].[Na+].[CH3:32][OH:33]>N1C=CC=CC=1>[CH3:4][CH2:3][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3[CH2:26][C@@H:32]([OH:33])[C:24](=[CH2:25])[C@H:23]([OH:28])[CH2:22]3)/[C@@H:13]2[CH2:12][CH2:11]1)[CH3:1]
Reactant: CO
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: C=C1[C@H](O)CC(=C/C=C2\CCC[C@]3(C)[C@@H]([C@@H](C)CC)CC[C@@H]23)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A solution of vitamin D2 (5 g, 12.7 mmol) in methanol (400 mL) and pyridine (5 mL) was cooled to −78° C. while purging with argon. The argon stream was stopped and a stream of ozone was passed until a blue color appeared. The solution was purged with oxygen until the blue color disappeared and treated with NaBH4 (1.2 g, 32 mmol). After 20 minutes, the second portion of NaBH4 (1.2 g, 32 mmol) was added and reaction was allowed to warm to room temperature. The third portion of NaBH4 (1.2 g, 32 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 70 mL of water and concentrated under vacuum. The residue was extracted with methylene chloride (3×100 mL). The organic phase was washed with 1M aqueous solution of HCl (2×100 mL), saturated aqueous solution of NaHCO3 (100 mL), dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography (25% ethyl acetate/hexane) to yield 2.05 g (9.69 mmol, 76% yield) of diol 1 as white crystals. [α]D+56.0 (c 0.95, CHCl3); mp 110-111° C.; 1H NMR (400 MHz, CDCl3) δ 0.96 (3H, s), 1.03 (3H, d, J=6.6 Hz), 3.38 (1H, dd, J=10.5 Hz, J=6.8 Hz), 3.64 (1H, dd, J=10.5 Hz, J=3.2 Hz), 4.09 (1H, d, J=2.3 Hz); 13C NMR (100 MHz, CDCl3) δ 13.6, 16.6, 17.4, 22.6, 26.6, 33.5, 38.2, 40.2, 41.3, 52.3, 52.9, 67.8, 69.2; MS (EI) m/z 212 (2, M+), 194 (17), 179 (18), 163 (10), 135 (19), 125 (34), 111 (100); exact mass calculated for C13H22O ([M−H2O]+) 194.1671, found 194.1665.
Reaction SMILES: CC1C=C(C2OC3C=CC=CC=3C=2)C=C(C)C=1.C1(C2OC3C=CC=CC=3C=2)C=CC=CC=1.[CH3:33][C:34]1[CH:35]=[C:36]([C:41]2[O:42][C:43]3[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=3[C:45]=2[C:46](=[O:55])[C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[CH:37]=[C:38]([CH3:40])[CH:39]=1.[CH2:60]([N:62]([CH2:67][CH3:68])[CH2:63][CH2:64]CCl)[CH3:61]>>[CH2:60]([N:62]([CH2:67][CH3:68])[CH2:63][CH2:64][CH2:54][O:53][C:50]1[CH:49]=[CH:48][C:47]([C:46]([C:45]2[C:44]3[CH:56]=[CH:57][CH:58]=[CH:59][C:43]=3[O:42][C:41]=2[C:36]2[CH:35]=[C:34]([CH3:33])[CH:39]=[C:38]([CH3:40])[CH:37]=2)=[O:55])=[CH:52][CH:51]=1)[CH3:61]
Reactant: COc1ccc(C(=O)c2c(-c3cc(C)cc(C)c3)oc3ccccc23)cc1
Reactant: CCN(CC)CCCCl
Agent: Cc1cc(C)cc(-c2cc3ccccc3o2)c1
Agent: c1ccc(-c2cc3ccccc3o2)cc1
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
Substitution of an equivalent amount of 2-(3,5-dimethylphenyl)benzofuran in the procedure of Example 1 for 2-phenylbenzofuran followed by demethylation of the 2-(3,5-dimethylphenyl)-3-(4-methoxybenzoyl)benzofuran thus formed and reaction of the resulting product with 3-diethylaminopropyl chloride as described therein gives the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:18][CH:19]([NH:24][S:25]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])(=[O:27])=[O:26])[C:20]([F:23])([F:22])[F:21])=[CH:12][NH:13]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:34][C:33]1[CH:32]=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[C:28]=1[S:25]([NH:24][CH:19]([CH2:18][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[OH:8])[NH:13][CH:12]=1)[C:20]([F:23])([F:21])[F:22])(=[O:27])=[O:26]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3cccc(OCc4ccccc4)c23)C(F)(F)F)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3cccc(O)c23)C(F)(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a stirred solution of 80 mg (0.15 mmol) of N-[1-(4-benzyloxy-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide in 5 mL of methanol was added 20 mg of 10% palladium on carbon followed by 48.7 mg (0.77 mmol) of ammonium formate. The reaction mixture stirred at room temperature for 1 hour and was then diluted with methanol, filtered through CELITE® filter aid, and concentrated in vacuo. The residue was diluted with cold water and the precipitate was filtered, washed with water, and dried to afford a white solid which was purified by preparative TLC eluting with ethyl acetate-hexanes (4:6) to afford 30 mg (45%) of the title compound as an off-white solid.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[C:9]1(=O)[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1>CO>[C:9]1(=[N:7][OH:8])[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1
Reactant: NO
Reactant: O=C1CC2c3ccccc3CC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CC2c3ccccc3CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (1.45 g, 17.7 mmol) and hydroxylamine hydrochloride (0.68 g, 9.75 mmol) were added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (1.4 g, 8.86 mmol) in MeOH (18 mL), and stirred overnight at room temperature. The reaction solution was concentrated via rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL), washed with H2O (50 mL), dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C11H1NO+H: 174, observed: 174.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30]1[CH2:40][CH2:39]N2C(=NCCC2)C[CH2:31]1.BrCC1CC1.O>C(O)C.C(OCC)(=O)C>[CH:30]1([CH2:31][O:28][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])=[O:18])[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:29])[CH2:39][CH2:40]1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(OCC3CC3)c2)n1
Reaction time: 8 h

Procedure:
A 0.12 g quantity of the compound obtained in Example 229 and 0.14 ml of DBU were dissolved in 3 ml of ethanol, 0.12 g of (bromomethyl)cyclopropane was then added to the obtained solution, and heating and refluxing were conducted overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from ethanol, thereby yielding 80 mg of white powdery 3-[2-(3-cyclopropylmethoxy-4-difluoromethoxy phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.