Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[OH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:19][CH2:20][N:21]([C:37](=[O:38])[C:36]([OH:35])([CH3:41])[CH3:40])[CH2:22][CH2:23]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCNCC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a mixture of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ol (150 mg, 0.32 mmol), 2-hydroxyisobutyric acid (41 mg, 0.39 mmol) and DIPEA (68 μL, 0.39 mmol) in DCM (2 mL) was added HATU (149 mg, 0.39 mmol). The resulting mixture was allowed to stir at r.t. for 18 h then diluted with DCM and washed with sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 790 (60 mg, 34%). LCMS (method I): RT 3.09 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.63 (1 H, m), 7.27-7.23 (2 H, m), 5.84 (1 H, s), 5.42 (1 H, s), 4.25 (6 H, brd s), 3.98 (3 H, s), 3.77 (4 H, t, J=4.55 Hz), 3.60 (1 H, brd s), 3.2-3.24 (3 H, m), 2.11-2.10 (2 H, m), 2.06-1.94 (2 H, m), 1.38-1.30 (9 H, m)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: CCCI
Reactant: CS(=O)(=O)c1cc(F)cc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCN1CCC(c2cc(F)cc(S(C)(=O)=O)c2)CC1
Temperature: 150 °C
Yield: 46.5 %

Procedure:
To a solution of 4-[3-fluoro-5-(methylsulfonyl)phenyl]piperidine (0.5 g, 1.94 mmol) in acetonitrile (5 ml) was added potassium carbonate (0.53 g, 3.83 mmol) and 1-iodopropane (0.189 ml, 1.94 mmol) and the mixture was heated with microwave irradiation for 20 min at 150° C. The mixture was cooled to ambient temperature and water (50 ml) was added. The aqueous residue was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried, concentrated, and purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.27 g, 46%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 187-189° C. MS m/z (relative intensity, 70 eV) 299 (M+, 3), 271 (15), 270 (bp), 147 (5) 133 (5).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:25].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N+:15]([O-:43])=[CH:16][CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:9]=2[C:8]1=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2c(-c3ccccc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C1c2c(-c3ccccc3)cc[n+]([O-])c2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (729 mg) was dissolved in methylene chloride (10 mL) and 3-chloroperbenzoic acid (524 mg) was added to the solution. The resulting mixture was then stirred at room temperature for 24 hours. The reaction mixture was purified on a silica gel column chromatography (ethyl acetate:methanol=5:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine 10-oxide (411 mg, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:17])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C(Cl)(Cl)Cl.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>[CH3:17][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:12]=2[S:13][C:14]2[C:5]1=[CH:4][CH:3]=[C:2]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:14][CH:15]=1)[CH:15]=2
Reactant: CN1c2ccc(Br)cc2Sc2cc(Br)ccc21
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CN1c2ccc(-c3ccccc3)cc2Sc2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g (6.7 mmol) of 3,7-dibromo-10-methylphenothiazine (C. Bodea and M. Terdic, Acad. Rep. Rom. 1962, 13, 81-87), 1.85 g (14.9 mmol) of 98% phenylboronic acid, 0.11 g (0.14 mmol) of bis(triphenylphosphine)palladium dichloride and 1.03 g (7.4 mmol) of potassium carbonate were heated to boiling (75° C.) under reflux under nitrogen for 5 hours in 55 ml of dimethoxyethane and 28 ml of water. The reaction mixture was cooled to room temperature and stirred further overnight. The precipitate was filtered off with suction, washed successively with 125 ml of ethanol and hot water and dried at 70° C. under reduced pressure. The crude product (2.30 g) was heated to boiling under reflux in cyclohexane for two hours. After the hot suspension had been filtered, the residue was dried, dissolved in 40 ml of methylene chloride and filtered through a silica-gel-filled glass fit. After the solvent had been removed, 1.05 g (43% of theory) of light yellow, analytically pure solid having a melting point of 239-241° C. were obtained, whose solution in chloroform fluoresced at λ=464 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([C:11]3[CH:18]=[CH:17][C:14]([CH3:15])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-methylbenzaldehyde using the method described in Example 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N+]([C:26]([CH3:34])=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-])=O>>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:26]1[CH3:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(=Cc1ccccc1)[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Cc1c(-c2ccccc2)c2c(n1Cc1ccccc1)CCNC2

Procedure:
The title compound (89.4 mg) was prepared from 0.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 272 μL of benzylamine, and 0.41 g of (2-nitro-propenyl)-benzene. MS (ESI): exact mass calculated for C21H22N2, 302.18; found, m/z 303.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.41-7.36 (m, 2H), 7.35-7.30 (m, 2H), 7.28-7.21 (m, 4H), 7.05-7.01 (m, 2H), 5.16 (s, 2H), 4.18 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.89 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1)=O.[O:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3](/[CH:1]=[C:24]2/[C:23](=[O:25])[NH:22][C:21](=[O:26])[O:20]/2)[CH:4]=1
Reactant: O=Cc1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: O=C1COC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)/C(=C/c2cccc(-c3ccccc3OC(F)(F)F)c2)O1

Procedure:
The title compound was prepared by reacting 3-formyl-(2′-trifluoromethoxy-1,1′-biphenyl) (from Example 56, Step A) with 2,4-oxazolidinedione in toluene in the presence of piperidine and benzoic acid as described in Example 56, Step B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH2:19][OH:20])[N:17]=[CH:18][C:13]=3[CH2:12][CH:11](C)[C:10]2=[O:22])=[CH:4][CH:3]=1.[C:23]([N:27]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2B(O)O)=[N:30][N:29]=[N:28]1)([CH3:26])([CH3:25])[CH3:24].[C:41]([O-])([O-])=O.[Na+].[Na+].CCO>C(Cl)Cl.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.C1(C)C=CC=CC=1>[OH:20][CH2:19][C:16]1[N:17]=[C:18]([CH3:41])[C:13]2[CH2:12][CH2:11][C:10](=[O:22])[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]4[N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:28]=[N:29][N:30]=4)=[CH:7][CH:6]=3)[C:14]=2[N:15]=1
Reactant: O=C([O-])[O-]
Reactant: CC1Cc2cnc(CO)nc2N(Cc2ccc(Br)cc2)C1=O
Reactant: CC(C)(C)n1nnnc1-c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc(CO)nc2c1CCC(=O)N2Cc1ccc(-c2ccccc2-c2nnnn2C(C)(C)C)cc1
Yield: 90 %

Procedure:
A mixture of 8-[(4-bromophenyl)methyl]-2-hydroxymethyl-6-methyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (0.95 g, 2.62 mmol), 2-[(1-tert-butyl)-1H-tetrazol-5-yl]phenylboronic acid (0.72 g, 2.90 mmol) (prepared according to J. W. Ellingboe, et al. U.S. Pat. No. 5,149,699), 2M Na2CO3 (5.5 mL), tetrakis(triphenylphosphine)palladium(0) (100 tug, 0.086 mmol), EtOH (3 mL)and toluene (16 mL) was heated under reflux for 20 h. The mixture was diluted with CH2Cl2 and the layers were separated. The organic phase was dried (MgSO4) and concentrated to give an orange oil. Purification by flash chromatography (4% MeOH/CH2Cl2) gave 1.20 g (90%) of product as a colorless foam.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]1(C)[C:9]([C:14](Cl)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(OCC)(=O)C>C(Cl)Cl>[C:14]([NH2:3])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1
Yield: 337.5 %

Procedure:
To a solution of 391 mg (1 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine in 3 mL of anhydrous methylene chloride, was added 0.42 mL (3 mmol) of triethylamine, then at room temperature, 0.12 mL (0.9 mmol) of orthotoluoyl chloride was added. After 15 hours at room temp ethyl acetate was added, washed with 5%. citric acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 420 mg of crude material. This was chromatographed on 40 g of silica gel using 50% ethyl acetate/hexane to afford 368 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl, m/e=516 (M+Li).
Reaction SMILES: C[Si]([C:5]1[NH:13][C:12]2[C:11](=[O:14])[NH:10][C:9]([N:15]([Si](C)(C)C)[Si](C)(C)C)=[N:8][C:7]=2[N:6]=1)(C)C.Cl[CH2:25][O:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(O)C>[OH2:14].[C:30]1(=[O:39])[N:29]([CH2:28][CH2:27][O:26][CH2:25][N:6]2[CH:5]=[N:13][C:12]3[C:11](=[O:14])[NH:10][C:9]([NH2:15])=[N:8][C:7]2=3)[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: C[Si](C)(C)c1nc2nc(N([Si](C)(C)C)[Si](C)(C)C)[nH]c(=O)c2[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CCOCCl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1nc2c(ncn2COCCN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Product: O
Yield: 172.4 %

Procedure:
To a stirred solution of tris trimethylsilylguanine (16.5 g) in toluene (50 ml) was added N-(2-chloromethoxyethyl)phthalimide (17.0 g) and triethylamine (23 ml). The reaction mixture was heated at reflux under nitrogen for 29 hours, cooled and evaporated under reduced pressure giving a dark brown oil. The oil was digested in ethanol (400 ml) on a steam bath for 40 minutes, giving a solid which was collected and washed with ethanol and ether. It was recrystallized from 2-methoxyethanol to give 9-(2-phthalimidoethoxymethyl)guanine hydrate (14.4 g), m.p. >240° C. (dec.). A mixture of 9-(2-phthalimidoethoxymethyl)guanine hydrate (0.94 g), hydrazine (2 ml) and ethanol (100 ml) was heated at reflux with stirring for one hour. The reaction mixture was filtered hot, and the filtrate was cooled and evaporated under reduced pressure. Ethanol was added and the mixture re-evaporated. This was repeated three times. The residual solid was stirred with 3% aqueous acetic acid (50 ml) for 30 minutes and filtered. The solids were washed with water (15 ml), and the wash and filtrate combined. The combined wash and filtrate was evaporated under reduced pressure at <35° C. to a small volume, diluted with ethanol and evaporated to dryness. The pasty, white solid was dispersed in a small amount of ethanol and diluted with a few ml ether to give a granular solid which was collected, washed with ethanol and dried. Recrystallization from ethanol-water gave 9-(2-aminoethoxymethyl)guanine acetate monohydrate (0.43 g), m.p. (~135° C. melts and resolidifies) 174°-176° C.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[ClH:13].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]=O>C(O)C>[ClH:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH:3]2[CH2:2][CH2:1][CH2:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:4]2=[O:5])[CH2:25][CH2:24]1
Reactant: C=O
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1CCCCc2ccccc21
Agent: Cl
Solvent: CCO
Product: COc1ccccc1N1CCN(CC2CCCc3ccccc3C2=O)CC1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A mixture of benzosuberone (4.5 g), N-(2-methoxyphenyl)piperazine, dihydrochloride (7.5 g), 37% formalin (2.5 g), and absolute ethanol (30 ml) is heated on a steam bath with stirring for 30 minutes. The solution is allowed to stand overnight at room temperature. The reaction mixture is then concentrated in vacuo, basified with concentrated ammonium hydroxide, and extracted with ether. Concentration of the dried ether solution gives a crude product that is chromatographed on a silica gel column using ethyl acetate. The ethyl acetate solution is concentrated and the residue treated with ethereal hydrogen chloride to provide 3.9 g (32%) of a crystalline solid. Crystallization from acetonitrile/ether gives 2.5 g of pure hydrochloride salt, melting point 164°-166° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 1.02 g (7.14 mmol) of 2-bromo-1-chloroethane, 0.83 g (6.04 mmol) of potassium carbonate, and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added 20 mL of n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 1.34 g (isolated yield: 97.8%) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate as a white crystalline product.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)C=CC=CC=1.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:15][CH3:16]>>[CH2:14]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][O:13][C:10](=[O:13])[CH:9]=[CH2:8])=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:15][CH3:16]
Reactant: CCCC1CCC(c2ccc(O)cc2)CC1
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: C=CC(=O)OCCCCCCOc1ccc([C@H]2CC[C@H](CCC)CC2)cc1

Procedure:
With the exception of replacing the 4-phenylphenol from the synthesis example 1 with 4-(4-propylcyclohexyl)phenol, 15 g of a monoacrylate containing a group (h): 1-propyl-4-(4-(6-acryloyloxyhexyloxy)phenyl)trans-cyclohexane was obtained in the same manner as the synthesis example 1. Hereafter this monoacrylate is abbreviated as (A-6).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][Cl:13].[Na+].[Cl-]>CN(C)C=O.O>[Cl:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: ClCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCOc1cccnc1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (12.00 g, 126.18 mmol) in N,N-dimethylformamide (DMF) (63 mL) was added drop-wise over 25 min to a cold (0-5° C.), stirring slurry of sodium hydride (6.17 g of an 80% dispersion in mineral oil, 205.7 mmol) in DMF (130 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-bromo-2-chloroethane (21.71 g, 151.37 mmol) was added drop-wise over 45 min. The resulting dark-brown mixture was stirred at ambient temperature for 24 h. Gas chromatographic analysis indicated an incomplete reaction; therefore, more 1-bromo-2-chloroethane (8.65 g, 60.3 mmol) and sodium hydride (2.09 g of an 80% dispersion in mineral oil, 69.7 mmol) were added. The mixture was stirred at ambient temperature for 40 h. Water (60 mL) was carefully added over 30 min, followed by saturated NaCl solution (40 mL), and the mixture was extracted with ether (6×50 mL). The combined orange-yellow ether extracts were washed with saturated NaCl solution (75 mL). The ether layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 2.87 g (14.4%) of a light-brown oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]2[S:32][C:20]3[N:21]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:22](=[O:27])[N:23]([CH3:26])[C:24](=[O:25])[C:19]=3[CH:18]=2)[CH:13]=[CH:14][CH:15]=1.CC1C=C[C:37]([S:40](OCCCO[Si](C)(C)C(C)(C)C)(=O)=S)=[CH:36]C=1.[C:55](=[O:58])([O-])O.[Na+]>O1CCCC1>[F:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]2[S:32][C:20]3[N:21]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:22](=[O:27])[N:23]([CH3:26])[C:24](=[O:25])[C:19]=3[C:18]=2[S:40][CH2:37][CH2:36][CH2:55][OH:58])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=S)OCCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc(F)c3)sc21
Reactant: O=C([O-])O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(Cc3cccc(F)c3)sc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A tetrahydrofuran solution of lithium diisopropylamide (5.0 ml, 0.72 mmol) was added to a solution of 6-(3-fluorophenyl)methyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 52, 0.24 g) in anhydrous tetrahydrofuran (5 ml), at −78° C. under nitrogen. After 15 minutes, further lithium diisopropylamide solution (2.5 mL, 0.36 mmol) was added. The reaction mixture was maintained at −78° C. for a further 3 hours. 3-{[Dimethyl-(1,1-dimethylethyl)silyl]oxy}propyl 4-methylphenylthiosulfonate (J. Med. Chem. 1995, 38, 2557., 0.286 g) was added and the mixture was heated at 50° C. for 30 minutes. The reaction mixture was added to saturated sodium hydrogen carbonate solution (50 ml) and extracted with ether (50 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was dissolved in acetonitrile (10 ml) and then treated with 40% hydrofluoric acid (1 ml). After 1 hour, the mixture was added to saturated sodium hydrogen carbonate solution (100 ml) and extracted with ether (2×50 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica, eluting with ethyl acetate:isohexane (1:1) followed by recrystallisation from ethyl acetate/isohexane to give the title compound (0.058 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][OH:30].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][O:30][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
1.02 g of p-toluensulfonyl chloride (5.35 mM), 1.24 ml of diisopropyl ethylamine (7.13 mM) and 86 mg of 4-(dimethylamino)pyridine (0.71 mM) were added to the reaction solution (3.57 mM) containing 500 mg of 2-(2-fluoro-phenyl)-ethanol (3.57 mM) dissolved in methylene chloride solution with stirring for 6 hrs at 0° C. under Ar atmosphere, and then the reaction mixture was stirred for 12 hrs at room temperature. The resulting mixture was neutralized with ammonium chloride, extracted with ethyl acetate and washed with saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:7) as an eluant to give 740 mg of toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u) (yield: 70%).