Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([OH:22])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27]C([O-])(C)C.[K+].CI>C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]([CH3:27])[C:20](=[O:22])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc2nc(O)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(sc(=O)n2C)c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a solution of (S)-2-(7-bromo-2-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67B) (40 mg, 0.090 mmol) in THF (1 ml) was added KOtBu (0.14 ml, 0.135 mmol, 1M in THF) slowly at −78° C. After 15 min, MeI (8.5 ul, 0.135 mmol) was added at −78° C. and stirred at −78° C. for 15 min. Then the reaction was reacted at rt for 3 hs. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 67C (30 mg, 73%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 110 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (200 mg, 1.15 mmol), 4-bromophenol (240 mg, 1.39 mmol), triphenylphosphine (398 mg, 1.50 mmol) and DIAD (202 mg, 1.39 mmol) in anhydrous THF (5 mL) was heated to 110° C. and stirred under nitrogen for 5 hours. The reaction mixture was concentrated in vacuo to give a brown residue, which was purified by flash chromatography (petroleum ether/ethyl acetate 10:1 to 4:1) to give tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (300 mg, 79.5%) as a white solid.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: Brc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
7.80 g (0.32 mol) of iodine-activated magnesium turnings in 20 ml of anhydrous THF are heated briefly to 60° C. Then 47.1 g (0.30 mol) of bromobenzene and 80 ml of THF are added dropwise over 30 min and the mixture is heated for 1.5 hours to 65° C. After cooling, the Grignard solution is added over 1 hour to a mixture of 51.6 g (0.28 mol) of cyanuric chloride and 140 ml of THF, while keeping the temperature of the mixture in the range from 10° to 20° C. When the addition is complete, the mixture is stirred at for 3 hours at 25° C. The mixture is then diluted with 280 ml of toluene, the resultant suspension is poured into 300 g of 12% aqueous HCl, the organic phase is separated, washed with a total amount of 400 g of water and concentrated. The resultant material (melting point 117°-120° C.) is recrystallised from hexane, giving the title compound in a yield of 61%.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:11]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a reactor was introduced 41 mL (55 mmol; 1.06 M THF solution) of benzylmagnesium chloride under a nitrogen atmosphere. The contents were cooled to 0° C. Thereafter, a solution prepared by mixing 9.11 g (50.0 mmol) of benzophenone with 18 mL of THF was gradually added dropwise thereto, and this mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was washed with 0.1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was dissolved in 46 mL of toluene, and 0.18 g of p-toluenesulfonic acid monohydrate was added thereto. Azeotropic dehydration was conducted for 2 hours with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 12.5 g (98%) of a transparent oily substance.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](OC([O-])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>ClCCl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: C1CCC2(C1)CCNCC2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 8-azaspiro[4.5]decane (which has been described in WO 9800404 A1 6.2 g, 44.5 mmol) in dichloromethane (130 ml), which was cooled to 0° C., triethylamine (7.5 ml, 53.4 mmol) was added then a solution of tert-butyl dicarbonate (10.68 g, 48.9 mmol) in dichloromethane (50 ml) was added in 20 minutes. The clear solution was maintained under stirring at room temperature for 18 hours, then dichloromethane (50 ml) was added and the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) then water (2×20 ml). The organic solvent was anhydrified (Na2SO4) and evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5) to give 6 g of the title compound (light yellow solid).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O1CCCC1>[CH2:7]([NH:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:22])[CH2:18][CH2:19][OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCNC(=O)CC(C)(C)CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCNCCC(C)(C)CCO
Temperature: 0 °C

Procedure:
Part B. A slurry of lithium aluminum hydride (5.50 g, 145 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C., and a solution of the amide prepared in Part A (11.48 g, 47.2 mmol) in tetrahydrofuran (50 mL) was added dropwise over 1 hour. The ice bath was removed, and the mixture was heated to reflux for 18 hours. After cooling to 0° C., the mixture was quenched by the slow dropwise addition of water (6 mL), aq. NaOH (18 mL, 15%), and water (18 mL). The solution was filtered through a plug of Celite®, dried over potassium carbonate, and concentrated under vacuum to afford N-heptyl-3,3-dimethyl-5-hydroxypentanamine as a clear, colorless oil (7.61 g, 33.2 mmol, 70%). 1H NMR (CDCl3) δ 3.70(dt,2H,J=10.2,7.0 Hz); 2.70-2.55(m,2H); 2.39-2.29(m,2H); 1.56(dt,2H,J=12-1,7.0 Hz); 1.51-1.41(m,6H); 1.36-1.24(m,8H); 0.91(s,6H); 0.88(t,3H, J=6.9 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][C:13]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:24](=[O:32])[NH:25][C:26]3[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=3)[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:22][C:20]1([CH3:23])[CH2:19][C:18]2[C:13]([O:12][C:8]3[CH:9]=[C:10]([F:11])[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[CH:14][C:15]([C:24](=[O:32])[NH:25][C:26]3[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=3)=[CH:16][C:17]=2[O:21]1
Reactant: COC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Yield: 87.3 %

Procedure:
To a solution of 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (949 mg, 2.15 mmol) in 12 mL THF was added 4 mL of 1.0 N aqueous NaOH. The mixture was heated at 60° C. for 1 hr, and concentrated in vacuo. The residue was acidified to pH ˜1 with 1N aqueous HCl, filtered, washed with water, and dried under vacuum at 60° C. overnight to give an off-white solid (800 mg, 87% yield). LCMS for C21H19FN4O5 m/z 427.20 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][O:6][C:5](=[S:8])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH2:3]1.C(=O)([O-])O.[Na+].Cl[C:31]([O:33][CH3:34])=[O:32].O>C(#N)C>[CH3:1][C:2]1([CH3:24])[CH2:7][O:6][C:5](=[S:8])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]([C:31]([O:33][CH3:34])=[O:32])[S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])[CH2:3]1
Reactant: CC1(C)COC(=S)N(Cc2ccccc2NS(=O)(=O)C(F)(F)F)C1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)N(c1ccccc1CN1CC(C)(C)COC1=S)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 46.6 %

Procedure:
5,5-dimethyl-3-[2-(trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazinan-2-thione (0.15 g, 0.39 mmol) and sodium hydrogen carbonate (0.05 g, 0.60 mmol) were suspended in acetonitrile (10 ml), added with methyl chloroformate (0.06 g, 0.60 mmol) and heated to reflux for three hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure after the organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:l) to obtain 5,5-dimethyl-3-(2-[N-(methoxycarbonyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-[1,3]-oxazinane-2-thione (0.08 g).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH2:8][N:15]1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:4]
Reactant: NC1CCCC1
Reactant: COC(=O)C(Br)CCBr
Product: COC(=O)C1CCN1C1CCCC1
Yield: 33 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with cyclopentylamine 18I yielded 1-cyclopentyl-azetidine-2-carboxylic acid methyl ester as a light brown solid (33%). MS ISP (m/e): 184.2 (100) [(M+H)]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]1[C@H:18]3[CH2:19][C@H:15]([CH2:16][CH2:17]3)[C@@H:14]1[CH2:20][N:21]([CH3:23])[CH3:22])[CH:7]=[CH:6]2.O>CN(C=O)C>[CH3:23][N:21]([CH2:20][C@H:14]1[C@@H:15]2[CH2:19][C@@H:18]([CH2:17][CH2:16]2)[C@@H:13]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2)[CH3:22]
Reactant: COc1ccc2cc([C@H]3[C@@H]4CC[C@@H](C4)[C@@H]3CN(C)C)ccc2c1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C[C@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2cc(O)ccc2c1

Procedure:
To a stirred solution of [(1S,2S,3S,4R)-3-(6-methoxy-2-naphthyl)bicyclo [2.2.1]hept-2-yl]-N, N-dimethyl methanamine in DMF was added sodium ethane thionyl. The mixture was heated to 100 C for 40 hours. When cool, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated in-vacuo. Purification was achieved by column chromatography, using flask silica and DCMM/eOH(M/eOH,NH40H at 10%) in a ration of 10/1/0.1 for eluant. Yield (10%). ME 296 (MH+).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:35][CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: NC1CCOCC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(NC2CCOCC2)n1
Temperature: 160 °C
Yield: 46.7 %

Procedure:
6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (100 mg, 0.27 mmol) and tetrahydro-2H-pyran-4-amine (55 mg, 0.54 mmol) were dissolved in DMSO (1.5 ml) in a microwave vial. DIPEA (0.282 ml) was added and the mixture was heated at 160° C. for 3 h under microwave irradiation. The reaction mixture was concentrated under a stream of nitrogen and redissolved in methanol. This solution was loaded onto a 2 g aminopropyl column, which was been preconditioned with methanol. The column was eluted with methanol (2 column volumes) and the desired fraction was blown to dryness under nitrogen. The sample was then purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound (57 mg) as a white solid.
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC(CSCCO)=CC=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2ccc(CSCCO)cc2)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 99 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was prepared as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (3.11 g, 9.83 mmol, 1 eq.) in anhydrous THF (100 mL) was treated with phenol (1.29 g, 13.76 mmol, 1.4 eq.), triphenylphosphine (3.61 g, 13.76 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (2.78 g, 2.71 mL, 13.76 mmol, 1.4 eq.) as described. When the reaction was complete, the reaction was worked up and the product purified via silica gel flash chromatography leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester (3.82 g, 99% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:13]2[N:26]([C:29](=[O:43])[CH:30]([NH:35]C(OC(C)(C)C)=O)[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:13]2[N:26]([C:29](=[O:43])[CH:30]([NH2:35])[C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(N)C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
A solution of carbamate 81 (542 g, 0.90 mmol) in DCM (10 mL) was treated with TFA (3 mL) at 0° C. After 20 min, the reaction mixture was warmed to ambient temperature. After 1 h, the solution was concentrated, diluted with EtOAc, washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, and filtered. The aqueous phase was back-extracted with DCM and the combined organic extracts were concentrated to afford 82 (401 mg, 89%) as a light yellow-colored foam was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.31-7.26 (m, 5H), 7.00-6.95 (m, 1H), 6.65-6.60 (m, 1H), 6.49-6.47 (m, 1H), 5.14-5.08 (m, 2H), 4.41 (m, 2H), 3.95-3.92 (m, 1H), 3.83-3.72 (m, 2H), 3.40-3.29 (m, 2H), 2.79 (app q, J=5.4 Hz, 1H), 2.34-2.19 (m, 1H), 1.66 (m, 2H), 0.94 (s, 9H) ppm. Mass spectrum, m/z [502.6] (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(C=C2CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Fc1ccc(CC2CCC3(CC2)OCCO3)cc1
Reaction time: 2.5 h

Procedure:
To a stirring degassed solution of 8-[(4-fluorophenyl)methylene]-1,4-dioxaspiro[4.5]decane (18. 9 g, 76 mmol) and 10% palladium on carbon (3.8 g, Aldrich) in 500 mL of ethyl acetate was added 40 psi of hydrogen gas. The reaction was stirred for 2.5 h and then filtered through a pad of silica gel. The silica gel was washed with ethyl acetate (300 mL). The organic layers were combined and conc in vacuo to a colorless oil yielding 18.0 g. MS (ESI) 253 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:28]=[O:29])C>>[C:1]1([C:7]2[N:8]=[C:9]([CH:28]=[O:29])[N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccccc2)nc1C=O
Yield: 97.8 %

Procedure:
Reaction of 4-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (380 mg, 1.39 mmol), 2.5 M n-BuLi (720 uL, 1.80 mmol), and DMF (323 uL, 4.17 mmol) for 4 h at −40° C. gave the title compound (411 mg, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.93 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=9.0 Hz), 5.83 (s, 2H), 7.26-7.46 (m, 3H), 7.65 (s, 1H), 7.83 (d, 2H, J=9.0 Hz), 9.89 (s, 1H).
Reaction SMILES: [C:1]([CH2:5][S:6](Cl)(=[O:8])=[O:7])([F:4])([F:3])[F:2].[NH4+:10].[OH-]>C(Cl)Cl.O>[C:1]([CH2:5][S:6]([NH2:10])(=[O:8])=[O:7])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)CC(F)(F)F
Temperature: 25 °C

Procedure:
The CF3CH2SO2NH2 was prepared by cooling a solution of commercially available CF3CH2SO2Cl (0.6 ml, 1 eq) in CH2Cl2 to 0° C. NH4OH (0.75 ml, 14.8 N, 2 eq) was then added dropwise. The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted three times with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated. The sulfonamide was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1.[OH-].[Na+]>O1CCCC1.O>[N:1]1([CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:26])[CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCc1ccccc1)N1CCC(CCCl)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1CCC(CCn2ccnc2)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of imidazole (1.4 g) in dry tetrahydrofuran (20 ml) was added dropwise with stirring to a mixture of sodium hydride (0.8 g, 60% dispersion in mineral oil) in tetrahydrofuran (20 ml) under nitrogen. The mixture was stirred at 20° C. for 3 hours and then a solution of the product from Example 42 (5.6 g) in dry tetrahydrofuran (50 ml) was added dropwise with stirring. The mixture was heated under reflux for 9 hours and then cooled to 20° C. Water (50 ml) was added and the solution stirred for 10 minutes. The mixture was basified with dilute sodium hydroxide solution and extracted with dichloromethane. The combined dichloromethane extracts were washed (water), dried and filtered before evaporation to give 4-[2-(imidazol-1-yl)ethyl]-1-(3-phenylpropionyl)piperidine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([N:21]2[CH2:26][C@H:25]([CH3:27])[NH:24][CH2:23][C@@H:22]2[CH3:28])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1C[CH2:40][CH2:39][CH2:38]1>>[CH2:40]([N:24]1[CH2:23][C@H:22]([CH3:28])[N:21]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:30][CH:29]=2)[CH2:26][C@@H:25]1[CH3:27])[CH:39]=[CH2:38]
Reactant: C[C@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=CCN1C[C@H](C)N(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C

Procedure:
The purified benzhydrylpiperazine (1.51 g, 3.1 mmol) was dissolved in 20 mL of dry tetrahydrofuran with 0.27 mL (3.2 mmol) of alkyl bromide and 1.6 g (15.5 mmol) of sodium carbonate and heated at reflux overnight under nitrogen. The cooled reaction solution was filtered and the solvent removed to give 1.62 g of crude (2S,5S)-1-allyl-4-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH2:22][O:23]CC3C=CC(OC)=CC=3)=[N:18][O:19][C:20]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH2:22][OH:23])=[N:18][O:19][C:20]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(COCc2noc(C)c2-c2ccccc2C(=O)c2ccc(Cl)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanone (69 mg, 0.154 mmol), DCM, and water. This solution was cooled to 0° C. before addition of DDQ (69.9 mg, 0.308 mmol) and the reaction stirred at 0° C. for 4 h before addition of NaHCO3 solution. The layers were separated and the aqueous extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone. LC/MS m/z 328 [M+H]+.