Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][I:13].[P:14](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>>[I:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][P:14](=[O:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(OCC)OCC
Reactant: ICCOCCOCCOCCI
Product: CCOP(=O)(CCOCCOCCOCCI)OCC
Temperature: 160 °C

Procedure:
1-iodo-2-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)ethane (1 eq) was mixed with triethyl phosphate (1 eq) then heated to 160° C. for 20 minutes by microwave. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the product as a yellow oil.
Reaction SMILES: [Na].[S:2](=[CH:5][C:6]1[CH:11]=[N:10][C:9]([CH3:12])=[CH:8][N:7]=1)(=[O:4])=[O:3].[CH3:13]I>>[CH3:13][N:10]1[C:9]([CH3:12])=[CH:8][N:7]=[C:6]([CH:5]=[S:2](=[O:3])=[O:4])[CH2:11]1
Reactant: Cc1cnc(C=S(=O)=O)cn1
Reactant: CI
Agent: [Na]
Product: CC1=CN=C(C=S(=O)=O)CN1C

Procedure:
2.0 g of 2-sulfonylmethyl-5-methylpyrazine sodium salt (3100) was added to a solution of 15 ml methyl iodide/25 ml methanol and refluxed for 5 days. The mixture was then cooled and filtered. The solid was purified by gel permeation chromatography (Biogel P-2/water) and freeze-dried to give 1.6 g of product (3200). It was recrystallized from propanol/water, m.p.>350° (dec.) UV H2O max: 213 (3.91), 293 (3.87).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:40][CH2:41][OH:42])[N:17]=[C:18]3[C:27]4[C:22](=[C:23]([O:28][CH2:29][C:30]5[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=5[CH3:38])[CH:24]=[CH:25][CH:26]=4)[C:21](=[O:39])[C:20]=1[C:19]=23.ClC1C=CC2N(CCO)N=C3C4C(=CC=CC=4OCC4C(C)=CC(C)=CC=4C)C(=O)C=1C=23>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:40][CH2:41][O:42][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[N:17]=[C:18]3[C:27]4[C:22](=[C:23]([O:28][CH2:29][C:30]5[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=5[CH3:38])[CH:24]=[CH:25][CH:26]=4)[C:21](=[O:39])[C:20]=1[C:19]=23
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCO)c(C)c1
Agent: Cc1cc(C)c(COc2cccc3c2-c2nn(CCO)c4ccc(Cl)c(c24)C3=O)c(C)c1
Product: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCOS(=O)(=O)c2ccccc2)c(C)c1

Procedure:
Starting with benzenesulfonyl chloride and the mixture of regioisomers of 5-chloro-2-(2-hydroxyethyl)-7-[(2,4,6-trimethylphenyl)methoxy]anthra-[1,9-cd]pyrazol-6(2H)-one II and 5-chloro-2-(2-hydroxyethyl)-10-[(2,4,6-trimethylphenyl) methoxy]anthra-[1,9-cd]pyrazol-6(2H)-one III, using the procedure of example 3, the title compound was prepared.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])N=1.C[OH:15]>>[CH3:12][C:6]1([CH3:13])[NH:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4](=[O:15])[CH2:3]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CO
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
17.2 g of acetonine hydrate, 3 g of methanol and 0.5 g of ammonium chloride are heated to 60° C. After a reaction time of 12 hours, it is shown by a gas-chromatographical analysis that about 80% of the employed amount of acetonine has been reacted to form triacetoneamine, which is isolated by distillation.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:23]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:23])[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A 66 mg (1.65 mmol) portion of sodium hydride was added to 10 ml of DMF solution containing 300 mg (1.10 mmol) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and stirred at room temperature for 30 minutes, and then 103 μl (1.65 mmol) of methyl iodide were added thereto and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the resulting oil was purified by a silica gel column chromatography (60 cc; elution by ethyl acetate-hexane=1:5) to obtain 200 mg of the title compound (63% in yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:3]=1>CO.C(OCC)(=O)C.[Pd]>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1
Reaction time: 0.75 h

Procedure:
To a solution of methyl 2-chloro-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate (750 mg, 1.76 mmol) from Step A in methanol (10 mL) and ethyl acetate (10 mL) was added 10% Pd/C (100 mg). The suspension was stirred under an atmosphere of hydrogen (balloon pressure) for 45 min and was then filtered to remove the catalyst. HPLC/MS indicated a mixture of starting material, desired product, and minor amounts of several possible phenyl ring dechlorination products. The filtrate was evaporated and the residue was purified by flash column chromatography on silica gel eluted with 5 to 20% ethyl acetate in hexanes. The fractions containing the title compound were repurified by preparative TLC eluted with 15% ethyl acetate in hexanes to give pure methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate. HPLC/MS: 392 (M+1), 394 (M+3); Rt=4.29 min. 1HNMR (CDCl3): δ 4.024 (s, 3H), 7.11 (br d, J=8.6 Hz, 2H), 7.23-7.35 (m, 4H), 7.36 (d, J=2.0 Hz, 1H), 7.37 (d, J=1.9 Hz,, 1H), 9.286 (d, J=1.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 36.8 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (200 mg, 0.68 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (172 mg, 0.96 mmol) to afford the title compound (110 mg), a white solid, in 37% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:28]([O:37][CH3:38])[CH:27]=1)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:33][CH2:32][CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][C:28]=3[O:37][CH3:38])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A mixture of 5.0 g (0.0165 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred and heated at 80° C. for two hours. The temperature was raised to 100° C. for one hour. After cooling, the reaction mixture was filtered and the dimethylformamide was removed at reduced pressure. The residual oil which crystallized on standing in ether was dissolved in benzene and placed on a Florisil® column. Using a gradient elution of acetone-benzene, 1.8 g (21.4%) of product was obtained from the column, m.p. 141.5°-143° C. (See Ex. 12, U.S. Pat. No. 3,956,296).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:16]>CO.O1CCOCC1.O>[ClH:16].[CH3:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 67, 1.58 g, 7.34 mmol) in methanol (20 mL) was added hydrochloric acid in 1,4-dioxane (4M, 10 mL) and the mixture stirred for 3 h at rt. Concentration in vacuo gave an oil which was redissolved in water (100 mL). The aqueous layer was washed with ethyl acetate (2×30 mL) and concentrated to give the title compound as colourless solid. δH (D2O): 1.80, 2.14 (4H, 2m), 3.13 (2H, m), 3.38 (2H, m), 3.40 (3H, s), 3.68 (m, 1H).
Reaction SMILES: [OH:1][C@:2]1([CH3:35])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:23])[CH3:22])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:34])([F:33])[F:32])=[N:27][NH:28][C:29]=2[CH3:30])=[O:8])[CH2:3]1.Cl.C[C@]1(O)CONC1.[N+](C1C=C(S(OC[C@@]2(C)CO2)(=O)=O)C=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[OH:1][C@@:2]1([CH3:35])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:22])[CH3:23])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:32])([F:33])[F:34])=[N:27][NH:28][C:29]=2[CH3:30])=[O:8])[CH2:3]1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cc1sc2c(c1C(=O)N1C[C@](C)(O)CO1)c(=O)n(C)c(=O)n2C(C)C
Agent: C[C@@]1(O)CNOC1
Agent: C[C@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1[nH]nc(C(F)(F)F)c1Cc1sc2c(c1C(=O)N1C[C@@](C)(O)CO1)c(=O)n(C)c(=O)n2C(C)C
Reaction time: 3 h

Procedure:
To a suspension of the product of example 10 part a) (0.130 mg) and (4R)-4-methyl-4-isoxazolidinol hydrochloride (42 mg, prepared by the method of example 1 steps a) to d) using [(2R)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate) in anhydrous THF (6 ml), was added triethylamine (120 mg) and the mixture was cooled in an icebath. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetamethyluronium hexafluorophosphate (120 mg) was added and the mixture was allowed to warm to, whereupon it was stirred for 3 hr. All volatiles were removed in vacuo and the residue was chromatographed (SiO2/1:1 CH2Cl2-EtOAc) to effect primary purification. Further purification by RPHPLC afforded the title compound as a solid (35 mg).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:13](=O)([O:16]C)[O:14][CH3:15].[H-].[Na+].Cl>O1CCCC1.O>[O:12]=[C:11]1[CH:10]([C:13]([O:14][CH3:15])=[O:16])[CH2:9][CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCCc2ccccc2C1=O

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (24.99 g, 156.0 mmol) and dimethyl carbonate (42.2 g, 468 mmol) in tetrahydrofuran (150 ml) was added a suspension (12.5 g, 312 mmol) of 60% sodium hydride in liquid paraffin at room temperature and the mixture was heated under reflux for 1 hr. The reaction solution was poured into water, acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16]O)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)(Cl)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])=[C:5]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 56.2 %

Procedure:
To a solution of (6-chloro-2-isobutyl-4-phenylquinolin-3-yl)methanol (0.70 g, 2.15 mmol) in toluene (15 ml) was added thionyl chloride (0.31 ml, 4.3 mmol), and the mixture was heated under reflux for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was washed with saturated brine (20 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in N,N-dimethylformamide (10 ml). Thereto was added potassium phthalimide (0.6 g, 3.2 mmol) and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (50 ml)-water (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the extract and the organic layer were combined. The mixture was washed twice with water (50 ml) and then saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 2-[(6-chloro-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1-H-isoindole-1,3(2H)-dione (0.55 g, yield 57%) as an orange oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]([CH2:22][CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:22]([CH:16]([C:15]([OH:30])([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:23]
Reactant: CCOC(=O)C(CC)C(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CC)C(O)(c1ccccc1)c1ccc(O)cc1
Yield: 95.4 %

Procedure:
8.0 g (0.020 mol) of ethyl 3-(p-benzyloxyphenyl)-2-ethyl-3-hydroxy-3-phenylpropionate were hydrogenated in ethanol solution using palladium-charcoal as catalyst to yield 6.0 g (96%) of the product, mp. 46°-53° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:10][C:8]1[CH:7]=[C:6]([F:11])[C:3]([C:4]#[N:5])=[C:2]([N:1]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:9]=1
Reactant: COC(OC)N(C)C
Reactant: N#Cc1c(N)cc(Br)cc1F
Product: CN(C)C=Nc1cc(Br)cc(F)c1C#N
Temperature: 25 °C

Procedure:
17.0 g (79.1 mmol) 2-amino-4-bromo-6-fluoro-benzonitrile in 140 ml of N,N-dimethylformamide dimethyl acetal are heated to 120° C. for 2 h. After cooling RT the solvent is evaporated and the residue taken up in diethyl ether, filtered and dried.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].FC(F)(F)C(C1C=CC(OC)=C(C=1)[CH:31]=[O:32])C(F)(F)F>>[F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:12]=1)[CH:31]=[O:32])([C:7]([F:8])([F:9])[F:10])[C:3]([F:6])([F:5])[F:4]
Reactant: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Product: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 16 in the same manner of Compound 9.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:13]([C:12]1[CH:17]=[CH:18][C:19]([CH2:21][Br:1])=[CH:20][C:11]=1[O:10][CH3:9])([O:15][CH3:16])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC

Procedure:
N-Bromosuccinimide (45.3 g) was added to methyl 2-methoxy-4-methylbenzoate (45.8 g) in carbon tetrachloride (~11) containing a trace of dibenzoyl peroxide. The suspension was heated under reflux until no orange colour persisted, then cooled, filtered and the filtrate evaporated to give the title compound, bp 136°-144°/7 mm. τ (CDCl3) 6.17 (3H, s), 6.13 (3H, s), 5.59 (2H, s), 2.9-3.15 (2H, m), 2.3 (1H, J=8 Hz).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH3:6][Si:7]([CH3:10])([CH3:9])Cl.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:6][Si:7]([CH3:10])([CH3:9])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Product: CCCCO[Si](C)(C)C
Yield: 92 %

Procedure:
1 mole of n-butanol and 1.5 moles of trimethylchlorosilane were heated to reflux (54°-91° C.) with the addition of 0.0005 moles of tetra-n-butyl ammonium bromide. Vigorous evolution of HCl was observed. When evolution of gas ceased, the IR spectrum did not show an OH band. When the product was worked up by distillation, pure 1-trimethylsiloxybutane was obtained as distillate.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B.C1COCC1.[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][C:37]([CH3:46])([C:42]([F:45])([F:44])[F:43])[CH2:36][C:35]2=[O:47].Cl>C1(C)C=CC=CC=1>[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][C:37]([CH3:46])([C:42]([F:43])([F:45])[F:44])[CH2:36][C@H:35]2[OH:47]
Reactant: CC1(C(F)(F)F)CC(=O)c2cc(Br)ccc2O1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: CC1(C(F)(F)F)C[C@@H](O)c2cc(Br)ccc2O1
Reaction time: 0.25 h

Procedure:
To a cooled (ice bath) solution of (s)-2-methyl-cbs-oxazaborolidine 1.0 M in toluene (100 μl, 100 μmol) was added borane-dimethyl sulfide 2.0 M in THF (500 μl, 1000 μmol). After stirred 15 min, a solution of 6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-one (309 mg, 1000 μmol) in toluene was added drop wise. The reaction was completed after stirring 9 h at 0° C. 2N HCl was added slowly to quench the reaction. The resulted mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column to afford the title compound.
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]N=O)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.[OH-].[Na+].C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(O)(=O)C>[C:1]1(=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCCCCCCCC1
Reactant: CC(C)(C)ON=O
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Cyclododecane (1.66 g; 9.88 mmol), t-butylnitrite (2 mmol), N-hydroxyphthalimide (0.4 mmol), and acetic acid (2 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas for 1 hour. The resulting mixture was further treated with scandium triflate (20 mg) with stirring at 80° C. for 30 minutes. The reaction mixture was neutralized with sodium hydroxide and was then analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 40%, 7%, and 3%, respectively.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[CH2:45][OH:46])[CH:36]=[CH2:37].[H-].[Na+]>CN(C=O)C>[CH2:35]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[CH2:45][O:46][CH2:20][C:18]1[CH:19]=[C:15]2[N:14]=[C:13]([CH3:22])[C:12]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([N:8]3[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:34])[CH2:6][CH2:7]3)[N:16]2[N:17]=1)[CH:36]=[CH2:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCc1cc(C)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C)cc4CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (144 mg, 0.247 mmol) and (2-allyl-4-methylphenyl)methanol (40 mg, 0.247 mmol) in DMF (5 mL) at 0° C. was added NaH (9.86 mg, 0.247 mmol). The reaction mixture was stirred h at 0° C. for 2 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((2-allyl-4-methylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.081 mmol, 32.8% yield) as an oil. LCMS (M+1)=619.4.
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][NH:35][CH3:36])[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O.C(Cl)Cl>[Si:18]([O:25][CH:26]1[CH2:27][CH2:28][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][N:35]([CH3:36])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])[CH2:30][CH2:31]1)([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Solid Teoc-OSu (1.35 g, 5.25 mmol) was added to a two-phase solution of (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate (2.0 g, 5.0 mmol), K2CO3 (0.75 g, 9.0 mmol) in H2O (6 ml) and CH2Cl2 (12 mL). The mixture was vigorously stirred for 2 h at rt. The product was extracted with CH2Cl2. The combined organic layers were washed with sat'd aq NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to provide (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (1.9 g, 3.49 mmol, 70% yield). 1H NMR (400 MHz, CD3OD): 0.05 (s, 15H), 0.87 (s, 9H), 1.40 (s, 9H), 1.69 (s, 3H), 2.96 (m, 3H), 3.40-3.52 (m, 1H), 3.81-3.92 (m, 1H), 4.12-4.29 (m, 2H). MS (E/Z): 545 (M+H+)