Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH:21]3[OH:36])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=2[CH:54]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH:21]3[O:36][CH2:38][C:39]3[CH:40]=[CH:41][C:42]4[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=4[CH:54]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)cc3)cc21

Procedure:
Analogously to Method D, 0.980 g of benzyl 4-[4-(1-tert-butoxycarbonylpyrrolidin-3(S)-yloxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 0.572 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.14 (1:1 EtOAc-heptane). Rt=5.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:30]([O:37][NH:38][C:14](=[O:15])[CH2:13][C:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH2:27][CH3:28])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(CCCCc1ccccc1)(CC(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(CCCCc1ccccc1)(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
To a solution of 0.4 g (0.99 mmol) of 3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanoic acid in 50 mL of methylene chloride is added 0.47 g (2.96 mmol, 3 eq) of O-benzyl-hydroxylamine hydrochloride, 0.13 g (0.247 mmol) of HOBT, 0.54 mL (4.94 mmol, 5 eq) of n-Methylmorpholine (NMM), and 0.25 g (1.28 mmol, 1.3 eq) of EDCl. After stirring for 18 hours at 25° C. the reaction is partitioned between methylene chloride and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 then concentrated in vacuo. Purification by flash silica gel chromatography afforded 0.463 g (92%) of N-benzyloxy-3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanamide in the form of a colorless oil.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1.CN(C1C=CC=CN=1)C>[C:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(C)=O)CC1
Yield: 98.6 %

Procedure:
To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at −78° C. Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[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][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=1.[Na+].C(O)C.S(O[CH:45]([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47])(C1C=CC(C)=CC=1)(=O)=O>O>[F:1][C:2]([F:28])([F:29])[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][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH3:51])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-[15-(trifluoromethyl)pentadecylamino]benzoate in 100 ml. ethanol is added 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield the product as colorless crystals.
Reaction SMILES: [N:1]1([C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[C:10](=O)[C:9](=[O:21])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:23][OH:24].N1CCCCC1>CO>[OH:21][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[C:10]=1[N:23]=[O:24]
Reactant: O=C1C=C(N2CCCCC2)c2oc3ccccc3c2C1=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: C1CCNCC1
Product: O=Nc1c(O)cc(N2CCCCC2)c2oc3ccccc3c12

Procedure:
4-Piperidinodibenzofuran-1,2-dione (18.4; 0.062 mol) was added in one portion to a vigorously stirred solution of hydroxylamine hydrochloride (22.9 g; 0.33 mol) and piperidine (28 g; 0.33 mol) in methanol (230 ml) at room temperature. After 1.75 hours the mixture was filtered and the resulting solid washed with water and dried to yield 2-hydroxy-1-nitroso-4-piperidinodibenzofuran as a red-brown solid (3.48 g; 19%), m.pt. 181°-185° C. (decomp 207° C.). ##STR12##
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15].Cl.C(N(CC)CCCN=C=NCC)C.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH2:14][C:13]([F:17])([F:16])[F:12])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 58.1 %

Procedure:
In a solution of 5.00 g of 4-bromo-2-methyl benzoic acid and 3.45 g of 2,2,2-trifluoroethylamine in 30 ml of N,N-dimethylformamide, 5.79 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added with stirring at room temperature, and stirred at the same temperature for 1.5 hour. After the completion of the reaction, 80 ml of water was added, and precipitated crystal was filtered off, washed with water and dried to obtain 4.00 g of the aimed product as white crystal.
Reaction SMILES: [CH2:1]([C:3]([OH:9])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH3:2].S(=O)(=O)(O)O.[CH3:15]O>>[CH2:1]([C:3]([OH:9])([CH2:7][CH3:8])[C:4]([O:6][CH3:15])=[O:5])[CH3:2]
Reactant: CO
Reactant: CCC(O)(CC)C(=O)O
Agent: O=S(=O)(O)O
Product: CCC(O)(CC)C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 2-ethyl-2-hydroxybutyric acid (5.00 g) in methanol (35 mL) was added conc. sulfuric acid (0.25 mL), and the mixture was refluxed at room temperature for 18 hours and then refluxed under heating for 18 hours. After cooling, the reaction mixture was concentrated in vacuo, and the resultant residue was diluted with diethylether. The mixture was washed successively with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. The residue was distilled to give methyl 2-ethyl-2-hydroxybutyrate (3.70 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([Sn](C)(C)C)[CH2:33][CH2:32]2.C(OCC)(=O)C>C1(C)C=CC=CC=1.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.[Cu]I>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[O:11])=[C:2]([C:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=3)[CH:35]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)cc2)c(Br)c1
Reactant: COc1ccc2c(c1)CCC([Sn](C)(C)C)=C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCC(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)cc1)=C2
Temperature: 100 °C
Reaction time: 5 h
Yield: 38.8 %

Procedure:
A suspension of (2-bromo-4-methoxyphenyl)[4-(2-piperidin-1-ylethoxy)phenyl]methanone (570 mg), (6-methoxy-3,4-dihydronaphthalen-2-yl)trimethyltin (542 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg) and copper(I) iodide (25 mg) in toluene (10 ml) was stirred for 5 hours at 100° C. under a nitrogen atmosphere. Ethyl acetate was added thereto, the insoluble material was removed by filtration, the solvent was evaporated in vacuo, and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (263 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C([O:16][C:17]([C:19]1[C:20](Cl)=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=O)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:20]2[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=2[C:17]1=[O:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCOC(=O)CCNC1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C2CCCC2)c2nc(SC)ncc2C1=O
Reaction time: 16 h

Procedure:
3-Cyclopentylamino-propionic acid ethyl ester (1.0 g, 5.4 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.25 g, 5.4 mmol) were combined in DCM (10 mL) and diisopropylethylamine (0.83 g, 6.5 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided the title compound that was directly carried on to the next step. Sodium (25 wt % dispersion in paraffin wax, 0.25 g, 6.0 mmol) was added to t-butanol (5.0 mL) at rt. After 10 minutes, a solution of 4-[cyclopentyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 5.4 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.26 g (14%). 1H-NMR (400 MHz, CDCl3:) 5 ppm 12.0 (br s, 1H), 8.20 (s, 1H), 5.10-5.18 (m, 1H), 4.26-4.31 (m, 3H), 3.72 (q, 2H, J=7.0 Hz), 2.50 (s, 3H), 1.63-1.86 (m, 5H), 1.20-1.35 (m, 5H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].O.Cl>N1C=CC=CC=1>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:12]2[CH2:13][CH2:14][CH:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]2)[CH:22]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCCC1CCC(c2ccccc2-c2cccc(O)c2)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC1CCC(c2ccccc2-c2cccc(OC(=O)CC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
Under a nitrogen atmosphere, 1.6 g of propanoyl chloride was added to 5.0 g of 3-((4-propylcyclohexyl)phenyl)phenol (1) dissolved in 10 mL (mili-litter) of pyridine under cooling with iced water, and after completing dropwise addition, the mixture was stirred at ambient temperature for 2 hours. The resulting solution was added to 20 mL of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.42 g of 3-((4-propylcyclohexyl)phenyl)phenyl propanoate (2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([NH:16][NH2:17])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccccc1OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOc1ccccc1C(=O)NN
Temperature: 25 °C

Procedure:
Ethyl 2-ethoxybenzoate (100 g, 128.7 mmol) and hydrazine hydrate (100%, 25 ml, 128.7 mmol) are dissolved in 200 ml of ethanol and heated under reflux for 5 hours. A further 12.5 ml (64.3 mmol) of hydrazine hydrate are added and the reaction mixture is heated under reflux for a further 7 hours. For working up, the reaction mixture is extensively concentrated and then stirred with 300 ml of cyclohexane at room temperature. After cooling to 0° C., the crystals are filtered off with suction, washed twice with 50 ml of cold cyclohexane each time and finally dried in a vacuum oven at 35° C. and 300 mbar overnight.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C>[OH:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
Nitric acid (95%, 42 g, 0.62 mol) was added dropwise (internal temperature kept below 5° C.) to a solution of methyl 3-hydroxy-4-methoxybenzoate (96.5%, 100 g, 0.53 mol) and acetic acid (250 mL) at 0° C. After 10 min at 0° C., a large amount of precipitate had formed and was collected by filtration. The filter cake was washed with water (100 mL×2), and then the crude product was recrystallized from methanol (40 mL) to give 33 g of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 7.49 (d, 1H), 7.22 (d, 1H), 3.93 (s, 3H), 3.76 (s, 3H); MS (ESI): 227.9.
Reaction SMILES: [CH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.[Li]C(CC)C.CN(CCN(C)C)C.[Si:20](Cl)([CH3:23])([CH3:22])[CH3:21]>>[CH:1]1([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1
Reactant: C1=CCC=CC1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Product: C[Si](C)(C)C1C=CCC=C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
1,4-Cyclohexadiene (0.47 mL, 5 mmol, 1 eq.) was dissolved in TBF (8 mL), cooled to −78° C. and s-BuLi (4.5 mL, 1.2 M, 5.5 mmol, 1.1 eq.) was added slowly. The resulting solution was treated with TMEDA (0.77 mL, 5 mmol, 1 eq.) and the reaction was allowed to warm to −45° C. over 2 hours. Me3SiCl (0.7 mL, 5.5 mmol, 1.1 eq.) was added, the reaction mixture was stirred for 1 hour at room temperature and then quenched with H2O and Et2O. The organic layer was separated and washed with H2O (2×30 mL), (aq) sat. NH4Cl (30 mL), brine (30 mL) and dried over MgSO4. Removal of the solvent in vacuo and distillation using Kugelrohr apparatus (30 mbar, 70° C.) afforded the product as colourless oil (0.53 g, 3.47 mmol, 70% yield): 1H NMR (400 MHz, CDCl3), δ 5.56 (2H, m, H-3), 5.55 (2H, m, H-4), 2.69 (2H, m, H-5), 2.22 (1H, m, H-2), 0.03 (9H, s, H-1); 13C NMR (100 MHz, CDCl3) δ 126.31 (C-3), 121.33 (C-4), 31.52 (C-5), 26.40 (C-2), −3.55 (C-1); IR (CDCl3, cm−1) 3027 (m, C—H), 2959 (m, C—H), 1622 (w, C═C), 743, (m, C—H); MS (FI+, m/z), 152.10 [M].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28](F)[CH:29]=1)[C:25]#[N:26]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][C:28]1[CH:29]=[C:22]([F:21])[CH:23]=[C:24]([C:25]#[N:26])[CH:27]=1
Reactant: CCOC(=O)Cc1ccc(Cl)c(O)c1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(F)cc(C#N)c2)c1
Temperature: 120 °C

Procedure:
To a solution of ethyl 4-chloro-3-hydroxyphenylacetate (34a; 1.4 g; 6.5 mmol) and NMP (13 mL) was added potassium carbonate (2.7 g; 19.6 mmol) and 1.2 g of 3,5-difluorobenzonitrile (1.2 g; 8.5 mmol). The reaction mixture was heated to 120° C. and monitored by TLC. After 3.5 h an additional 0.9 g of K2CO3 was added and at 5.5 h an additional 0.9 g of K2CO3 and 0.3 g of 3,5-difluorobenzonitrile was added. After 8 h of heating the reaction was cooled to rt and the reaction mixture was filtered through a pad of CELITE® and the solid cake was washed well with EtOAc. The filtrate was washed with 2 portions of 2N HCl 1N NaOH, water and brine. The organic extract was dried (MgSO4), filtered and evaporated to yield 1.3 g of the ether 35a.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])S[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:5]1=2)[CH3:2].Cl.OO[S:22]([O-:24])=[O:23].[K+]>CO.O>[CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:22](=[O:24])(=[O:23])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:14][C:5]1=2)[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCNC1CC(C)(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
A solution of 5,6-dihydro-4-ethylamino-6,6-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide (3.95 g, 0.013 mol) in methanol (85 ml) was acidified with 6.25N methanolic hydrogen chloride (2.1 ml). With stirring, a solution of `Oxone` (11.68 g, 0.019 mol) in water (65 ml) was added 15 minutes. After stirring at ambient temperature for 17.5 hours, the mixture was filtered and the solid was washed with methanol. The combined filtrate and washings were concentrated in vacuo below 55° C. to remove methanol and the cloudy aqueous solution was basified with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (150 ml and 2×100 ml), and the combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo. The amorphous residue was converted to the crystalline hydrochloride salt using ethanolic hydrogen chloride to yield 2.16 g (44%) of analytically pure product melting at 255°-255.5° C.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH3:27])[CH:11]=1.CN(CN(C)C)C>O>[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18](=[O:26])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH2:1])=[C:12]([CH3:27])[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)c(C(=O)Cc2ccccc2)cc1OC
Agent: CN(C)CN(C)C
Solvent: O
Product: C=C(C(=O)c1cc(OC)c(OC)cc1C)c1ccccc1

Procedure:
240 ml of acetic anhydride are added dropwise in the course of 20 minutes at room temperature, while stirring, to a mixture of 135.0 g (0.50 mole) of 1-(4,5-dimethoxy-2-methylphenyl)-2-phenyl-1-ethanone and 250 ml of bis-(di-methylamino)-methane, the temperature being held at 40° by cooling with an ice bath. The reaction mixture is stirred at 40° for a further hour and is then poured into a 2 kg mixture of ice and water, during which the crude product crystallises. After stirring for 15 minutes at 15° the crude product is filtered off, the filtered material is washed with cold water and then dried for 18 hours at 30° under approximately 100 mbar, yielding 1-(4,5-dimethoxy-2-methylphenyl)-2-phenyl-2-propen-1-one having a melting point of 57°-59°.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([CH3:37])=O.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[C@@H:17]([O:18][CH2:34][S:35][CH3:37])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
3.0 g N6-Benzoyl-5′-O-tert-butyldimethylsilyl-2′-deoxyadenosine (5a) (6.38 mmol) was dissolved in a mixture consisting of 11.96 mL DMSO, 5.46 mL acetic acid, and 17.55 mL acetic anhydride and stirred at room temperature for 48 h. The reaction mixture was then neutralized treating with a sufficient amount of saturated NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extract was then washed with a saturated NaHCO3 solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The resultant yellowish oil was then purified on silica gel column (Hex: EtOAc/1:1 to 1:4) to obtain the product N6-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (6a) as white powder in 71% yield (2.4 g, Rf0.6, EtOAc: hex/7:3). HR-MS: obs. m/z 530.2273, calcd. for C25H36O4N5SiS 530.2257 [M+H]+. 1H-NMR (CDCl3): δH 9.00 (s, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 8.05 (d, J=7.6 Hz, 2H), 7.62 (m, 1H), 7.55 (m, 2H), 6.55 (t, J=7.19 Hz, 1H), 4.73 (m, 2H), 4.68 (m, 1H), 4.24 (m, 1H), 3.88 (dd, J=11.19, 3.19 Hz, 1H), 2.74-2.66 (m, 2H), 2.35 (s, 3H), 0.94 (s, 9H) and 0.13 (s, δH) ppm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([B:14]([CH:16]([O:23][CH:24]([B:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([Cl:40])[CH:34]=2)[OH:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH:10]=[CH:11][C:12]=1[CH3:13]>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([B:14]([CH:16]([O:23][CH:24]([B:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([Cl:40])[CH:34]=2)[O:32][CH2:4][CH2:3][NH:2][CH3:1])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:5][CH2:4][CH2:3][NH:2][CH3:1])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1ccc(B(O)C(OC(B(O)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl
Reactant: CNCCO
Solvent: CCO
Product: CNCCOB(c1ccc(C)c(Cl)c1)C(OC(B(OCCNC)c1ccc(C)c(Cl)c1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (31 mg) was obtained by allowing 32 mg of N-methylethanolamine to act on 99 mg of bis(4,4′-(3-chloro-4-methylphenyl-hydroxyboryl)benzyl) ether in 0.5 mL of ethanol.