Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([CH3:17])[C:3]=1[OH:18].Br[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:18][C:3]1[C:4]([CH3:17])=[CH:5][C:6]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(C)c(O)c(C)c2)cc1
Yield: 79.1 %

Procedure:
A solution of 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (525 mg, 2.12 mmol), methyl 4-bromobenzoate (460 mg, 2.14 mmol), PdCl2(dppf) (80 mg, 0.11 mmol) and Cs2CO3 (1.40 g, 4.31 mmol) in DMF (10 mL, 5% H2O) was heated at 80° C. for 1 h. The reaction mixture was diluted with EtOAc (50 mL), washed with H2O (2×50 mL), and dried over Na2SO4. Purification on a silica gel column gave the desired product as a pale yellow solid (430 mg). NMR (CDCl3): δ 8.08 (d, 2H), 7.62 (d, 2H), 7.29 (s, 2H), 4.75 (s, 1H), 3.95 (s, 3H), 2.35 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C.Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([B:19]([OH:22])[OH:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)cc1C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C(C)(C)C
Reaction time: 2 h

Procedure:
4 g (16.5 mmol) of 3-tert-butyl-4-methoxybromobenzene and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 7.9 ml (19.8 mmol) of n-butyllithium (2.5 M in hexane) are added dropwise at −78° C., the mixture is stirred for 15 minutes at this temperature, 5.6 ml (49.5 mmol) of trimethyl borate are added and the mixture is stirred for 2 hours. 20 ml of hydrochloric acid (1 N) are added at −50° C. and the mixture is allowed to return to room temperature. The reaction medium is extracted with ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 3.79 g (100%) of the expected boronic acid are collected, which is used in its present state for the rest of the synthesis.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.CN(C)C(=O)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>O>[CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])(=[O:16])=[O:17])=[CH:11][CH:10]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NS(=O)(=O)c1ccc(NC(=O)OCC(C)C)cc1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a mixture of 54.4 g of p-isobutyloxycarbonylaminophenyl sulfonamide, 40 g of triethylamine, 2 g of N,N-dimethylaminopyridine and 150 ml of N,N-dimethylacetamide was then added dropwise 22.8 g of methacrylic chloride under cooling with ice. After the completion of the dropwise addition, the reaction mixture was stirred for 2 hours. The reaction product was then poured into water. The resulting crystal was then withdrawn by filtration. The crystal was then recrystallized from a 3/7 (by volume) mixture of toluene and ethyl acetate to obtain 40 g of N-(p-isobutyloxycarbonylaminophenylsulfonyl)methacrylamide in the form of white crystal (m.p. 194°-196° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:9][CH2:10][CH2:11][CH2:12][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: BrCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCBr)c1ccccc1
Yield: 37.7 %

Procedure:
N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 23a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:21]1([C:27]2[N:32]=[N:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[OH-].[Na+]>>[C:21]1([C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:14]([CH2:13][C:9]4[CH:10]=[C:11]5[C:6](=[CH:7][CH:8]=4)[N:5]=[CH:4][C:3]([OH:2])=[CH:12]5)=[N:34][N:33]=3)[N:32]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.3 g, 11 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.3 g, 2 mmol), and HYDROCHLORIC ACID (0.3 ml, 11 mmol) as solvent. The vial was sealed and first heated at 100° C. for 20 min then placed into CEM microwave for 20 min. at 180° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH. The ppt. was collected by filtration. The ppt. was washed with water and dried. The solid was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, DCM:MeOH=95%:5%, Flow=40 mL/min) to afford the desired product as gray solid. MS m/z: 354.2 (M+H). Calc'd. for C21H15N5O−353.37.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12
Reactant: COc1ccc(C(O)c2cnc3[nH]ccc3c2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2cnc3[nH]ccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-methoxyphenyl)methanol (2.34 g, 8.10 mmol, prepared using S from Preparation #1, Step B with (4-(2-methyl-1,3-dioxolan-2-yl)phenyl)magnesium bromide [NOVEL]) and DCM (30 mL) was added Dess-Martin periodinane (3.44 g, 8.10 mmol). The mixture was stirred at rt for about 3 h. Water was added (15 mL) and the resulting precipitate was collected by filtration and dried under reduced pressure at about 60° C. for about 2 h to give (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-methoxyphenyl)methanone (2.14 g, 92%): LC/MS (Table 2, Method b) Rt=2.17 min.; MS m/z: 287 (M+H)+.
Reaction SMILES: C1(N[N:8]=[C:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][C:11]3[CH:17]=[CH:18][CH:19]=[N:20][C:10]2=3)C=CC=CC=1.[K+].[Br-].[C:23](#N)[CH3:24].O>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:20]1[C:10]2[C:9]3[NH:8][C:24]4[C:23]([C:15]=3[CH2:14][C:13](=[O:16])[NH:12][C:11]=2[CH:17]=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:15]=4
Reactant: CC#N
Reactant: O=C1CCC(=NNc2ccccc2)c2ncccc2N1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1Cc2c([nH]c3ccccc23)-c2ncccc2N1

Procedure:
Prepared according to general procedure B from 72.4 mg (0.27 mmol) 7,8-dihydro-5H-pyrido[3,2-b]azepine-6,9-dione 9-(phenylhydrazone) in 30 ml diphenyl ether. Recrystallization from ethanol afforded a brown solid. Yield: 17 mg (25%); m.p. >330° C.; IR (KBr): 3054 cm−1 (CH-arom.), 2974 cm−1 (CH-aliph.), 1675 cm−1 (C═O), 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=3.66 (s, 2H, azepine-CH2), 7.06-7.09 (m, 1H, arom. H), 7.18-7.22 (m, 1H, arom. H), 7.40 (dd, 1H, 8.2/4.5 Hz, arom. H), 7.47 (d, 1H, 8.2 Hz, arom. H), 7.62 (dd, 1H, 8.2/1.4 Hz, arom. H), 7.70 (d, 1H, 8.0 Hz, arom. H), 8.48 (dd, 1H, 4.5/1.4 Hz, arom. H), 10.22 (s, 1H, NH), 11.70 (s, 1H, NH); 13C-NMR (DMSO-d6, 100.6 MHz): δ (ppm)=31.9 (azepine-CH2), 111.9, 118.4, 119.1, 122.5, 122.8, 129.3, 144.3 (tert. arom. C), 108.9, 126.3, 132.0, 132.5, 137.5, 140.5 (quat. arom. C), 171.1 (C═O); C15H11N3O (249.27); purity (HPLC): 98.8% (ts=3.25 min, acetonitrile/water 35:65).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[C:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:9](=[O:11])[CH3:10])[CH:17]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CC(=O)c1cccc(-c2ccccc2Cl)c1
Reaction time: 0.03 h

Procedure:
To a solution of iodochlorobenzene (8.64 g, 55 mmol) in n-propanol (85.8 mL), 3-acetylphenylboronic acid (10.0 g, 50 mmol) was added and the solution was stirred for 2 min. Then triphenylphosphine (118 mg, 0.45 mmol), palladium acetate (33 mg, 0.15 mmol), 2M sodium carbonate (30 mL, 60 mmol) and water (17.68 mL) were added and the reaction mixture was refluxed for 16 h. It was quenched with water and partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Finally it was filtered, concentrated and purified by chromatography (hexane:ethyl acetate; 4:1) to yield the product.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17](OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:35].[Li+].CN(C)C=O>O>[CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@@H:17]([Cl:35])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1Cl
Temperature: 75 °C
Reaction time: 9 h
Yield: 48.9 %

Procedure:
A mixture of 553 g of 2-benzyl-6-((3R,4R)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 79 mg of lithium chloride and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 9 hours. After cooling as it was, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (5:1), to give 391 mg of the target compound.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>C(Cl)(Cl)Cl>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: OCCNCCO
Solvent: ClC(Cl)Cl
Product: CC1CCC(C(C)C)C(C(=O)N(CCO)CCO)C1
Reaction time: 2 h

Procedure:
A solution of p-menth-3-oyl chloride (4.0 g., 0.020 moles) in chloroform (30 ml.) was added dropwise to a stirred solution of diethanolamine (4.2 g., 0.044 moles) in chloroform (50 ml.). The reaction mixture goes cloudy and a yellow oil separates out. After 2 hours at room temperature, the yellow oil (upper layer) was separated. Infra red spectographic analysis indicated this to be (HOCH2CH2)2NH2+Cl-. Removal of the chloroform left a viscous oil (6 g.). Thin layer chromatography (CHCl3 and CHCl3 +10% CH3OH) indicated it to consist of one major component and a minor component of larger Rf value. This was separated by column chromatography on neutral alumina (activity 1). Eluting with chloroform (200 ml.) removed the minor component and the major product was eluted from the column with chloroform+5% methanol. The major component was shown to be N,N-bis(2-hydroxyethyl)-p-menthane-3-carboxamide.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]([C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:8].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=1)#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:18]2[CH2:17][CH2:16][C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([C:7]([O:6][CH3:5])=[O:8])=[CH:23][CH:22]=3)([OH:21])[CH2:20][CH2:19]2)=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(CC=O)cc1
Reactant: COC(=O)c1ccc(OCC2(O)CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Temperature: 0 °C
Yield: 39.1 %

Procedure:
Acetic acid (11.5 mL) was added to a dichloromethane solution (450 mL) of the compound (17.7 g) obtained in Step 6 and the compound (19.4 g) obtained in Step 1 of Example 1 at room temperature and the mixture was stirred at the same temperature for thirty minutes. Sodium triacetoxyborohydride (56.6 g) was added to the mixture under cooling with ice-water and the mixture was stirred at the same temperature for thirty minutes and further stirred at room temperature for five hours. The solvent was removed under reduced pressure and insoluble matter (16.1 g) precipitated by adding water (250 mL) and ethyl acetate (250 mL) was collected by filtration. To the obtained insoluble matter (13.0 g) was added water (50 mL) and saturated aqueous sodium hydrogencarbonate solution (150 mL) and the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was crystallized from ether-hexane to obtain the titled compound (10.3 g) as crystals. The physical data of the obtained compound accord with those of the compound of Example 3.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]#[N:18])=[CH:12][C:11]=2[Cl:19])[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[N:23][CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:19][C:11]1[CH:12]=[C:13]([C:17]#[N:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][N:23]=2)[CH:7]=1)=[O:20]
Reactant: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Br)c2)c(Cl)c1
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Nc3ccncn3)c2)c(Cl)c1
Temperature: 140 °C
Yield: 64.9 %

Procedure:
A mixture of N-(2-bromopyridin-4-yl)-2,6-dichloro-4-cyanobenzamide (74 mg, 0.20 mmol), pyrimidin-4-amine (38 mg, 0.40 mmol), Pd2(dba)3 (18 mg, 0.020 mmol), Xantphos (23 mg, 0.040 mmol), Cs2CO3 (131 mg, 0.40 mmol), dioxane (1.2 mL) was heated to 140° C. for 1 hour in a microwave reactor under nitrogen atmosphere. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford the desired product (50 mg, yield: 65%). 1H NMR (500 MHz, MeOH-d4): δ 8.68 (s, 1H), 8.36 (d, J=5.5 Hz, 1H), 8.27 (d, J=5.5 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 2H), 7.71 (d, J=5.5 Hz, 1H), 7.36 (m, 1H). LC-MS (ESI) m/z: 385.0 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15](O)[CH2:16][OH:17].C[Si](O[Si](C)(C)C)(C)C.CCCCCC>C(Cl)CCl.C(OCC)(=O)C>[O:1]1[C:2]2([CH2:3][CH2:4][CH:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[O:17][CH2:16][CH2:15]1
Reactant: OCCO
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Solvent: CCCCCC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Oc1ccc(C2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C

Procedure:
A suspension of 13.7 g of 4-(4-hydroxyphenyl)cyclohexanone in 350 ml of ethylene chloride was heated to reflux for 3 hours with 11.6 ml of ethylene glycol and 1.6 g of Amberlyst® 15 (strongly acidic ion exchang resin, Fluka AG) while stirring and separating water. Thereafter, the brown reaction solution was cooled to room temperature and washed twice with 200 ml of water each time. The aqueous phases were backextracted with 200 ml of methylene chloride. The organic phases were dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The brown crystals obtained (17.4 g) were dissolved in 50 ml of hot ethyl acetate. The solution was treated with 50 ml of hexane and left to crystallize in a water bath. The precipitate was filtered off under suction and dried at 50° C., there being obtained 12.4 g of crude product as brown crystals. Working-up of the mother liquor gave a further 4.8 g of crude product. The crude product was purified by chromatography on silica gel with methylene chloride/acetone (volume ratio firstly 97:3, then 95:5) at 0.4 bar. Recrystallization of the orange, crystalline product from ethyl acetate/hexane (vol. 1:2) gave 15.0 g of 4-(1,4-dioxa-8-spiro[4.5]decyl)phenol as yellow-orange crystals with m.p. 151.7°-152.6° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C@H:9]([C:18]1[O:19]C=CC=1)[C@H:10]([CH3:17])[CH2:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH2:24].C(Cl)(Cl)(Cl)Cl.CC#N>CC#N.[Ru](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[C:18]([OH:19])=[O:24])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: C[C@H](CCC(C)(C)O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: C[C@H](CCC(C)(C)O)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ruthenium(III) chloride (0.031 g, 0.15 mmol) was added to a well-stirred mixture of NalO4 (0.567 g, 2.65 mmol) in water/CCl4/CH3CN (4.5/3/4.5 mL). After 15 minutes of stirring, at 0° C., 2.12e (0.144 g, 0.442 mmol) in MeCN (0.3 mL) was added. After stirring at room temperature for 30 minutes, another 1 equivalent of NalO4 was added and the resulting mixture was stirred for another 20 minutes. The reaction was quenched with water and extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with 20% NaHSO3 aq. solution and brine, dried over MgSO4 and concentrated to give 2.12f (134 mg) which was used in the next step with out purification. MS m/z (M+23) 326.2.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][NH2:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH3:18][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29]([NH:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:30])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1c2ccccc2-c2ccccc21

Procedure:
To 3.88 g (0.02 mol of 9-fluorenemethyl amine in 100 ml of ethyl acetate was added, in one portion, 4.06 g (0.02 mol) of 2,6-diisopropylphenyl isocyanate in 100 ml of ethyl acetate.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C1C=NC2N(O)N=NC=2C=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:50]([N:52]([CH2:67][CH3:68])[CH2:53][CH2:54][O:55][C:56]1[CH:61]=[CH:60][C:59]([CH:62]([NH2:66])[CH2:63][CH2:64][CH3:65])=[CH:58][CH:57]=1)[CH3:51]>CN(C=O)C.C(OCC)(=O)C>[C:1]([CH2:3][C:4]([NH:66][CH:62]([C:59]1[CH:58]=[CH:57][C:56]([O:55][CH2:54][CH2:53][N:52]([CH2:67][CH3:68])[CH2:50][CH3:51])=[CH:61][CH:60]=1)[CH2:63][CH2:64][CH3:65])=[O:6])#[N:2]
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
To an ice cooled solution of cyanoacetic acid (37 mg, 0.43 mmol) in DMF (2 mL) was added 7-aza-1-hydroxybenzotriazole (HOAt; 59 mg, 0.43 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 165 mg, 0.43 mmol), diisopropylethylamine (DIPEA; 167 μL, 0.958 mmol) and 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-amine (25; 115 mg, 0.43 mmol). The resulting mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with sat. aqueous NaHCO3 (2×) and sat. brine, dried over sodium sulfate, and concentrated to a thick yellow oil. Purification by flash silica gel column chromatography, eluting with 5:95 methanol/dichloromethane, afforded 29 (116 mg, 80%) as a yellow oil: MS (ES+) m/z 332.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:24])(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Intermediate 17-acetoxy-heptadecanol (220 mg, 0.7 mmol) and CBr4 (302 mg, 0.91 mmol) were dissolved in CH2Cl2 (2 ml) and a solution of Ph3P (238 mg, 0.91 mmol) in CH2Cl2 (1.5 ml) was added via cannula at 0° C. The reaction was stirred at 0° C. for 2 h and then quenched with MeOH (0.3 ml), stirred for additional 10 min at room temperature, diluted with EtOAc and washed with aqueous NaHCO3 solution. The organic extract was dried over Na2SO4 and evaporated. Silica gel chromatography in hexane-EtOAc (99:1, 95:5) provided 261 mg (99%) of 17-acetoxy-heptadecyl bromide (40).