Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1c[nH]c(Br)c1
Reactant: OB(O)c1ccccc1Br
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: [Na+]
Product: O=Cc1c[nH]c(-c2ccccc2Br)c1

Procedure:
By a similar operation as in Reference Example 148 and using 5-bromo-1H-pyrrole-3-carbaldehyde (870 mg), (2-bromophenyl)boronic acid (1.20 g), sodium carbonate (1.27 g) and tetrakis(triphenylphosphine)palladium (289 mg), the title compound was obtained as colorless crystals (yield 396 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A solution of (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added with a solution of 1.0 N ethyl chloroformate in dichloromethane (0.3 mL, 0.3 mmol) dropwise and was stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (48 mg, 49%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.99 (s, 3H), 1.21 (t, J=7.03 Hz, 3H), 1.31-1.54 (m, 6H), 1.58-2.00 (m, 9H), 2.06-2.35 (m, 3H), 2.88-3.04 (m, 2H), 3.04-3.18 (m, 2H), 3.29-3.44 (m, 2H), 3.48-3.69 (m, 3H), 4.08 (q, J=7.03 Hz, 2H). MS (M+1): 393.2.
Reaction SMILES: [CH2:1](I)[CH3:2].[Mg].[Cl:5][C:6]1[CH:16]=[C:10]([C:11]([O:13]CC)=O)[C:9]([OH:17])=[CH:8][CH:7]=1.[CH3:18][CH2:19]OCC>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:17])=[C:10]([C:11]([CH2:1][CH3:2])([CH2:18][CH3:19])[OH:13])[CH:16]=1
Reactant: CCI
Reactant: CCOC(=O)c1cc(Cl)ccc1O
Reactant: CCOCC
Agent: [Mg]
Product: CCC(O)(CC)c1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
A solution of 124.8 g of ethyl iodide in 200 ml of anhydrous ether was added dropwise to a stirred dispersion of 19.5 g of magnesium turnings in 100 ml of anhydrous ether and the mixture was refluxed for 45 minutes and cooled in a ice water bath. A solution of 37.2 g of ethyl 5-chloro-salicylate in 120 ml of anhydrous ether was added thereto dropwise and the ether was distilled off while being replaced with 350 ml of anhydrous benzene. The solution was refluxed for 6 hours and was then cooled to room temperature and poured into an ice solution of 2 N hydrochloric acid. The decanted aqueous phase was washed 3 times with 75 ml of ether and the ether phase was washed twice with 100 ml of water until the wash water was neutral. The organic phase was dried over magnesium sulfate, was treated with activated carbon and was filtered. The filtrate was evaporated to dryness to obtain 38.3 g of raw product which was crystallized from 100 ml of cyclohexane and dried to obtain 27.5 g of 5-chloro-α,α-diethyl-2-hydroxy-benzene-methanol melting at 76° C.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO.[CH2:22]([O:29][C:30]1[CH:45]=[CH:44][C:43]([CH:46]=[O:47])=[CH:42][C:31]=1[C:32]([O:34][CH2:35]C1C=CC=CC=1)=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C.O>[CH2:22]([O:29][C:30]1[CH:45]=[CH:44][C:43]([C:46]2[O:47][CH:12]=[N:11][CH:10]=2)=[CH:42][C:31]=1[C:32]([O:34][CH3:35])=[O:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2cnco2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
p-Toluenesulfonylmethyl isocyanide (0.55 g) and potassium carbonate (0.39 g) were added to a methanol (9 mL) suspension of the obtained benzyl 2-(benzyloxy)-5-formylbenzoate (0.93 g), followed by heating to reflux for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, and then p-toluenesulfonylmethyl isocyanide (0.079 g) and potassium carbonate (0.058 g) were added thereto, followed by heating to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 70-50% hexane/ethyl acetate] to obtain 0.56 g of methyl 2-(benzyloxy)-5-(oxazol-5-yl)benzoate as a light yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1ccc(F)cc1Br
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1Br
Yield: 78.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 260 mg of 2-bromo-4-fluoroaniline in place of the 2,4-difluoroaniline. 310 mg of N-(2-bromo-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.F[C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (30 mg, 0.11 mmol) from Example 5 step 3 was dissolved in NMP (0.21 mL), DBU (24.4 mg, 0.16 mmol) was added, stirred at room temperature for 5 minutes. 1-fluoro-4-(methylsulfonyl)benzene (22.3 mg, 0.13 mmol) was added. Reaction was heated to 110° C. for 17 hours. The reaction was cooled down to room temperature, water (10 mL) was added, extracted with EtOAc (10 mL×2), second wash with Brine (10 mL). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 30% acetone/hexanes to give the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][C:33]#[C:34][CH2:35]O>C(Cl)Cl>[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][C:33]#[C:34][CH2:35][I:20]
Reactant: COC(=O)COCC#CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COCC#CCI
Reaction time: 1 h
Yield: 38.6 %

Procedure:
Triphenylphosphine (6.23 g, 23.8 mmol), iodine (6.03 g, 23.8 mmol) and imidazole (1.57 g, 23.8 mmol) were added sequentially to a solution of (4-hydroxy-but-2-ynyloxy)-acetic acid methyl ester (3.13 g, 19.8 mmol) in CH2Cl2 (30 mL). After 1 h at rt, the reaction was filtered through activity I basic alumina, washing with 20% EtOAc/Hexane. The filtrate was concentrated in vacuo then purified by flash column chromatography on silica gel (Hexane→20% EtOAc/Hexane, gradient) to afford 2.05 g (39%) of (4-iodo-but-2-ynyloxy)-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18](Cl)=[O:19])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:31]([NH2:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18](=[O:19])[NH:37][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCCCCCN
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCNC(=O)C1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1

Procedure:
To one of the above aliquots of crude 2-(chlorocarbonyl)-2,5,7,8-tetramethylchroman-6-yl acetate in 10 mL CH2Cl2 was added 1.0 mL diisopropylethylamine followed by 315 mg 1-hexylamine and overnight stiffing. The reaction mixture was poured into 1.0 M citric acid and 50 mL EtOAc added. The organic layer was separated and purified by flash chromatography to give 781 mg of 2-(hexylcarbamoyl)-2,5,7,8-tetramethylchroman-6-yl acetate, as a clear syrup. MS (m/z): M+376.3
Reaction SMILES: [Br-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[C:4]=1[CH2:18][CH3:19].[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CCOCC>C(O)(=O)C>[Br-:1].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:5]2[CH:6]=[CH:7][N+:3]([N:2]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=3)=[C:4]2[CH2:18][CH3:19])=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N
Agent: [Br-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension consisting of 1.72 g (5 mmol) of 1-amino-3-(p-chlorophenacyl)-2-ethylimidazolium bromide and 0.74 g (5 mmol) of 4-dimethylaminobenzaldehyde in 15 ml of glacial acetic acid is stirred at room temperature for 48 hours, treated with ether and filtered. The filtered-off crude product is chromatographed on 30 g of silica gel (particle size 0.063-0.200 mm) while eluting with methylene chloride/methanol (9:1 v/v) and then recrystallized from methylene chloride/methanol/ether. There is obtained 3-(p-chlorophenacyl)-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium bromide of melting point 252°-253°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]NC1C=CC(C(F)(F)F)=CN=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: FC(F)(F)c1ccc(NCl)nc1
Solvent: Cc1ccccc1
Product: Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Into the same 300 ml four-necked flask as used in Example 1, 16.2 g (0.1 mol) of 2-amino-5 -trifluoromethylpyridine and 150 g of toluene were added, and 42.2 g of a 30% sodium dichloroisocyanurate aqueous solution (sodium dichloroisocyanurate: 0.0575 mol) was dropwise added thereto over a period of one hour while stirring at 20° C. After the dropwise addition, the reaction mixture was heated to 80° C., and the reaction was conducted for 10 hours with stirring. During the reaction, formation of 2-chloroamino-5-trifluoromethylpyridine was confirmed. After completion of the reaction, the reaction mixture was cooled to room temperature, and an aqueous layer and an oil layer were separated. A 20% hydrochloric acid aqueous solution was added to the oil layer, and the mixture was stirred. An aqueous layer and an oil layer were further separated. The aqueous layer was neutralized with a 25% sodium hydroxide aqueous solution. Precipitated slightly yellow crystals were collected by filtration and dried to obtain 15.7 g 2-amino-3-chloro-5-trifluoromethylpyridine (purity as measured by liquid chromatography: 96%, yield: 77%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH:17]([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:20]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:8]=[C:7]([I:20])[C:6]=1[O:15][CH2:16][CH:17]([F:18])[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)c1ccc(OCC(F)F)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(I)c(OCC(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 100.1 %

Procedure:
2,4-Di-tert-butyl-1-(2,2-difluoro-ethoxy)-benzene (6.75 g, 25 mmol), N-iodosuccinimide (6.74 g, 30 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10 mmol) were combined in dichloromethane (75 mL) and heated at 38° C. for 7 h. TLC (hexanes) indicated a small amount of starting material still present and the reaction was treated with additional N-iodosuccinimde (0.33 g). After 4 h the reaction was washed with 10% Na2SO2O3 solution (50 mL). The aqueous was backwashed with dichloromethane (100 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide an orange oil (9.92 g). The material was purified by flash chromatography using hexane to give 8.88 g (90%) of a light pink oil which solidified over time. 1H NMR (250 MHz, CDCl3): δ 7.66 (d, 1H, J=2.4), 7.36 (d, 1H, =2.4), 6.29 (tt, 1H, J=55.3, J=4.3), 4.24 (td, 2H, J=13.2, J=4.3), 1.40 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1>>[ClH:1].[CH2:28]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:27]1.[Cl:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][C:24]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:26])[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: O=C(O)CCCN1CCN(c2ccc(OC(F)(F)F)c(Cl)c2)CCC1=O
Agent: O[C@@H]1CNCCC12CC2
Product: Cl
Product: O=C1CCN(c2ccc(OC(F)(F)F)c(Cl)c2)CCN1CCCC(=O)N1CCC2(CC2)[C@H](O)C1

Procedure:
In analogy to the procedure described for example 15, 4-[4-(3-chloro-4-trifluoromethoxy-phenyl)-7-oxo-[1,4]diazepan-1-yl]-butyric acid (intermediate 40) and (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave the title compound in 54% yield as light yellow oil. MS: 504.19 (MH+, Cl).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:17])[CH2:7][C:8]([CH3:16])([CH2:13][CH2:14][CH3:15])[O:9]2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:17])[CH2:7][C:8]([CH3:16])([CH2:13][CH2:14][CH3:15])[O:9]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCCC1(C)CC(=O)c2ccc(O)c(C)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC1(C)CC(=O)c2ccc(OCc3ccccc3)c(C)c2O1
Yield: 91 %

Procedure:
The mixture of 11.7 g. of the compound obtained in (1), 11.1 g. of benzyl bromide, 10.2 g. of potassium carbonate, and 100 ml of acetone was refluxed for 2 hours, followed by filtration. The filtrate was concentrated. Ether was added to the concentrate. The ether solution was washed successively with water, 1 N aqueous solution of sodium hydroxide, and again with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to column chromatography filled with silica gel, to obtain 11.5 g. (yield: 91.0%) of the subject compound. Melting point: 45° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11]O.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:24][C:25]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:29][CH2:28][CH2:27][O:26]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:33]1[CH2:32][CH2:31][CH:30]([C:25]2([CH3:24])[O:26][CH2:27][CH2:28][O:29]2)[CH2:35][CH2:34]1
Reactant: CC1(C2CCNCC2)OCCO1
Reactant: OCC1COc2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1(C2CCN(CC3COc4ccccc4O3)CC2)OCCO1
Temperature: 75 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 22.5 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol 4-methylbenzenesulfonate (ester), 11.1 parts of 4-(2-methyl-1,3-dioxolan-2-yl)piperidine, 15 parts of sodium carbonate and 135 parts of N,N-dimethylacetamide was stirred overnight at 75° C. Water was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 20.6 parts (100%) of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-(2-methyl-1,3-dioxolan-2-yl)piperidine as an oily residue (intermediate 86).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH3:22])=[C:7]([C:9]2[N:17]=[C:16]3[C:12](=[N:13][N:14]=[N:15]3)[C:11](=[O:18])[N:10]=2)[CH:8]=1)#[N:2].S(=O)(=O)(O)[OH:24]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH3:22])=[C:7]([C:9]2[N:17]=[C:16]3[C:12](=[N:13][N:14]=[N:15]3)[C:11](=[O:18])[N:10]=2)[CH:8]=1)(=[O:24])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: CCCOc1ccc(C#N)cc1C1=NC(=O)C2=NN=NC2=N1
Solvent: O
Product: CCCOc1ccc(C(N)=O)cc1C1=NC(=O)C2=NN=NC2=N1
Reaction time: 3 h

Procedure:
2-(5-Cyano-2-propoxyphenyl)-8-azapurin-6-one (2.0 g; prepared as described in Example 6) was carefully added with stirring to concentrated sulphuric acid (20 ml) during 10 minutes. The resulting solution was allowed to stand at room temperature for 3 hours, and then it was poured into iced water (100 ml) and the mixture was allowed to stand for 2 hours. The resulting solid was then filtered off and dissolved in aqueous sodium carbonate solution (2 N; 50 ml). This solution was treated with charcoal, filtered, and acidified by the addition of concentrated hydrochloric acid, and the resulting white solid was recrystallised from dimethylformamide. The recrystallised solid was dissolved in aqueous sodium carbonate solution (2 N; 50 ml) and the solution was acidified by the addition of concentrated hydrochloric acid and the resulting solid was filtered off to give 2-(5-carbamoyl-2-propoxyphenyl)-8-azapurin-6-one (0.9 g), m.p. 273°-275° C. (with decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][OH:13].O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccnc2c1nc(CO)n2C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc1)n2C

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.50 g of 3,7-dimethyl-2-hydroxymethylimidazo[5,4-b]pyridine (prepared as described in Preparation 40), 3.94 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.11 ml of tributylphosphine, 2.14 g of 1,1'-(azodicarbonyl)dipiperidine and 30 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent, to give 1.11 g of the title compound, melting at 92°-105° C. (softening).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][CH:10]2[CH:15]([N:16]=1)[CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11]2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1=CC2N=C(N3CCC[C@@H]3C)C(=O)NC2C=C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-((S)-2-methylpyrrolidin-1-yl)-2-oxo-1,2,4a,8a-tetrahydroquinoxaline-6-carboxylate (140.0 mg, 0.48 mmol) in dichloromethane (50 mL) was added pyridine (152 mg, 1.92 mmol) and Tf2O (271 mg, 0.96 mmol), and the reaction mixture was stirred overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3×15 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (195 mg, crude), which was used in the next step directly.