Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH:14]=O)=[CH:9][CH:8]=2)[CH3:3].[NH2:16][C:17]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:18]=1[C:19]([NH2:21])=[O:20].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:3][N:2]([CH2:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[NH:21][C:19](=[O:20])[C:18]3[C:17](=[CH:25][C:24]([O:26][CH3:27])=[CH:23][C:22]=3[O:28][CH3:29])[N:16]=1)=[CH:9][CH:8]=2)[CH3:1]
Reactant: CN(C)Cc1cc2cc(C=O)ccc2[nH]1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CN(C)C)cc4c3)nc2c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a solution of 2-dimethylaminomethyl-1H-indole-5-carbaldehyde (0.88 g crude, 4.35 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.85 g, 4.35 mmol) in N,N-dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt %, 0.95 g, 5.22 mmol) and p-toluenesulfonic acid (0.99 g, 5.22 mmol). The reaction mixture was stirred at 120° C. for 5 hours under nitrogen, then cooled to room temperature, and concentrated under reduced pressure. 30% aqueous sodium carbonate (50 mL) was then added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and 7 N ammonia in methanol 5% in CH2Cl2 as eluent) to give the title compound as an off-white solid. Yield: 0.83 g (50%). MP 187-188° C. 1H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 1H), 11.34 (s, 1H), 8.38 (s, 1H), 7.93 (d, J=8.59 Hz, 1H), 7.40 (d, J=8.59 Hz, 1H), 6.73 (s, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.57 (s, 2H), 2.21 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])=[C:4]([CH3:16])[CH:3]=1.[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NC(=S)NCC(N)=O
Reactant: CCI
Agent: Cl
Product: CCSC1=NCC(=O)N1c1ccc(Cl)cc1C

Procedure:
The title compound was prepared by the procedure described in Example 6 using 18.0 g of 2-[3-(4-chloro-2-methylphenyl)-thioureido]-acetamide, and 25.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as an off-white solid, mono-hydrochloride (17.6 g), m.p. 166°-168° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S. HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 47.24; H, 4.45; N, 9.05. Mass spectrum (+FAB, [M+H]+) m/z 269/271 1H-NMR (DMSO-d6 ; 400 MHz) δ9.05-9.78 (broad s, 2H), 7.53 (m, 1H), 7.44 (d, 1H), 7.41 (d, 1H), 7.33 (d, 1H), 4.48 (q, 2H), 3.20 (m, 2H), 2.13 (s, 3H), and 1.29 ppm (t, 3H).
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]=[CH2:4].[CH3:6][C:7]1([CH3:16])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]1=[O:15].Cl>O.C(OCC)C>[CH2:4]([C:8]1([OH:15])[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:16])[CH3:6])[CH:3]=[CH2:2]
Reactant: C=CCBr
Reactant: CC1(C)CCCC(C)(C)C1=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: C=CCC1(O)C(C)(C)CCCC1(C)C
Temperature: 25 °C
Yield: 68 %

Procedure:
Magnesium (11.5 g, 0.48 moles) and dried diethyl ether (300 ml) were added, in this order, to one liter four-necked flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, a reflux condenser and a nitrogen gas inlet tube and stirred at room temperature. While stirring at room temperature, a mixed solution of allyl bromide (57.7 g, 0.48 moles)/dried diethyl ether (100 ml) was dropped to the mixture in 2 hours. The resulting mixture was heated under reflux for 30 minutes. Into the mixture was dropped a mixed solution of 2,2,6,6-tetramethylcyclohexanone (49 g, 0.32 moles)/dried diethyl ether (100 ml) in about 40 minutes while stirring under heating and refluxing conditions. The mixture was further stirred for 2 hours under refluxing conditions. The resultant reaction mixture was poured into iced water, followed by adding a 1N hydrochloric acid aqueous solution to render the mixture weakly acidic and separating it into two layers. The organic layer was washed with a saturated sodium bicarbonate aqueous solution (50 ml) and then with water (50 ml) three times. The organic layer was dried over anhydrous magnesium sulfate and separated by filtration, followed by concentration and fractionation to obtain 42.7 g (yield 68%) of the captioned compound. This compound was a colorless transparent liquid having a woody, green, earthy and patchuli oil-like odor.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[C:22]([CH2:24][C:25]([O:27]CC)=[O:26])[N:23]=[C:3]12.[ClH:30]>O>[ClH:30].[O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([OH:18])=[O:17])[C:13]=3[CH2:14][C:5]=2[N:4]2[CH:21]=[C:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=[C:3]12
Reactant: CCOC(=O)Cc1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)OCC)c1C3
Agent: Cl
Solvent: O
Product: O=C(O)Cc1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)O)c1C3

Procedure:
A mixture of 0.68 g of diethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2,9-diacetate and 20 ml of 6 N hydrochloric acid is heated for 16 hours at a temperature close to 100° C. The reaction mixture is cooled on a water and ice bath and the suspension is filtered. The insoluble matter is washed with 3×10 ml of acetone and dried under vacuum (1 mm Hg; 0.13 kPa) at close to 60° C. 0.43 g of 4,5dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2,9-diacetic acid hydrochloride is obtained in the form of a dark beige solid melting above 250° C. [Analysis: C17H13N3O5, HCl, % calculated C: 54.34, H: 3.76, Cl: 9.43, N: 11.18, O: 21.29, % found C: 53.9, H: 3.4, Cl: 9.8, N: 10.9, O: 20.9].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]2[C:11]=1[CH:10]([C:12]([OH:14])=[O:13])[N:9]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:8][CH2:7]2.OS(O)(=O)=O.[CH2:38](O)[CH3:39]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]2[C:11]=1[CH:10]([C:12]([O:14][CH2:38][CH3:39])=[O:13])[N:9]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH2:8][CH2:7]2
Reactant: O=C(O)C1c2c(Br)ccc(O)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1c2c(Br)ccc(O)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 5 h

Procedure:
0.60 g (1.2 mmol) of 8-bromo-2-[4-(4-fluorophenoxy)benzenesulfonyl]-5-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (crude product, 21C) are mixed with 0.25 ml of conc. H2SO4 in 10 ml of ethanol and heated to reflux. After five hours, a further 0.25 ml of conc. H2SO4 is added, and heating to reflux is continued for one hour. For workup, the mixture is concentrated, and the residue is taken up in sat. Na2CO3 solution and extracted twice with dichloromethane. The organic phases are dried with MgSO4, and the solvent is removed in vacuo. The crude product obtained in this way can be reacted further without purification.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18]C)[C:6]1=[O:7])[CH2:2][CH2:3]C.Br[CH2:21][CH2:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][CH2:22][CH2:23][P:24](=[O:28])([O:29][CH2:30][CH3:31])[O:25][CH2:26][CH3:27])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:7])[CH2:2][CH3:3]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCCn1c(=O)c2c(ncn2CCCP(=O)(OCC)OCC)n(CCC)c1=O

Procedure:
The title substance was prepared from 1,3-dibutylxanthine and diethyl 3-bromopropanephosphonate analogously to Example 9.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([N+:19]([O-])=O)=[C:17]([OH:22])[C:16]([Br:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25].O>C(O)(=O)C.[Fe]>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:22])[C:16]([Br:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c(O)c2[N+](=O)[O-])c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c(O)c2N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A stirred solution of 16.0 grams (0.037 mole) of 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione and 10 mL of water in 120 mL of glacial acetic acid was heated to 50° C., and 16.0 grams (excess) of iron dust was slowly added. The reaction mixture was then cooled to ambient temperature where it stirred for one hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was partitioned in a mixture of 150 mL portions each of water and ethyl acetate. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 12.0 grams of title compound; mp 98-100° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O>[CH2:13]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1ccc2cccnc21
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a suspension of sodium hydride in anhydrous N,N-dimethylformamide (40.0 mL) was added 1H-pyrrolo[2,3-b]pyridine (5.00 g, 42.4 mmol) at 0° C. The reaction mixture was stirred for 0.5 h, followed by the addition of 1-bromopentane (9.25 g, 61.2 mmol). The reaction mixture was stirred at ambient temperature for 3.5 h, quenched with water (20.0 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (8.00 g, 100%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.29 (dd, 1H), 7.86 (d, 1H), 7.19 (d, 1H), 7.02-6.98 (m, 1H), 6.41 (d, 1H), 4.25 (t, 2H), 1.89-1.79 (m, 2H), 1.35-1.25 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 147.4, 142.6, 128.6, 127.9, 120.6, 115.5, 99.2, 44.6, 30.1, 29.0, 22.4, 13.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 4-chlorophenylboronic acid (269 mg, 1.71 mmol) the subtitle compound was obtained (323 mg, 74%). The product was used directly in the next step without purification.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([O:14][CH2:15][C:16]([C:19](F)=[O:20])([F:18])[F:17])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].S(=O)(=O)(O)[OH:23]>>[C:1]([C:5]([C:8]([C:11]([O:14][CH2:15][C:16]([C:19]([OH:23])=[O:20])([F:17])[F:18])([F:13])[F:12])([F:9])[F:10])([F:6])[F:7])([F:3])([F:2])[F:4]
Reactant: O=C(F)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Product: O=C(O)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A 28-g portion of the CF3CF2CF2CF2OCH2CF2COF obtained was hydrolyzed by gradually pouring the same into dilute sulfuric acid with stirring. The product was washed several times with dilute sulfuric acid and distilled under reduced pressure to give 25.7 g of pure CF3CF2CF2CF2OCH2CF2COOH. The CF3CF2CF2CF2OCH2CF2COOH obtained had a boiling point of 75.5° C. at a pressure of 1.3×103 Pa. A 3.0-g portion of the CF3CF2CF2CF2OCH2CF2COOH obtained was neutralized with an aqueous solution of sodium hydroxide, and the product was dried to give the desired compound. A 0.2% (by mass) aqueous solution of this CF3CF2CF2CF2OCH2CF2COONa had a surface tension of 63.4 mN/m. A 2.0% (by mass) aqueous solution thereof had a surface tension of 37.5 mN/m.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:11][CH3:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:13]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:11][CH3:12])[C:8]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: CCC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 122 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.89–7.74 (br, 1H), 7.48–7.05 (m, 13H), 6.89–6.74 (d, 1H, J=7.2 Hz), 6.46–6.25 (br, 1H), 3.30–3.15 (m, 2H), 3.15–3.01 (m, 2H), 2.38–2.25 (m, 3H), 2.25–2.09 (m, 2H), 1.99–1.78 (m, 3H), 1.78–1.60 (m, 5H), 1.60–1.47 (m, 1H), 1.12–1.01 (m, 2H), 0.90–0.71 (m, 2H), 0.75 (t, 3H, J=7.2 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[Li][CH2:16]CCC.CI>C1COCC1>[F:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1
Reactant: [Li]CCCC
Reactant: Fc1cccc(OC2CCCCO2)c1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)cccc1OC1CCCCO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
To a chilled solution (−78° C.) of 9.33 g (47.55 mmol) of 2-(3-fluorophenoxy)-tetrahydro-2H-pyran in 150 mL of THF was added 38 mL (95.1 mmols) of n-BuLi (2.5 M soln in hexanes). The reaction mixture was stirred at −78° C. for 45 minutes and slowly added 11.9 mL (190.2 mmol) of methyl iodide via syringe. The reaction was allowed to warm to room temperature and was stirred overnight. Quenched reaction with satd ammonium chloride and transferred to a round bottom flask. Removed volatiles in vacuo and partitioned mixture between EtOAc and water. Separated layers and washed organics with water (×2) and brine. Dried over Na2SO4, filtered, and concd to afford a 9.01 g (90%) of a yellow oil: 1H NMR (CDCl3/400 MHz) 1.46-2.09 (m, 6H), 2.21 (d, 3H, J=2.0 Hz), 3.60-3.65 (m, 1H), 3.86-3.92 (m, 1H), 5.44 (t, 1H, J=3.2 Hz), 6.70 (t, 1H, J=8.8 Hz), 6.90 (d, 1H, J=8.4 Hz), 7.08 (dd, 1H, J=8.0, 15.2 Hz); HRMS (EI+) m/z calcd for (C12H15FO2) 210.1056, found 210.1070.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[H-].[Na+].CS([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:35][C@@H:34]([C:36]3[CH:47]=[CH:46][C:39]4[O:40][C:41]([CH3:45])([CH3:44])[O:42][CH2:43][C:38]=4[CH:37]=3)[O:33][C:32]2=[O:48])=[CH:25][CH:24]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:44][C:41]1([CH3:45])[O:40][C:39]2[CH:46]=[CH:47][C:36]([C@H:34]3[O:33][C:32](=[O:48])[N:31]([CH2:30][CH2:29][C:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:19][CH2:11][C:8]5[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=5)=[CH:24][CH:25]=4)[CH2:35]3)=[CH:37][C:38]=2[CH2:43][O:42]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Reactant: CC(C)Oc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)cc1
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of (4-isopropoxyphenyl)methanol (93 mg) in DMF (2 ml) was treated with sodium hydride (27 mg) under nitrogen and stirred for 0.5 h. To this was added the 2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl methanesulfonate (357 mg) {Example 15 i)} and the resulting solution was stirred for 18 h under nitrogen. The solution was then diluted in EtOAc, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 40 g) eluting with 40-60° C. petroleum ether-EtOAc (2:1) to give the title compound (156 mg). LCMS RT=3.76 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16]CC)=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i97 (0.55 g, 1 eq, 1.94 mmol) and lithium hydroxide monohydrate (0.16 g, 2 eq, 3.89 mmol) in tetrahydrofurane/water (28 ml 1:0.1, v/v) is stirred at room temperature for 1 h 30. The mixture is diluted with water and extracted with ethyl acetate. The aqueous layer is then acidified to pH 2 with 2 N hydrochloric acid. The precipitate that forms is filtered and washed with water to give 0.48 g of 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylic acid i98.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([CH:6]([OH:7])[C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])=[O:24])=[CH:21][CH:20]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](C(O)C(=O)c3ccc(Cl)cc3)O2)c(=O)[nH]c1=O
Yield: 80 %

Procedure:
Reaction of thymidine with 4-chlorobenzoyl chloride in pyridine at 5° to 20° C. forms 5'-(4-chlorobenzoyl)thymidine (yield: 80%), which is then allowed to react with diethylaminosulfur trifluoride in methylene chloride at -78° C., thus giving 3'-deoxy-3'-fluorothymidine (yield: 19.9%) [Japanese Patent Kokai No. 68325 (1989)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:16]([O:18][CH2:19][C:20]([O:22]CC1C=CC=CC=1)=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:16]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(=O)OCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of 2-(benzyloxy)-2-oxoethyl 3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-4-methoxybenzoate (0.508 g, 1.029 mmol) in MeOH (30 m) and EtOAc (3 ml), 10% w/w Pd/C (a catalytic amount) was added, and the mixture was hydrogenated in a Parr apparatus at 20 psi for 3 hours. The catalyst was filtered off and the filtrate was evaporated to dryness affording 2-(3-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-4-methoxybenzoyloxy)acetic acid (0.387 g, 0.959 mmol, 93% yield, MS/ESI+not detectable [MH]+). This product was used without any further purification.
Reaction SMILES: [OH-].[NH4+:2].[O-][N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2[N:14]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:15]3=[N:16][C:6]=2[CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:2][C:5]1[C:6]2[N:16]=[C:15]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:14]3[C:7]=2[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3c[n+]([O-])c4ccccc4c32)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4ccccc4c32)C1

Procedure:
Concentrated ammonium hydroxide (160 mL) was added with vigorous stirring to a solution of tert-butyl 5-oxido-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (28.49 g, 83.7 mmol) in dichloromethane (300 mL). p-Toluenesulfonyl chloride (15.96 g, 83.7 mmol) was added in small portions over a period of five minutes, after which an analysis by HPLC indicated that the reaction was complete. The aqueous layer was then extracted with dichloromethane (3×150 mL), and the combined organic fractions were washed with 1% aqueous sodium carbonate (2×150 mL). The combined aqueous washings were extracted with dichloromethane (200 mL), and all organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 6-amino-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH2:19][C:20](OCC)=[O:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]1[CH:19]=[C:20]([OH:21])[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=2)[N:1]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc2nc(-c3ccccc3F)cc(O)c2c1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Ethyl p-aminophenylacetate (8 g), ethyl 2-fluorobenzoylacetate (10 g) and p-toluenesulfonic acid (1 g) were dissolved into benzene (150 ml) and, providing Dean Stalk dehydrating apparatus placed molecular sieve (MS 4 angstroms) therein, the solution was refluxed for 4.5 hours under heat. Solvent was distilled off under reduced pressure and water was added to the residue, which was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. After diphenyl ether (60 ml) was added to the residue, the mixture was stirred at 240° to 250° C. for 30 minutes under heat. After cooling, ether was added and the crystals deposited were collected by filtration to obtain crude ethyl 2-(2-fluorophenyl)-4-hydroxyquinoline-6-acetate (9.5 g). After phosphorus oxychloride (40 ml) was added thereto, the mixture was refluxed for 2 hours under heat. After cooling, this was thrown into ice and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain ethyl 4-chloro-2-(2-fluorophenyl)quinoline-6-acetate (9.2 g). This was dissolved into ethanol (200 ml) and, after 10% palladium carbon (1 g) was added, hydrogenation was conducted at a hydrogen pressure of 40 kg/cm2 and at 80° C. Catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by means of silica gel column chromatography (development solvent: methylene chloride) to obtain aimed product (3.7 g) as a pale yellow oily substance.