Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]1[C:19]2[C:14](=[C:15]([CH3:24])[CH:16]=[C:17]([C:21]([OH:23])=[O:22])[C:18]=2[CH3:20])[S:13](=[O:26])(=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=[O:39].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:9][CH:10]1[C:19]2[C:14](=[C:15]([CH3:24])[CH:16]=[C:17]([C:21]([O:23][C:38]3[CH2:37][CH2:36][CH2:35][C:34](=[O:39])[CH:33]=3)=[O:22])[C:18]=2[CH3:20])[S:13](=[O:25])(=[O:26])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1=O
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2OC(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1S(=O)(=O)CCC2OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.80 g (2.1 mmol) of 4-benzoyloxy-5,8-dimethyl-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid in 30 ml of methylene chloride was admixed with 2 drops of N,N-dimethylformamide and 1.69 g (13.3 mmol) of oxalyl chloride, and the mixture was boiled under reflux for 3.5 h. The solvents were subsequently stripped off using a rotary evaporator, and the residue was taken up in 100 ml of methylene chloride and, at 0° C., admixed with 0.25 g (2.2 mmol) of cyclohexanedione and 0.44 g (7.4 mmol) of triethylamine. The mixture was stirred at room temperature for 4 h and subsequently concentrated using a rotary evaporator, and the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:26](O)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:10]([CH3:26])[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=C(C)C(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 6.019 g of ethyl 3.3-bis(4-methoxyphenyl)acrylate (prepared as described in Preparation 107), 120 ml of ethanol and 80 ml of a 10% w/v aqueous solution of sodium hydroxide was stirred for 14 hours at room temperature. At the end of this time, the reaction mixture was heated on an oil bath at 100° C. for 4 hours, and then ethanol was distilled off. The residue was diluted with ice-water and washed with ethyl acetate. Concentrated hydrochloric acid was dropped onto the aqueous phase on an ice bath, to adjust the pH to a value of 2. The aqueous phase was extracted twice with methylene chloride. The combined methylene chloride extracts were washed with water dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure, to afford 5.117 g of the title compound as white crystals melting at 134°-135° C. (after recrystallisation from a mixture of methylene chloride and hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1>Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: Cl
Solvent: CCO
Product: C[C@H]1CNCCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.2 %

Procedure:
A mixture of 224a (3.0 g, 6.9 mmol) and 4.0M HCl/ethanol (20 mL) was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to afford crude 224b as a yellow solid (2.5 g, 98%), which was used for the next step without further purification. MS-ESI: [M+H]+ 335.1.
Reaction SMILES: CC([C@@H]1[C@@]2(C)CC[C@@H]3[C@]4(C)C(=CC(CC4)=O)CC[C@H]3[C@@H]2CC1)=[O:3].[CH3:24][C:25]([C@:27]1([OH:47])[C@@:31]2([CH3:46])[CH2:32][CH2:33][C@@H:34]3[C@:44]4([CH3:45])[C:38](=[CH:39][C:40]([CH2:42][CH2:43]4)=[O:41])[CH2:37][CH2:36][C@H:35]3[C@@H:30]2[CH2:29][CH2:28]1)=[O:26].C(OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(=O)C)C=1)C.[O:73]=[O:74].[K]>O1CCCC1.CN(C)C=O.C(O)(C)(C)C>[O-:73][OH:74].[CH3:24][C:25]([C@:27]1([O:47][OH:3])[C@@:31]2([CH3:46])[CH2:32][CH2:33][C@@H:34]3[C@:44]4([CH3:45])[C:38](=[CH:39][C:40]([CH2:42][CH2:43]4)=[O:41])[CH2:37][CH2:36][C@H:35]3[C@@H:30]2[CH2:29][CH2:28]1)=[O:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=O
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CCOC1=CC2=CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(=O)[C@@]1(OO)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Product: [O-]O

Procedure:
The direct introduction of a hydroxyl group at the 17 position of progesterone, protected as its Δ3,5 methyl enol ether, would be a valuable process for the synthesis of 17α-hydroxyprogesterone, and could be readily adapted to other corticosteroid intermediates. Unfortunately, this oxidation has heretofore been a poor process. D. Barton [J. Chem. Soc., 1578(1962)] developed a method for the hydroperoxylation of the 17(20)-enolate of 3-ethoxypregna-3,5-dien-20-one using oxygen and potassium and tert-butyl alcohol, dimethylformamide (DMF), and tetrahydrofuran (THF). The intermediate hydroperoxide was isolated in 30% yield and hydrolyzed to 17α-hydroperoxyprogesterone in 75% yield. This process was ultimately improved when J. Garnder [J. Org. Chem., 33, 3294(1968)] found that the addition of trialkylphosphites reduced the intermediate hydroperoxide to the alcohol in situ and was stable to the reaction conditions. Gardner used his modifications of the Barton procedure to oxygenate pregnen-20-ones to their 17α-hydroxy compounds; in a similar fashion, pregnan-20-ones, were converted in yields between 60-70 %.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[C:12](Cl)([Cl:14])=[S:13]>ClCCl>[Cl-:14].[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][CH:12]=[S:13])=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: S=C(Cl)Cl
Reactant: NCc1ccc2c(c1)OCO2
Solvent: ClCCl
Product: S=CNCc1ccc2c(c1)OCO2
Product: [Cl-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of piperonylamine (0.1 mL, 0.77 mmol) in dichloromethane (20 mL) was slowly added thiophosgene (0.06 mL, 0.83 mmol) under cooling with an ice bath. After the reaction mixture was stirred for four hours at room temperature, it was washed with water and brine, dried over anhydrous sodium sulfate, filtered, evaporated and dried under vacuum; and the product was used immediately for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1.[Br:27]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[N:13]=2)=[O:9])[C:5]([Br:27])=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCc1cccc(CNC(=O)c2cc(-c3ccc(C)o3)nc(N)n2)n1
Solvent: CC(=O)O
Product: COCc1cccc(CNC(=O)c2nc(N)nc(-c3ccc(C)o3)c2Br)n1
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of 2-amino-N-(6-methoxymethyl-2-pyridylmethyl)-6-(5-methyl-2-furyl)pyrimidine-4-carboxamide (50 mg, 0.142 mmol) in acetic acid (10 mL) at room temperature was treated with N-bromosuccinimide (28 mg, 0.156 mmol), stirred for 2 h, concentrated in vacuo and partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was dried (MgSO4), concentrated in vacuo and the resulting solid was triturated with diethyl ether and filtered to give the title compound (50 mg, 82%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:33](=[O:35])=[O:34]>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]3[N:7]=[C:2]([CH2:1][C:33]([OH:35])=[O:34])[CH:3]=[CH:4][CH:5]=3)(=[O:11])=[O:10])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: O=C=O
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)n1

Procedure:
This material was obtained in analogy to example 71 step A] from 4′-fluoro-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide (0.5 g, product of example 17), 1.46 mL of a 2 M lithium diisopropylamide solution in THF/heptane/ethylbenzene, and dry ice to give [6-(4′-fluoro-biphenyl-4-sulfonylamino)-pyridin-2-yl]-acetic acid as a gum (0.69 g) that was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH2:11]>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:11][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution (10 mL) of 2-methylbenzoyl chloride (4.16 mL) in THF was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=9:1) to afford phenyl 2-methylbenzoate (2.88 g, 64%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH:20]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CNCc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
Benzyl 4-formylbenzoate (618 mg, 2.57 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (622 mg, 3.09 mmol) were dissolved in 20 mL of toluene and 2.0 mL of methanol, and the solvent was evaporated under reduced pressure. The resulting white solid was dissolved in 15 mL of 2-propanol, sodium triacetoxyborohydride (1.64 g, 7.72 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure, and the resulting yellow oily substance was purified by silica gel chromatography (n-hexane:ethyl acetate, 90:10→80:20, v/v) to give the title compound (0.54 g; yield, 54%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[CH2:12]([N:15]1[CH2:20][NH:19][C:18](=[S:21])[NH:17][CH2:16]1)[CH:13]=[CH2:14]>CC(C)=O>[BrH:1].[CH2:12]([N:15]1[CH2:20][N:19]2[C:6]([C:5]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)([OH:9])[CH2:7][S:21][C:18]2=[N:17][CH2:16]1)[CH:13]=[CH2:14]
Reactant: C=CCN1CNC(=S)NC1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CC(C)=O
Product: Br
Product: C=CCN1CN=C2SCC(O)(c3ccc(Br)cc3)N2C1
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of 6.95 grams (0.025 mole) of p-bromophenacyl bromide in 60 milliliters of acetone was mixed with a solution of 3.93 grams (0.025 mole) 5-allyl-3,4,5,6-tetrahydro-s-triazin-2(1H)-thione in 1100 milliliters of acetone and the mixture was left for 1 hour at room temperature. The solution was then concentrated to 200 milliliters. 10.1 Grams (89% yield) of 3-allyl-6-(p-bromophenyl)-6-hydroxy-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide 1/3 acetonate crystallised as a colourless solid of melting point 146°-148° C. (with decomposition).
Reaction SMILES: C(=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18][Cl:19])[CH2:14][S:15][C@H:10]12)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.CO>[NH2:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18][Cl:19])[CH2:14][S:15][C@H:10]12
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CCCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCCl)CS[C@H]12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of XVII from Preparation No. 7 (180 mg, 0.34 mmole) in ethyl acetate (10 ml) was added to a solution of Girard Reagent T [(carboxymethyl)trimethylammonium chloride hydrazide] (251 mg, 1.5 mmole) in CH3OH (10 ml) containing acetic acid (0.25 ml), at 5° C. After stirring for 30 minutes at 5° C., the mixture was concentrated to remove the CH3OH and then ethyl acetate (20 ml) was added. The ethyl acetate solution was washed with H2O (2×5 ml), saturated aqueous NaHCO3 (5 ml) and brine (5 ml), successively and dried over MgSO4. Evaporation of the solvent gave 145 mg (97%) of the title compound XVIII (Z isomer) as a yellow powder. M.p. >100° C. (dec.).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br-].[Li+].[F:12][C:13]([F:29])([F:28])[C:14]1[CH:15]=[C:16]([C:20]2([CH:26]=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.[CH3:30][CH2:31][O:32][C:33]([CH3:35])=[O:34]>C1COCC1.Cl>[F:12][C:13]([F:29])([F:28])[C:14]1[CH:15]=[C:16]([C:20]2([CH:26]=[CH:35][C:33]([O:32][CH2:31][CH3:30])=[O:34])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(C)=O
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
N,N-diisopropylethylamine (2.95 mL, 16.9 mmol) and anhydrous lithium bromide (489 mg, 5.63 mmol) were added to a stirred solution of 4-(3-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbaldehyde (485 mg, 1.88 mmol) in THF (15 mL). After 20 min., triethyl phosphonoacetate (1.12 mL, 5.63 mmol) was added and the mixture was stirred at room temperature for 16 h. Additional N,N-diisopropylethylamine (980 μL, 5.64 mmol) was added and stirring was continued for additional 160 min. The reaction mixture was diluted with EtOAc and 1N aq. HCl solution. The organic layer was separated, washed with 1N aq. HCl solution, brine, dried (Na2SO4), filtered, and concentrated under vacuum to obtain a thin yellow oil which was chromatographed on silica gel (Teledyne-Isco RediSep 12 g column). Elution with 5%, 10%, and 20% EtOAc in hexanes afforded ethyl 3-(4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)acrylate (569 mg, 92% yield) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3): δ ppm 7.38-7.68 (m, 4H), 6.98 (d, 1H), 5.71 (d, 1H), 4.19 (q, 2H), 3.76 (dd, 4H), 2.06-2.34 (m, 4H), 1.29 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 12 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (7.3 g, 30.5 mmol) in DMF (20 ml) was added potassium carbonate (5.47 g, 39.6 mmol) at room temperature followed by drop wise addition of 4-Trifluoromethylbenzyl bromide (6.04 g, 33.6 mmol). The reaction mixture was stirred for 12 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether 5:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C@H:29]([CH3:42])[CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH3:28].[CH3:41][O:40][C:38](=[O:39])[CH2:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][C@H:29]([NH:28][CH2:16][C@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH2:26][OH:27])[CH:11]=2)[CH3:42])[CH:32]=1
Reactant: COC(=O)Cc1cccc(C[C@@H](C)N)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Product: N
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
A solution of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 23) (12.5 g, 27.7 mmol) and methyl {3-[(2R)-2-aminopropyl]phenyl}acetate (Preparation 25) (11.5 g, 55.4 mmol) in dichloromethane (130 ml) was heated to 90° C., allowing the dichloromethane to evaporate. The resulting melt was left at 90° C. for a further 16 hours. The reaction mixture was cooled to room temperature and purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97:3:0.3, by volume) to give the title compound (12.1 g) as a white oil. 1H NMR (400 MHz, CD3OD): δ=7.47-7.45 (2H, m), 7.39-7.29 (4H, m), 7.19-7.15 (1H, t), 7.13-7.07 (2H, m), 7.03 (1H, s), 7.01-6.99 (1H, d), 6.93-6.91 (1H, d), 5.12 (2H, s), 4.76-4.73 (1H, t), 4.67-4.66 (2H, d), 3.66 (3H, s), 3.58 (2H, s), 2.95-2.80 (2H, m), 2.68-2.55 (3H, m), 1.06-1.05 (3H, d), 0.83 (9H, s), 0.00 (3H, s), −0.19 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 578, [M+Na]+ 600.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16](C(OC(C)(C)C)=O)[CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(OCC)C>[CH2:1]([O:8][CH:9]1[CH2:15][CH:14]2[NH:16][CH:10]1[CH2:11][O:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(OCc1ccccc1)C2
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COC2CC3COCC2N3)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A 250-mL round-bottomed flask was charged with tert-butyl 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (4.40 g, 13.78 mmol J. Org. Chem. 2010, 75, 1643) and 15 mL of CH2Cl2. To this was added TFA (10.61 mL, 138 mmol). After 2 h at room temperature, the mixture was concentrated and diluted with saturated aqueous NaHCO3 and CH2Cl2. The layers were separated, the organics were dried (MgSO4), filtered, and concentrated to give a white solid. This solid was slurried with 50 mL of diethyl ether. The resulting white solid was collected by filtration to give 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane (3.02 g)
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=O)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:9]=[N:8][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]=2[CH3:12])=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1C1CCCCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
1-Cyclohexyl-5-methylpyrazole-4-carboxylic acid (1.2 g), 5-amino-2-neopentyloxybenzonitrile (1.1 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.4 g) were added to dimethylformamide (15 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (1.2 g), melting point: 126–128° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:8]([O:10]C)=[O:9])[OH:4].[OH-].[Na+].Cl>>[OH2:4].[NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:8]([OH:10])=[O:9])[OH:4]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C(O)CN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1C(O)CN
Product: O
Temperature: 25 °C
Reaction time: 4 h
Yield: 152.9 %

Procedure:
A mixture of methyl 3-[2-amino-1-(R,S)-hydroxyethyl]-4-[(methylsulfonyl)amino]benzoate (50 mg, 0.17 mmol) in 1N sodium hydroxide (44 μL, 0.44 mmol) was stirred at room temperature for 4 h. The mixture was neutralized with dilute hydrochloric acid and let stand overnight at room temperature. A white precipitate accumulated which was collected by filtration, washed with water, and dried to give 38 mg (81%) of the title compound as a white powder, mp 274°-276° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1.C(OCC)(=O)C>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
5.0 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 150 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour at -60°, combined with 2.5 g of cyclopentanone, further stirred for 1 hour, and heated to 25°. Then water is added to the mixture, the latter is diluted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 6.9 g of crude 4-[1-hydroxycyclopent-1-yl-1-(imidazolyl)methyl]benzonitrile.