Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:3]1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:16]([O:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:3]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCO[PH](=O)CCCCC1=CC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO[PH](=O)CCCCC1=CC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution of (±)-ethyl (3-hydroxycyclopentenyl)butylphosphinate (7) (3.66 g, 15.8 mmol) in anhydrous DMF (100 cm3) was treated with t-butyldimethylsilyl chloride (2.62 g, 17.4 mmol), triethylamine (4.55 cm3) and DMAP (425 mg). The reaction mixture was stirred at room temperature for 16 h, after which time the solvent was removed in vacuo. The residue was partitioned between DCM (50 cm3) and water (30 cm3) and the aqueous layer was further extracted with DCM (3×20 cm3). The combined organic layers were washed with water (2×30 cm3) and brine (40 cm3), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was purified by short column vacuum chromatography on silica gel (15% ethanol/ethyl acetate) to yield the desired title compound (8) as a colourless oil (3.35 g, 61%): 1H-NMR (300 MHz, CDCl3) δH 0.09 (6H, s, Si(CH3)2), 0.89 (9H, s, SiC(CH3)3), 0.91 and 0.93 (3H, 2×d, J=7.2 and 7.2 Hz, PCH2CH2CH2CH3), 1.22-1.83 (9H, m, POCH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3), 2.26-2.72 (4H, m, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′), 3.84-4.19 (2H, m, POCH2CH3), 4.97 (1H, m, C(3)—H), 6.50 and 6.54 (1H, 2×d, J=9.6 and 9.6 Hz, C(2)—H); 13C-NMR (75 MHz, CDCl3) δC −4.81 and −4.74 (d, 6JPC=5.7 Hz, Si(CH3)2), 13.48 (s, PCH2CH2CH2CH3), 16.43 and 16.51 (d, 6JPC=6.23 Hz, SiC(CH3)3), 18.08 (s, POCH2CH3), 23.43 (t, 2JPC=3.15 and 3.15 Hz, PCH2CH2CH2CH3), 23.69 and 23.90 (d, 3JPC=15.90 Hz, PCH2CH2CH2CH3), 25.75 (s, SiC(CH3)3), 27.22 and 28.54 (2×d, JPC=99.6 and 99.0 Hz, PCH2CH2CH2CH3), 31.55 and 31.70 (2×d, 3JPC=11.63 and 11.63 Hz, C(4)), 34.54 (t, 2JPC=8.25 and 8.55 Hz, C(5)), 60.15 (2×d, 2JPOC=6.30 and 6.83 Hz, POCH2CH3), 77.97 and 78.22 (d, 3JPC=18.45 Hz, C(3)), 136.64 and 138.24 (2×d, JPC=119.78 and 120.08 Hz, C(1)), 148.51 (d, 2JPC=9.38 Hz, C(2)); 31P-NMR (121 MHz, CDCl3) δP 42.77 and 43.15; MS (CI, CH4) m/z 347.2 (16%) (MH+), 215.1 (100), 375.3 (44), 289.2 (39). Synthesis of (±)-cis-ethyl [3(t-butyldimethylsilyloxy)cyclopentanyl]butylphosphinate (9)
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:10][C:4]1([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1
Reactant: CC(C)(C)OO
Reactant: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CC(=O)CC(C)(OOC(C)(C)C)C1

Procedure:
A reaction mixture of 62.2 g. (0.45 mole) of isophorone, 104 g. (0.9 mole) of 78% t-butyl hydroperoxide and 32.4 g. of Amberlyst 15® sulfonic acid type ion-exchange resin was stirred at 40° C. for 48 hours and at 50° C. for one hour. The ion-exchange resin was separated by filtration, the filtrate diluted with pentane and the pentane solution washed with water and sodium bisulfite solution. After drying over anhydrous magnesium sulfate, the pentane was removed under reduced pressure. The recovered product weighed 74.7 g. (72.8% of the calculated amount). The infrared spectrum had a strong absorption band in the 880 cm-1 region usually associated with t-butylperoxy groups. Iodometric assay showed the presence of active oxygen.
Reaction SMILES: [Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)[CH3:3].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:16])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Br)c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-bromoethyl)benzoic acid (50.7 mg, 0.221 mmol) in methylene chloride (4.0 mL, 62 mmol) was added 2.0 M of oxalyl chloride in methylene chloride (0.25 mL) followed by 3 drops of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for one hour, and then evaporated in vacuo to remove dichloromethane and excess oxalyl chloride. The crude product was carried forward without purification.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[N:5]([CH2:8][C@@H:9]1[C@H:13]([OH:14])[C@H:12]([OH:15])[C@H:11]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[O:10]1)=[N+]=[N-]>C(O)C.[Pd]>[CH2-:1][C:2]([CH3:4])=[O:3].[NH2:5][CH2:8][C@@H:9]1[C@H:13]([OH:14])[C@H:12]([OH:15])[C@H:11]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[O:10]1
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cnc3c(C4CCOC4)ncnc32)[C@@H](O)[C@H]1O
Agent: [Pd]
Agent: [CH2-]C(C)=O
Solvent: CCO
Product: NC[C@H]1O[C@@H](n2cnc3c(C4CCOC4)ncnc32)[C@@H](O)[C@H]1O

Procedure:
10% Pd/C (100 mg) was added to a solution of (4S,2R,3R,5R)-2-azidomethyl-5-[6-(tetrahydrofuran-3-yl)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide, a compound of formula (10) (314 mg), in ethanol (20 mL) and stirred under an atmosphere of hydrogen at room temperature for 16 hours. The catalyst was removed by filtration, and the solvent evaporated from the filtrate to give (4S,2R,3R,5R)-2-aminomethyl-5-[6-(tetrahydrofuran-3-yl)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide, a compound of formula (11).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:17][N:8]1[C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:10]=[C:9]1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2[nH]c(C(F)(F)F)nc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
5-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (4.45 g, 19.1 mmol, 1.0 eq.), K2CO3 (3.2 g, 23.0 mmol, 1.2 eq.) and methyliodide (1.2 ml, 19.1 mmol, 1.0 eq.) were dissolved in DMF (anhydrous, 50 ml). The reaction was stirred at RT for 2 h. TLC showed mostly starting material. The mixture was stirred at RT for another 16 h. The DMF was removed in vacuo and the residue redissolved in a minimum of hot EtOAc and recrystallized (gave mixture). Crystals and mother liquor were combined and evaporated down. Purification by column chromatography (0-25% EtOAc/Hex) yielded 1-methyl-5-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (1 g) and 1-methyl-6-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole. Structures confirmed by NOESY NMR.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].O1CCCC1.S([O-])([O-])(=O)=S.[Na+:30].[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[Na+:30].[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=CCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
To a cooled solution (0° C.) of 16-hydroxyhexadecanoic acid (800 mg, 2.9 mmol) in dichloromethane (10 ml) and tetrahydrofurane (20 ml) Dess-Martin periodinane (1636 mg, 3.7 mmol) was added at 0° C. The mixture was stirred for 3.5 hrs at 0° C. and 2.5 hrs at room temperature under Ar-atmosphere. Then a 15%-solution of sodium thiosulfate in saturated sodium bicarbonate solution was added, the mixture was stirred at room temperature for 1.5 hrs. Intermediate 1 was extracted with diethylether, after drying over sodium sulfate the organic layer was evaporated to dryness and purified by column chromatography using silica gel as separating agent and a solvent mixture of toluene/ethylacetate. Yield: 34% (white solid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)cc1F
Yield: 46.5 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (100 g, 373 mmol) in DMF (190 mL) and water (10 mL) was added sodium cyanide (22 g, 448 mmol). The reaction was heated to 70 degrees Celsius for 3 hours, concentrated to a volume of 100 mL, and then the solution was diluted with 100 mL of ethyl acetate. After the solids were removed by filtration, water (250 mL) was added and the layers were separated. The organic layer was further washed with 3×100 mL of water. The organic layer was dried over MgSO4, filtered to remove solids, and then concentrated. Purification by distillation gave the desired product (37.124 g, 46%). B.P.=72-75 degrees Celsius.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:15][O:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH2:18][NH2:19].Cl>C1C=CC=CC=1>[ClH:26].[CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:19][CH2:18][CH:17]([O:16][CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(CN)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(SC(C)C)cc1
Agent: Cl
Solvent: c1ccccc1
Product: COC(CNC(C)Cc1ccc(SC(C)C)cc1)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
1-(4-Isopropylthiophenyl)propan-2-one (4.16 g) and 2-methoxy-2-(3-chlorophenyl)ethanamine (3.71 g) in dry benzene (100 ml) was boiled under reflux for two hours in an apparatus incorporating a water trap. The solution was cooled and the solvent removed under reduced pressure. The residue was dissolved in ethanol (80 ml), cooled to less than 10° C. and treated portionwise with sodium borohydride (3.0 g) over 30 minutes. The mixture was stirred for one hour and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane, washed with water, dried over magnesium sulphate, filtered and evaporated. Chromatography of the residue on silica gel in 2-4% methanol-dichloromethane gave an oil which was converted to its hydrochloride salt by addition of ethereal hydrogen chloride. Crystallisation from methanol-ethyl acetate-hexane gave the title compound, m.p. 133°-9° C., as a 70:30 mixture of diastereoisomers.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][C@H:14]3[CH2:18][O:17][C:16](=[O:19])[NH:15]3)[CH:11]=2)[NH:6][CH:5]=1)#N.[CH3:20][NH:21][CH3:22]>[Pd]>[CH3:20][N:21]([CH2:1][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][C@H:14]3[CH2:18][O:17][C:16](=[O:19])[NH:15]3)[CH:11]=2)[NH:6][CH:5]=1)[CH3:22]
Reactant: N#CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Reactant: CNC
Agent: [Pd]
Product: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Reaction time: 24 h

Procedure:
A suspension of the product from step (c) (1.3 g) and 10% w/w Pd/C (1.0 g) in 30% w/w ethanolic dimethylamine (25 ml) was hydrogenated for 24 hours and filtered through Hyflo. Fresh Pd/C (0.7 g) and ethanolic dimethylamine (5 ml) were added to the filtrate and hydrogenation continued for a further 16 hours. The mixture was filtered through a silica column using DCM/EtOH/NH4OH (40:8:1) as eluant to give the desired product as a colourless foam (0.3 g). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].[C:12]1([C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])[OH:13].O=O>CO.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:14]1(=[O:15])[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[O:13].[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10]
Reactant: Oc1ccccc1O
Agent: [Cu+2]
Agent: CNCCCCCCN(C)C
Agent: O=O
Solvent: CO
Solvent: O
Product: O=C1C=CC=CC1=O

Procedure:
About 37.93 g (0.24 mol) trimethyl-hexamethylene-diamine and about 0.6 g (0.0024 mol) copper sulfate pentahydrate were dissolved in about 400 mL of methanol. About 26.4 g (0.24 mol) of catechol (chemical name 1,2-dihydroxybenzene) acting as both the quinone precursor and catalyst was added to the reactant mixture. A gentle stream of oxygen at a flow rate of about 50 cc/min was then passed through the reaction mixture for about three hours, while maintaining the reaction temperature around 20°-25 ° C. At the end of three hours the oxygen supply was cut off and the reaction mixture was concentrated under vacuum using a rotary evaporator. The o-benzoquinone-trimethyl-hexamethylene-diamine polymer was precipitated in excess water, washed extensively and dried under vacuum for about 6 hours at a temperature of about 30° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:6][C@@H:5]2[C:7]([CH2:11][O:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1.N1C=CC=CC=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:40](=[O:41])([O:42][CH3:43])[O:10][C@@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:32])([CH3:1])[O:3]2)[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8]1
Reactant: COC(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@@H]2O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)O[C@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 0 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-1) (1.44 g, 3.36 mmol, 1.0 equiv) as dissolved in DCM (11.2 mL). Pyridine (0.489 mL, 6.05 mmol, 1.8 equiv) was added and the mixture stirred at 0° C. After 1 hour DMAP (164 mg, 1.34 mmol, 0.4 equiv) was added followed by methyl chloroformate (1.04 mL, 13.44 mmol, 4 equiv). The resulting mixture was stirred 12 h, and the temperature was allowed to slowly increase to 23° C. The reaction was partitioned between DCM and water, and the organic layer was separated and washed with water, dried (MgSO4), and concentrated to yield (3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methyl carbonate (1-2) as a white foam. 1H NMR (00 MHz, CDCl3) δ 7.21-7.47 (m, 15H), 6.03 (d, 1H, J=3.0 Hz), 5.32 (brm, 1H), 4.93 (t, 1H, J=9 Hz), 4.85 (d, 1H, J=10 Hz), 3.96 (d, 1H, J=24.5 Hz), 3.83 (s, 3H), 3.67 (d, 1H, J=24.5 Hz), 1.36 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C(O)C>[CH2:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCCCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Reaction time: 2 h
Yield: 98.9 %

Procedure:
First, 2.7 g of sodium ethoxide and 100 ml of dry ethanol were placed in a 200 ml flask. Then, 20 ml of an ethanol solution containing 7 g of diethyl malonate was added dropwise to the reaction mixture at 60° C., and the resultant reaction mixture was stirred for 2 hours. Then, 20 ml of an ethanol solution containing 9 g of 1-bromo-6-benzyloxyhexane was added dropwise to the reaction mixture, and the resultant reaction mixture was stirred under reflux for 3 hours. The reaction mixture was poured into diluted hydrochloric acid, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 11.5 g of diethyl 2-(6-benzyloxyhexyl)malonate (Y: 98%). The compound thus obtained had a purity of 86.3% by GC.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].F[C:18]1C=CC=C(C=C)C=1O>>[C:1]([Si:5]([O:8][C:9]1[C:14]([CH:15]=[CH2:18])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reactant: C=Cc1cccc(F)c1O
Product: C=Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared in an analogous way to tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane in Step A of Intermediate J using 2-fluoro-6-vinylphenol. 1H NMR (500 MHz, CDCl3) δ 7.26 (m, 1H), 7.03 (dd, J=17.8, 11.1, 1H), 6.96 (m, 1H), 6.89-6.81 (m, 1H), 5.68 (dd, J=17.8, 1.3, 1H), 5.34-5.24 (m, 1H), 1.02 (s, 9H), 0.19 (d, J=2.4, 6H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:13]=[N:12]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2ccccc2C=O)cn1
Temperature: 150 °C
Yield: 97.2 %

Procedure:
A microwave vial (20 ml) was charged with 2-bromo-benzaldehyde (208 mg, 1.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (222 mg, 1.2 mmol) and 8 ml of acetonitrile. To this mixture was added 2.4 ml of aqueous sodium carbonate (1M), followed by 50 mg of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide crude material which was purified by ISCO to give 181 mg of 2-(1-methyl-1H-pyrazol-4-yl)-benzaldehyde (96% yield).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[Cl:8][C:9]1[C:17]([Cl:18])=[C:16]2[C:12]([CH2:13][C:14]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]2=[O:19])=[CH:11][C:10]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:8][C:9]1[C:17]([Cl:18])=[C:16]2[C:12]([CH2:13][C:14]([CH3:26])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:15]2=[O:19])=[CH:11][C:10]=1[O:27][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Reaction time: 18 h

Procedure:
A solution containing chloroacetone (11 g., 0.12 mole) and potassium iodide (0.5 g.) in acetone (30 ml) is stored in the dark for 18 hours then added in portions over a one hour period to a stirred refluxing mixture of 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone (24.5 g., 0.08 mole) and potassium carbonate (11.0 g., 0.08 mole) in acetone. The acetone is distilled at reduced pressure and the residue slurried with ether and water to give 6,7-dichloro-2-methyl-5-(2-oxopropoxy)-2-phenyl-1-indanone which melts at 144° C. after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])[OH:12])=[O:5])[CH3:2].O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][CH3:26])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccccc2OC)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate C, 3.5 g, 8.4 mmol) in dioxane (80 ml)/H2O (20 ml) were added 2-methoxy-phenyl boronic acid (2.0 g, 13.2 mmol), K2CO3 (3 g, 21.7 mmol). The mixture was degassed for 5 min and then Pd(PPh3)4 (1.7 g, 1.5 mmol) was added. The mixture was stirred at 100° C. for 2 h to give a complete conversion. Dioxane was removed under reduced pressure. The residual material was dissolved in EtOAc and extracted with brine. The aqueous layer was washed with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The product was fixed on silica gel and purified by flash chromatography (silica gel, solvent: CH2Cl2/EtOAc, 100:0→80:20) to give the title compound as a yellow foam. tR: 1.27 min (LC-MS 2); ESI-MS 433.3 [M+H]+ (LC-MS 2). 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.56-7.48 (m, 2H), 7.29-7.05 (m, 3H), 7.34-7.29 (m, 1H), 7.10-7.96 (m, 1H), 6.94-6.91 (m, 1H), 6.52 (d, 1H), 4.58-4.52 (m, 1H), 4.24 (q, 2H), 3.73/3.68 (s, 3H), 2.16 (s, 3H), 1.27 (t, 3H), 1.05 (d, 3H), 0.58 (d, 3H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(F)cc2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccc(F)cc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(4-fluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.23 g, 0.93 mmol) and hydrazine hydrate (0.046 g, 0.91 mmol) was heated at 120° C. for 3.5 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.22 g, 96%) as white solid, which was used in the next step without further purification. MS m/e: 253 (M+H+).