Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([O:8][C:9](=[O:11])[CH3:10])[C:5]1=[O:12].[N+](=C(C(=O)CC)C(OCC1C=CC=CC=1)=[O:17])=[N-].C([O-])(O)=O.[Na+]>ClCCl.[Cl-].[Zn+2].[Cl-]>[OH:17][C:4]1([CH2:3][CH3:2])[CH2:7][N:6]([O:8][C:9](=[O:11])[CH3:10])[C:5]1=[O:12]
Reactant: CCC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Reactant: CC(=O)ON1CC(CCO)C1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC1(O)CN(OC(C)=O)C1=O
Yield: 77 %

Procedure:
A mixture of the hydroxyethyl acetoxy azetidinone of Formula 10 (112 mg, 0.65 mmol) and silyl enol ether of benzyl 2-diazo-3-oxopentanoate (394 mg, 1.3 mmol) was dissolved in sieve dried dichloromethane (2 mL) and added to a suspension of fused (under vacuum) zinc chloride (55 mg, 0.4 mmol) in dichloromethane (2 mL). After refluxing gently for 12 hours, the mixture was poured into saturated NaHCO3 (50 mL) and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with brine, dried over MgSO4, and concentrated to an oil. Chromatography on silica gel gave the compound of Formula 12 in 77% yield.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-:7][Cr](Cl)(=O)=O.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2(O)[CH2:24][CH2:23][CH:22]=[C:21]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>C(Cl)Cl.CCOCC>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:21]2[C:22](=[O:7])[CH2:23][CH2:24][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=2)=[CH:26][CH:27]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CSc1ccc(C2(O)CCC=C2c2ccc(F)cc2)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CSc1ccc(C2=C(c3ccc(F)cc3)C(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a suspension of PCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4 Å molecular sieves in 150 mL of CH2Cl2 was added a solution of 2.2 g (7.3 mmol) of 1-(4-(methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclopenten-1-ol in 20 mL CH2Cl2. The mixture was stirred for 1 h at r.t. and then diluted with 300 mL of Et2O. After filtration and concentration, the residue was flash chromatographed with 2:1 hexane/EtOAc to give 1.5 g of the title product. 1H NMR (CDCl3) d 2.45 (3H, s), 2.68 (2H, m), 3.00 (2H, m), 7.02 (2H, J=8.6 Hz, t), 7.11 (2H, J=8.6 Hz, d), 7.15-7.23 (4H, m).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:10])([F:11])[CH2:3][CH2:4][C:5]([CH2:13][CH2:12][C:14](=[O:15])[CH3:16])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: C=CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CCC(C#N)(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
3.2 g of 2-(3,3,3-trifluoropropyl)malononitrile and 2.1 g of methyl vinyl ketone were dissolved in 30 ml of acetone, 3.3 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.7 g of 2-(3,3,3-trifluoropropyl)-2-(3-oxobutyl)malononitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=O)(C)(C)C.Cl.[CH2:38](Cl)Cl>CO.O1CCOCC1>[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[C:17]4[CH:34]=[CH:35][C:14]([C@H:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]5[OH:36])=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][N:22]3[CH:21]=2)=[N:30][C:29]([CH3:38])=[N:28]1)([CH3:33])[CH3:32]
Reactant: ClCCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@H]4CCNC[C@H]4O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of cis-racemic-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (17 mg, 0.36 mmol) in DCM (1 mL) and methanol (0.6 mL) was added 4M HCl in dioxane (1.5 mL) slowly and the reaction mixture stirred at RT for 2.5 h before being concentrated in vacuo. The resultant residue was triturated in diethyl ether to give racemic cis-4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-ol which was resolved as the (3R,4S) enantiomer 328 as a white solid (10 mg, 67%). MS RT2.47, [M+H]+=409. 1H NMR (DMSO-d6) δ: 8.92 (1H, br, d), 8.33 (1 H, d, J=8.30 Hz), 7.97 (1 H, s), 7.08 (1 H, d, J=8.36 Hz), 6.96 (1 H, d, J=1.66 Hz), 5.79 (1 H, t, J=6.59 Hz), 4.50 (4 H, d, J=7.99 Hz), 4.06 (1 H, s), 3.27 (2 H, m), 3.17 (2 H, m), 2.97 (2 H, d, J=14.58 Hz), 2.32-2.27 (1H, m), 2.29 (3 H, s), 1.74 (1 H, d, J=13.43 Hz), 1.46 (6 H, d, J=6.59 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)c2cccnc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid (2.6 g) and 4-nitrophenol (1.42 g) in 35 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (1.91 g). The mixture was stirred at room temperature for 18 hours, and after the usual work up, the ester was crystallized from ether to give 3.65 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester 51°-56° C. Recrystallization of a portion from ether afforded the analytical specimen, mp 54°-56° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:15])[CH:4]=1)#[N:2].C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:15])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1ccc(C#N)cc1F
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1F

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-cyano-2-fluorophenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.07 Hz, 3 H) 2.71 (br. s., 6 H) 4.00 (quin, J=6.76 Hz, 2 H) 7.37 (t, J=7.71 Hz, 1 H) 7.60 (dd, J=7.96, 1.64 Hz, 1 H) 7.64 (s, 1 H) 7.75 (dd, J=9.47, 1.64 Hz, 1 H). MS m/z [M+H]+ 236.2, 263.2.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10]([O:13][CH2:14]Cl)([CH3:12])[CH3:11]>>[CH:10]([O:13][CH2:14][O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([O:6][CH2:14][O:13][CH:10]([CH3:12])[CH3:11])[C:3]=1[O:4][CH2:14][O:13][CH:10]([CH3:12])[CH3:11])([CH3:12])[CH3:11]
Reactant: Oc1cccc(O)c1O
Reactant: CC(C)OCCl
Product: CC(C)OCOc1cccc(OCOC(C)C)c1OCOC(C)C

Procedure:
Using pyrogallol in place of phloroglucinol used in Synthesis Example 13 and isopropoxymethylchloride obtained in Synthesis Example 2, the reaction and treatment were carried out in the same manner as described in Synthesis Example 13 to give the corresponding 1,2,3-tris(isopropoxymethoxy)benzene as a yellow oil.
Reaction SMILES: [C:1]([NH:11][CH:12]([CH2:16][O:17][CH3:18])[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([NH:41][C:13](=[O:15])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][O:17][CH3:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCC(NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 11 (0.52 g, 2.04 mmol) in dry tetrahydrofuran (10 mL) was cooled to −78° C. in a dry ice-acetone bath under a N2 atmosphere. To this was added via a dry syringe 4-methylmorpholine (0.34 mL, 3.06 mmol). After stirring for 5 minutes, isobutyl chloroformate (0.4 mL, 3.06 mmol) was added via dry syringe and then the mixture stirred for 5 minutes. This was followed by the addition of benzylamine (0.32 mL, 3.06 mmol). After stirring at −78° C. for 5 minutes, the reaction was allowed to warm to room temperature, and stirring was continued at room temperature (30 min). The hydrochloride salt of 4-methyl morpholine was removed from the reaction by filtration. The clear filtrate was evaporated in vacuo and the residue was triturated with ethyl ether (5.0 mL). The white crystalline product obtained was isolated by filtration after washing with small amounts of ether and air-dried (0.55 g, 78%): mp 112°-114° C., Rf 0.6 (10% MeOH/CHCl3)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([CH2:19][O:20][CH2:21][C:22](=[O:27])NCOC)[C@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1>O1CCCC1.[Cl-].[NH4+]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([CH2:19][O:20][CH2:21][C:22]([C:33]1[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=1)=[O:27])[C@H:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COCNC(=O)COC[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of {(1R,2R)-2-benzyloxy-1-[(methoxymethylcarbamoyl)methoxymethyl]propyl}carbamic acid t-butyl ester (2.42 g) in tetrahydrofuran (50 mL) was cooled to −40° C. and to the mixture was then dropwise added 4-chlorophenylmagnesium bromide (18.3 mL, 1 M tetrahydrofuran solution). The resultant solution was stirred for 1 hour at −40° C., after which the temperature was slowly raised to 0° C. The solution was then diluted with saturated aqueous ammonium chloride. The resultant solution was extracted using ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/1), to thereby obtain the titled compound (2.61 g). The physical properties of this crude product were as follows.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:31])([F:30])[C@@H:27]([OH:29])[CH3:28]>CS(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:6]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[N:3][C:2]=2[O:29][C@@H:27]([CH3:28])[C:26]([F:31])([F:30])[F:25])=[CH:9][CH:10]=1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of methyl 5-bromo-6-(4-chlorophenyl)pyrazine-2-carboxylate (0.847 g, 2.59 mmol, Eq: 1.00) in dry DMSO (8 ml) was added cesium carbonate (1.54 g, 2.84 mmol, Eq: 1.1) and (S)-1,1,1-trifluoro-2-propanol (324 mg, 233 μl, 2.84 mmol, Eq: 1.1) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was dried over MgSO4 evaporated and purified by flash chromatography (silica gel, 100 g, 10% to 50% EtOAc in heptane) to yield the title compound as light yellow oil (0.724 g, 77.6%), MS 361.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[P:13](=O)([OH:16])([OH:15])[OH:14]>>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([O:4][P:13]([OH:16])([OH:15])=[O:14])=[C:5]1[OH:6]
Reactant: O=P(O)(O)O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1OP(=O)(O)O

Procedure:
The solution E contained sodium salts of L-ascorbic acid, phosphoric acid and some L-ascorbyl 2-monophosphate, and can be recycled to the phosphorylation process for producing further ascorbyl monophosphate. The solution F contained only a small amount of the remaining L-ascorbic acid and can be recycled to the next batch for separation.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1.O.[NH2:12][NH2:13].C(O)CC>ClC>[Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Cl)c(F)nc1F
Reactant: NN
Agent: CCl
Solvent: O
Solvent: CCCO
Product: NNc1nc(F)c(F)cc1Cl
Yield: 85.24 %

Procedure:
16.6 g of the compound obtained in Step 1 and 20.12 ml of hydrazine monohydrate were added to 100 ml of n-propanol, and the resulting mixture was refluxed 3 hours, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 100 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under a reduced pressure to obtain 15.9 g (yield: 85.24%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C@@H:11]([OH:14])CO)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>CO>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH:11]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H](O)[C@@H](COCc1ccccc1)Cc1cccc2ccccc12
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: O=C[C@@H](COCc1ccccc1)Cc1cccc2ccccc12
Temperature: 0 °C
Yield: 92.6 %

Procedure:
740 mg of (2R,3R)-4-benzyloxy-3-(1-naphthylmethyl)butan-1,2-diol was dissolved in 50 ml of methanol, and 19 ml of an aqueous solution of 568 mg of sodium metaperiodate was added thereto under stirring at 0° C. The mixture was stirred at room temperature for 4 hours. The insolubles were removed by filtration, and then the solvent was concentrated under reduced pressure. The residue was diluted with a saturated sodium hydrogencarbonate aqueous solution, and extracted with diethyl ether. Then, the extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 620 mg of (2R)-3-benzyloxy-2-(1-naphthylmethyl)-1-propanal thereby obtained as oily substance, was dissolved in 50 ml of acetone, and Jones' reagent was added thereto under stirring at 0° C. The mixture was stirred at the same temperature for 1.5 hours. To the reaction solution, isopropanol was added for decomposition of the reagent. Then, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate, washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to obtain 457 mg of the above identified compound as colorless oily substance.
Reaction SMILES: [O:1]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:36][C:33]([C:34]#[N:35])=[C:32]([N+:43]([O-])=O)[CH:31]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([N+:21]([O-])=O)[CH:9]=1>CC(O)=O.CC(O)C.[Fe]>[O:1]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:36][C:33]([C:34]#[N:35])=[C:32]([NH2:43])[CH:31]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH2:21])[CH:9]=1
Reactant: COCCOc1cc(C#N)c([N+](=O)[O-])cc1OCCOCCOCCOCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COCCOc1cc(C#N)c(N)cc1OCCOCCOCCOCCOc1cc(N)c(C#N)cc1OCCOC
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4,4′-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))-bis(oxy))bis(5-(2-methoxyethoxy)-2-nitrobenzonitrile) (0.3 g) in AcOH (10 mL) and i-PrOH (10 mL) was added iron powder (0.75 g). The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was cooled to room temperature, filtered, the precipitate washed with EA (10 mL). The combined washings and filtrate were concentrated under reduced pressure and purification by silica chromatography to give 0.22 g of 4,4′-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))-bis(oxy))bis(2-amino-5-(2-methoxyethoxy)benzonitrile). 1H-NMR (400 MHz, CDCl3): δ: 6.88 (s, 2H), 6.33 (s, 2H), 4.28 (br, 4H), 4.15-4.12 (m, 4H), 4.05-4.02 (m, 4H), 3.86-3.83 (m, 4H), 3.72-3.68 (m, 8H), 3.66-3.64 (m, 4H), 3.42 (s, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1([C:37](O)=[O:38])[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O.CCOC(C)=O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:37]([C:22]2([CH2:21][NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:23][CH2:24][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
(S)-3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (247 mg, 1.33 mmol) was added in one portion to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (500 mg, 1.33 mmol) and DIPEA (0.698 mL, 4.00 mmol) in DMA (6 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (557 mg, 1.47 mmol) was added and the resulting solution was stirred at 20° C. for 2 hours then 20° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl (4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (428 mg, 59.2%) as a colourless gum. The product (428 mg) was dissolved in dioxane (6.00 mL) and 4M hydrogen chloride in dioxane (0.925 mL, 26.64 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-(aminomethyl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (192 mg, 32.5%) as a white dry film.
Reaction SMILES: BrC1C=C2C(C=C(C)C(C(OCC3C=CC(OC)=CC=3)C(OCC)=O)=C2[O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14])=CC=1.[C:37]([O:41][CH:42]([C:48]1[C:57]([CH3:58])=[CH:56][C:55]2[C:50](=[CH:51][C:52]([Cl:59])=[CH:53][CH:54]=2)[C:49]=1[OH:60])[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][CH:42]([C:48]1[C:57]([CH3:58])=[CH:56][C:55]2[C:50](=[CH:51][C:52]([Cl:59])=[CH:53][CH:54]=2)[C:49]=1[O:60][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12])[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:38])([CH3:40])[CH3:39]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1OS(=O)(=O)C(F)(F)F

Procedure:
Ethyl 2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar manner to ethyl 2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)-naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate of Example 67, except using ethyl 2-tert-butoxy-2-(7-chloro-1-hydroxy-3-methylnaphthalen-2-yl)acetate. 1H-NMR: (400 MHz, CDCl3): δ 8.00 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.65 (s, 1H), 7.49 (dd, J=8.6, 2.0 Hz, 1H), 5.72 (s, 1H), 4.26-4.08 (m, 2H), 2.54 (s, 3H), 1.20 (s, 9H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[Mg].C(O[Si:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])OCC)C>CCOCC>[F:8][C:7]1[C:2]([Si:17]([C:2]2[C:3]([F:12])=[C:4]([F:11])[C:5]([F:10])=[C:6]([F:9])[C:7]=2[F:8])([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [Mg]
Solvent: CCOCC
Product: CCO[Si](OCC)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 35 °C
Reaction time: 16 h

Procedure:
265.2 mL (1.95 mol, 525.353 g) bromopentafluorobenzene, 52.11 g (2.144 mol) magnesium powder and 216 mL (0.975 mol, 203.025 g) tetraethoxysilane are mixed together at room temperature and diethylether is added dropwise to the vigorously stirred solution until an exothermic reaction is observed (˜240 mL). The solution is stirred for 30 minutes after which additional 90 mL of Et2O is carefully added. After stirring at 35° C. for 16 h the mixture is cooled to room temperature and diethylether evaporated. An excess of n-heptane (˜600 mL) is added to precipitate the magnesium salts. Solution is filtrated and evaporated to dryness. The residue is fractionally distilled under reduced pressure to yield di(pentafluorophenyl)diethoxysilane.