Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:26][C:9]1([CH3:27])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH2:10]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(F)(F)F)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
A mixture of 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 7.96 mmol), lithium hydroxide hydrate (3.34 g, 79.6 mmol), water (10 mL) in methanol (10 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.64 g, 95%) as a white solid which was used for next step without further purification: MS (ESI) M+1=350.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][C:21]([CH3:27])([CH3:26])[C:20]=3[CH:28]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:29]I.[OH-].[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[N:24]([CH3:29])[C:23](=[O:25])[O:22][C:21]([CH3:26])([CH3:27])[C:20]=3[CH:28]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)OC(C)(C)c2cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc21

Procedure:
A solution of 1.1 gm (0.0025 mol) of 6-[4-(3,4-dichloro-phenylsulfinyl)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 1 ml of methyl iodide in 30 ml of methylene chloride are mixed with 30 ml of 2N sodium hydroxide solution (0.06 mol) and a spatula tip of tetrabutylammonium hydrogen sulfate, and the mixture is stirred for 18 hours at ambient temperature. The organic phase is separated, washed twice with water, and dried with sodium sulfate, and the methylene chloride is distilled off. The residue is purified by column chromatography [silica gel; chloroform/acetone (40:1)]. The uniform fractions are concentrated by evaporation, the residue is stirred with diisopropylether, and the crystal slurry is subjected to suction filtration and dried.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][S:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][NH2:18].O>O1CCCC1.C(N(C(C)C)C(C)C)C>[CH3:1][O:2][C:3]([NH:18][NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][S:7][CH3:6])=[O:4]
Reactant: CSCCOc1ccccc1NN
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NNc1ccccc1OCCSC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
5.6 ml of chloroformic acid methyl ester are added dropwise at 0° C. to 14.4 g of 2-(2-methylthioethoxy)-phenylhydrazine in 100 ml of tetrahydrofuran and 14 g of N-ethyldiisopropylamine. The reaction mixture is stirred at 20° C. for 2 hours; H2O is then added, and the mixture is repeatedly extracted with ethyl acetate. After customary further processing, a solid is obtained, and this is recrystallised from alcohol to thus yield the compond of the formula ##STR62## having a melting point of 92°-94° C.
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+].C(O)(C)(C)C>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:29]([O:28][C@:4]1([CH2:1][CH2:2][OH:37])[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CCO)(OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of nucleoside 2 (1.00 g, 2.09 mmol) in THF (5.4 cm3) and water (5.4 cm3) was added sodium periodate (1.34 g, 6.27 mmol) and a 2.5% solution of osmium tetraoxide in tert-butanol (w/w, 0.265 cm3, 19 μmol). The solution was stirred at room temperature for 45 min. Water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was redissolved in THF (5.4 cm3) and water (5.4 cm3). The mixture was stirred at room temperature and sodium boronhydride (79 mg, 2.08 mmol) was added. After stirring for 1.5 h, water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 9 as a white solid material (488 mg, 48%). δH (CDCl3) 9.14 (1H, br s, NH), 7.60 (1H, d, J 1.1, 6-H), 7.40-7.22 (10H, m, Bn), 6.25 (1H, d, J 7.7, 1′-H), 4.59 (1H, d, J 7.1 Bn), 4.49 (1H, d, J 7.1 Bn), 4.39-3.30 (m, 8H, 4′-H, 2′-H, Bn, 5′-Ha, 5′-Hb, 2″-Ha, 2″-Hb), 2.23-2.00 (2H, m, 1″-Ha, 1″-Hb), 1.49 (3H, d, J 0.7, CH3). δC (CDCl3) 163.5 (C-4), 151.2 (C-2), 137.1, 136.5 (Bn), 135.7 (C-6), 128.7, 128.5, 128.2, 127.8, 127.6, 127.2 (Bn), 111.3 (C-5), 87.0, 82.7, 81.1, 78.3 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.6 (Bn), 64.4 (C-5′), 57.0 (C-2″), 32.4 (C-1″), 11.8 (CH3) (Found. C, 63.9; H, 6.3; N, 5.4. C26H30N2O7, 0.25H2O requires C, 64.1; H, 6.3; N, 5.75%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N+:22]([O-])([O-:24])=[O:23].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:22]([O-:24])=[O:23])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1c(F)c(F)c([N+](=O)[O-])c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 69.4 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (490 mg) in concentrated sulfuric acid (5 ml) was added potassium nitrate (235 mg) below 5° C. under stirring portionwise. After stirring for 45 minutes, the reaction mixture was poured into ice water (25 ml) and the resulting precipitate was collected by filtration, washed with cold water sufficiently, recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (392 mg) as yellow prisms, mp 215.5°-221° C. (decompd.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CS([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=1)(=O)=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)nc1
Yield: 55 %

Procedure:
To 18.4 g of 4-bromophenol dissolved in a 80 ml THF/80 ml DMSO mixture was added 13.1 g of t-BuOK and then 25.0 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled overnight and then poured into 3 volumes of water and stirred. The pink-white crystalline product was filtered, dissolved in CH2Cl2 and dried over MgSO4. Recrystallization from ethanol gave purified 2-(4-bromophenoxy)-5-(methylsulfonyl)pyridine, (55% yield), as white shiny needles, m.p. 125°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].C1COCC1.C([N-]C(C)C)(C)C.[Li+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCC.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccccc1OC
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)C(Cc1ccccc1)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A 500 mL round-bottom flask is charged with methyl 2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, 1 eq) and THF (200 mL). The homogeneous mixture is cooled to 0° C. in an ice bath. Lithium diisopropyl amide (23.5 mL of a 2.0M solution in heptane/THF) is added, maintaining a temperature less than 3° C. The reaction is stirred 45 minutes at this reduced temperature. Benzyl bromide (5.6 mL, 47 mmol, 1 eq) is added dropwise. The reaction is allowed to gradually warm to room temperature and is stirred for 18 hours. The reaction is quenched with 1N HCl and extracted 3 times with equal portions of EtOAc. The combined extracts are washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified over silica to afford 4.433 g (35%) of the desired compound. ESI+ MS 293 (M+Na).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[CH:34]1[C:46]2[CH:45](O)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:45]1[C:46]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]3[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: OC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OC1c2ccccc2-c2ccccc21)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (95 mg, 0.50 mmol), EDC (143 mg, 0.74 mmol), triethylamine (242 μl, 1.73 mmol), and HOBT (114 mg, 0.74 mmol) were dissolved in dry THF (5 ml). 9H-fluoren-9-ol (99 mg, 0.54 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. The resulting suspension was stirred at room temperature overnight. The mixture was evaporated, and the crude taken up with EtOAc and washed sequentially with water and sat. NaHCO3. The organic phase was dried over sodium sulfate, filtered. and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/1) to afford 9H-fluoren-9-yl quinuclidine-3-carboxylate (102 mg, racemic mixture).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:19]=[C:18]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[CH:17]=2)=[CH:8][C:7]=1[CH3:40].[Li+].[OH-].O.Cl>C1COCC1.CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]#[C:31][C:18]2[CH:17]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:7]([CH3:40])[CH:8]=3)[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:19]=2)=[CH:34][CH:35]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(Cl)cc3)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(Cl)cc3)c2)ccc1OCC(=O)O
Temperature: 0 °C
Reaction time: 7.67 h

Procedure:
To a solution of (4-{3-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (63 mg, 0.11 mmol) in THF (1.25 ml) and methanol (0.25 ml) was added a ice-cold solution of LiOH (1 M, 1.25 ml). The reaction mixture was stirred at 0° C. for 460 min., after which water (10 ml) and aqueous HCl (1M, 1.75 ml) were added. The mixture was extracted with ethyl acetate (2×10 ml), and the combined organic phases were dried and evaporated to give the title compound in 29 mg (48%) yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9]2)[N:7]=1.C(=O)(O)[O-].[Na+]>Cl.C1COCC1.CCOC(C)=O.O>[Br:1][C:2]1[C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[CH2:9]2)[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1ncc(C2CCCC(O[Si](C)(C)C(C)(C)C)C2)nc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)nc1Br
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of (+/−)-N-(3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide (97 mg, 0.206 mmol) in 6N HCl (687 μL), THF (687 μL) MeOH (687 μL) was stirred for 2 h. LCMS indicated that the reaction was completed. Solid sodium bicarbonate was added to neutralize the HCl. Dissolved in EtOAc and water. Organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to provide 72 mg of crude (+/−)-N-(3-bromo-5-((1R,35)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide in 98% yield. LCMS (m/z): 358.6 (MH+), 0.70 min.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:23][C@@:16]2([C:20](=[O:21])[NH:19][C:18](=[O:22])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:24])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:26][CH2:27][CH2:28][Cl:29].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:23][C@@:16]2([C:20](=[O:21])[N:19]([CH2:26][CH2:27][CH2:28][Cl:29])[C:18](=[O:22])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:24])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Reaction time: 5 h
Yield: 80.4 %

Procedure:
To a solution of (2S,4S)-N-butyl-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (25.0 g, 74.6 mmol) in N,N-dimethylformamide (125 ml, 1.62 mmol) was added 1-bromo-3-chloropropane (23.5 g, 149 mmol). After adding 60% NaH (3.00 g, 75.0 mmol) over 30 minutes at 15°-22° C., the mixture was stirred for 5 hours at 25°-28° C. The reaction mixture was poured into iced water (500 ml), extracted with AcOEt (1000 ml×3), dried over MgSO4. The solvent was distilled off, the residue was chromatographed on silica gel, eluted with CH2Cl2 -CH2Cl2 /MeOH (9/1), and recrystallized from AcOEt to give the desired compound (24.7 g, 80.5%) as colorless prism crystals.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[C:21]([Si:18]([CH3:20])([CH3:19])[O:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[CH3:5])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(C(C)(C)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 24 h
Yield: 90.3 %

Procedure:
To a solution of 2-methyl-2-p-tolyl-propan-1-ol (405 mg, 2.46 mmol) in DMF (5 mL) was added imidazole (335 mg, 4.92 mmol) followed by tert-butyldimethylsilyl chloride (465 mg, 3.08 mmol). The reaction was stirred for 24 h and water was added. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with water (4×). The organic solution was dried (MgSO4), filtered and concentrated. Medium pressure chromatography (hexanes) provided tert-butyl-dimethyl-(2-methyl-2-p-tolyl-propoxy)-silane (619 mg). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, 2H), 7.10 (d, 2H), 3.49 (s, 2H), 2.31 (s, 3H), 1.27 (s, 6H), 0.85 (s, 9H), −0.06 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:50])[C:5]([CH3:49])([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[N:17]2CC2C=CC(OC)=CC=2)=[CH:9][CH:8]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.O>[CH2:1]([O:3][C:4](=[O:50])[C:5]([CH3:49])([O:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2)cc1)Oc1ccccc1
Yield: 98.8 %

Procedure:
A solution of 3-(4-{2-[3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.54 g, 2.29 mmol) and triethylsilane (0.53 g, 4.56 mmol) in trifluroacetic acid (40 mL) is stirred at room temperature under N2 for 4 hours. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried and the solvent removed in vacuo to afford crude product that is purified by flash chromatography using 3:1 then 1:1 hexanes:acetone to afford 1.25 g (100%) 2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy)-phenyl}-2-phenoxy-propionic acid ethyl ester. The diastereomeric mixture could be separated by chiral HPLC (2:3 IPA:heptane mobile phase, 14 mL/min, 225 nm) to afford >99% de 2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl esters. Rf=0.19 (1:1 acetone:hexanes). 1H NMR. MS (ES+) Calc'd for C34H37N2O5 (M+1) 553. Found m/z 553 (100%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]=[O:17])[CH:4]=[CH2:5].ClS([N:22]=[C:23]=[O:24])(=O)=O.C(O)(=O)C>C1COCC1.O>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:23]([NH2:22])=[O:24])[CH:11]=[C:10]2[CH:16]=[O:17])[CH:4]=[CH2:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=CCOc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(c1)c(C=O)cn2C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of NaH (60% in mineral oil, 352 mg, 8.79 mmol) in THF (12 mL) under nitrogen atmosphere at 5° C. was added a solution of 5-allyloxy-1H-indole-3-carbaldehyde (1.18 g, 5.86 mmol) in THF (28 mL) and the resulting mixture was stirred at 5° C. for 30 min before slow addition of chlorosulfonyl isocyanate (11.02 mL, 11.7 mmol) while maintaining the temperature between 5° C. and 10° C. The solution was further stirred at RT for 4 h, acetic acid (11 mL) was added and the solution was stirred at RT for 1 h. Ice cubes and water (100 mL) were added and the mixture was stirred at RT for 30 min. The solution was extracted twice with EtOAc and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (100% c-hexane to 100% EtOAc) to give the title compound. TLC, Rf (c-hexane/EtOAc 1:2)=0.36; MS (LC/MS): 245.1 [M+H]+, 267.0 [M+Na]+, 200.1 [M−CONH2]−; tR (HPLC conditions a): 2.95 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:36][NH:37][O:38][CH3:39]>ClCCl>[CH3:39][O:38][N:37]([CH3:36])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:4]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(-n2cccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)c(-n2cccc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
5.0 g of 4-chloro-3-(1H-pyrrol-1-yl)benzoic acid in 200 ml of dichloromethane were treated in succession with 3.13 ml of triethylamine and 4.33 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC.HCl). The mixture was stirred at room temperature until it became clear and was then cooled to 0° C. and 2.21 g of N,O-dimethylhydroxylamine hydrochloride were added. The mixture was then left to come to room temperature and was stirred for a further 18 hours, washed with 1M aqueous hydrochloric acid and with brine and then dried over anhydrous magnesium sulphate. Evaporation under reduced pressure gave 5.73 g of N-methoxy-N-methyl-4-chloro-3-(1H-pyrrol-1-yl)benzamide as a viscous oil.
Reaction SMILES: [BH4-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.B(F)(F)F.CCOCC>[Hg]>[O:3]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][OH:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Hg]
Solvent: CCOCC
Product: OCc1cccc(Oc2ccccc2)c1
Temperature: 20 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
A 500-milliliter, 4-necked glass reaction vessel equipped with a magnetic stirring bar, pressure-equalizing addition funnel, thermometer, and reflux condenser vented to a mercury bubbler was charged with 9.6 grams (0.248 mole plus 5% excess) of sodium borohydride and 64 grams (0.30 mole) of m-phenoxybenzoic acid and flushed 10 minutes with dry nitrogen. The reaction vessel was cooled in an external ice/water bath as 0.2 liter of tetrahydrofuran was added dropwise followed by 40.6 milliliters (0.33 mole) of boron trifluoride diethyl etherate over a 1 hour period while maintaining a temperature of 0°-10°C. The reaction mixture was then stirred for 12 hours at 20°C followed by 2 hours at 40°C. The product was isolated using a procedure similar to that described in Example 1 giving 48 grams (80% yield) of m-phenoxybenzyl alcohol, n20D 1.5935.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH2:8])=[NH:7].[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20].CN1CCOCC1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:7][C:6](=[NH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([F:2])[CH:4]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: Cc1ccc(C(=N)N)cc1F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=N)NS(=O)(=O)c2ccc(F)c(Cl)c2)cc1F
Yield: 35.8 %

Procedure:
Add 3-fluoro-4-methylbenzamidine hydrochloride (0.025 g, 0.133 mmol) in THF (0.5 mL) to 3-chloro-4-fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol) followed by N-methylmorpholine (0.2 mL). The reaction mixture was concentrated and chromatographed using reverse phase chromatography (gradient of 5–95% (0.1% TFA in CH3CN) in (0.1% TFA in H2O). A white solid (16.4 mg, 36%) was isolated. ES Positive Ion MS [M+H]+ ions observed: m/z 345 (35Cl) and m/z 347 (37Cl).