Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:24]([O:26]C)=[O:25].[I-].[Li+].N1C=CC=CC=1>O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:24]([OH:26])=[O:25]
Reactant: CCC(CC)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)OC)cnc3c2c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
A mixture of methyl 4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (3.2 g), anhydrous lithium iodide (8.0 g) and dry pyridine (32 ml) was stirred at 120° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water. Insoluble materials were removed by filtration. The aqueous layer was adjusted to pH 1-2 with conc. hydrochloric acid to give crystals, which were separated by filtration and dried. The crude crystals were washed with methanol three times and recrystallized from acetonitrile to give 4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (0.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][O:15][C:14](=[O:18])[NH:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[CH:22]=[O:23])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:26]([N:13]1[C:12]2[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]([CH:22]=[O:23])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:17]=2[CH2:16][O:15][C:14]1=[O:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)COC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)COC(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.36 g (7.5 mmol) of the compound from Example VII are dissolved in 20 ml of anhydrous dimethylformamide, and the mixture is treated with 0.28 g (9.4 mmol) of 80% strength sodium hydride under a gentle stream of argon. The mixture is stirred at room temperature for 15 min and treated with 1.54 g (9 mmol) of benzyl bromide. After 60 min, 30 ml of water are cautiously added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness in vacuo. The residue which remains is chromatographed in a column (φ 3 cm) on 50 g of silica gel 230-400 mesh using petroleum ether/ethyl acetate 4:1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]#[CH:12])=O)=[CH:4][CH:3]=1.[ClH:13].O1CCOCC1>O1CCOCC1>[Cl:13][CH2:12][C:11]1[C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:8][CH:10]=1
Reactant: C#CCS(=O)c1ccc(C)cc1
Reactant: Cl
Solvent: C1COCCO1
Product: Cc1ccc2scc(CCl)c2c1
Temperature: 100 °C
Yield: 61 %

Procedure:
In 15 mL of dioxane, was dissolved 873.4 mg (4.9 mmol) of the compound obtained in Example 11. The resulting solution was stirred with heating at 100° C. for 70 minutes. The reaction system was cooled to room temperature, and 1.5 mL (6 mmol) of a 4 M hydrogen chloride-dioxane was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction system was vacuum concentrated, and was added 0.80 mL of cyclohexane. The obtained mixture was heated at 70° C. for 10 minutes and cooled to room temperature. The resulting precipitates were filtered to obtain 590.6 mg of 3-(chloromethyl)-5-methylbenzo[b]thiophene. The yield was 61%.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C:7](=[O:9])[CH3:8])[CH:6]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.P(OC)(OC)OC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:7]([N:5]1[CH:6]=[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])[CH:3]=[N:4]1)(=[O:9])[CH3:8]
Reactant: C=CC(=O)OC
Reactant: CC(=O)n1cc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COP(OC)OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cnn(C(C)=O)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A 5-L multineck flask was fitted with a mechanical stirrer, a gas inlet adapter, and a thermometer and cooled in a salt-ice bath to between −10 and −15° C. The system was purged with dry nitrogen for a few minutes. A solution of 1-(4-iodo-1H-pyrazol-1-yl)ethanone (100 g, 0.425 mol) 1.2 L of N,N-dimethylformamide (DMF) was added followed by methyl acrylate (110 g, 1.275 mol), triethylamine (64 mL, 0.458 mol), trimethyl phosphite (5.27 g, 42.5 mmol), and palladium acetate (4.76 g, 21.25 mmol). The mixture was then warmed to 110° C. under dry nitrogen atmosphere and stirred for 1 hour. LC/MS analysis of an aliquot showed only 10% product formation. Trimethyl phosphite (5.27 g, 42.5 mmol), and palladium acetate (4.76 g, 21.25 mmol) were then added to the reaction mixture. The reaction went to completion after another 1.5 h as monitored by LC/MS. The mixture was allowed to cool to room temperature and the DMF was removed under reduced pressure. The residue was stirred with 1.5 L of methylene chloride, and the suspension was filtered through a plug of silica gel. The filtrate was collected and washed with 1 L of 3% hydrochloric acid, 1 L of water, and 1 L of saturated brine. The solution was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (Hexane/EtOAc 10:1 to 1:1) to give (E)-methyl 3-(1-acetyl-1H-pyrazol-4-yl)acrylate as a solid (70 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[CH:30]1([NH2:34])[CH2:33][CH2:32][CH2:31]1>>[CH:30]1([NH:34][C:19]([C:8]2[C:9]3[C:13]([CH3:14])([CH3:15])[O:12][C:11]([CH3:16])([CH3:17])[C:10]=3[S:18][C:7]=2[NH:6][C:4](=[O:5])[C:3]2[C:22]([C:26]([F:28])([F:29])[F:27])=[CH:23][CH:24]=[CH:25][C:2]=2[F:1])=[O:20])[CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCC1
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NC1CCC1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available cyclobutylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.43 (s, 6H), 1.47 (s, 6H), 1.55-1.68 (m, 2H), 1.87-2.01 (m, 2H), 2.10-2.20 (m 2H), 4.21-4.35 (m, 1H), 7.66-7.80 (m, 3H), 8.28 (d, J=7.5 Hz, 1H), 11.55 (br s, 1H). MS (ESI+) m/z 485 (M+H)+. Anal. calcd. for C23H24F4N2O3S: C, 57.02; H, 4.99; N, 5.78. Found: C, 57.05; H, 5.02; N, 5.81.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH3:16])[C:8]=1[C:9]#[N:10]>O1CCCC1>[Cl:15][C:13]1[CH:12]=[C:11]([CH3:16])[C:8]([C:9]#[N:10])=[C:7]([S:5][CH2:3][CH3:4])[CH:14]=1
Reactant: CCS
Reactant: Cc1cc(Cl)cc(Cl)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cc(Cl)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil, 0.54 g, 13.6 mmol) in dry tetrahydrofuran (15 ml) is added ethanethiol (0.36 ml, 4.84 mmol) at 0° C. After effervescence has ceased, a solution of 2,4-dichloro-6-methyl-benzonitrile (1.00 g, 5.37 mmol) in THF (5 ml) is added drop wise at 0° C. The reaction mixture is stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction is quenched with ice water and extracted with ethyl acetate (3×30 ml). The organic layer is washed with saturated sodium hydrogen carbonate solution (20 ml), water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 5% dichloromethane/hexane) to yield 4-chloro-2-ethylsulfanyl-6-methyl-benzonitrile (0.50 g, 2.37 mmol, 44%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1>C1COCC1>[F:17][C:18]1[CH:23]=[C:22]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2cccc(F)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (41 mg, 0.20 mmol) in THF (2 mL) at −78° C. was added. 1.0 M 3-fluorophenylmagnesium bromide in THF (0.4 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3-fluoro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Yield: 89 %

Procedure:
A stirred mixture of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate, 66.63 g (0.269 mole) and phosphorous oxychloride (350 ml) was warmed until all the solid had dissolved and then heated at reflux temperature for two hours. After cooling to below 100° C. the mixture was concentrated in a rotary evaporator. The residual oil was dissolved in 100 ml acetone and the solution poured onto an ice-water mixture (800 ml). The mixture was neutralized with 6 N sodium hydroxide solution and the solid product extracted successively with 450 ml, 250 ml and 100 ml portions of methylene chloride. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to yield 68.16 g crude product. This crude product was dissolved in 500 ml hot toluene and filtered to remove a small quantity of insoluble material. The toluene solution was filtered through a bed of 250 g fluorisil followed by two liters of toluene and four liters of chloroform. The purified solution was concentrated to give 64.17 g of oil (89%) which crystallized to an off-white solid on cooling. The solid melted at 75°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH:9]=2)=[O:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(O)c2ccc(-c3ccc(OC)cc3)cc2sc1=O
Yield: 71.2 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) (180 mg, 0.57 mmol) in dimethoxyethane (DME) (2.5 mL) was added 4-methoxyphenylboronic acid (104 mg, 0.69 mmol), Pd(PPh3)4 solid (66 mg, 0.06 mmol) and then 2M aqueous Na2CO3 solution (0.7 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 2 h. After cooling the reaction mixture was diluted with water (50 mL) and acidified using 1 N HCl to pH 3-4. The precipitate was collected by filtration, rinsed with water and dissolved in CH2Cl2. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (5 mL) and the solid collected, rinsed with MeOH (2 mL) and dried in vacuo to provide 4-hydroxy-7-(4-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (139 mg). MS ESI(+) m/e: 343.11 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].Br[C:7]1[C:15]2[O:16][CH2:17][CH2:18][C:14]=2[C:13]2[C:12](=[O:19])[CH2:11][CH2:10][C:9]=2[C:8]=1Br.[H][H]>C(O)(=O)C.[C].[Pd]>[CH2:18]1[CH2:17][O:16][C:15]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C:12](=[O:19])[C:13]=3[C:14]1=2
Reactant: O=C1CCc2c(Br)c(Br)c3c(c21)CCO3
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCc2ccc3c(c21)CCO3

Procedure:
5% Palladium carbon (50% hydrous, 2.9 g) and sodium acetate (17.9 g, 0.22 mol) were added to a solution of 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (29.0 g, 87.4 mmol) in acetic acid (550 ml), and the mixture was catalytically reduced in a hydrogen atmosphere at ordinary temperature and ordinary pressure. After absorption of the calculated amount of hydrogen, the palladium carbon was filtered off and the solvent was distilled off under reduced pressure. Water was added to the residue and the organic matter was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatogarphy (ethyl acetate:hexane=15:85) to give the target compound. The yield was 13.5 g (89%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c1=O
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cc(-c3ccc(S(C)(=O)=O)cc3)nn(CC3CC3)c2=O)CC1
Yield: 80.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 80.9%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].B(Br)(Br)Br.CO>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine (150.0 mg, 0.3803 mmol) in dichloromethane (10 mL, was added dropwise 1.0 M of boron tribromide in dichloromethane (1.2 mL, 1.2 mmol). The mixture was stirred for 1 hour at room temperature then methanol (5 mL) was added slowly. The mixture was evaporated to dryness. Additional methanol (10 mL) was added and the mixture was evaporated to dryness. The brown solid was suspended in saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a solid. 4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol was isolated without further purification as a light brown solid (0.115 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 0.9 Hz, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.5 Hz, 2H), 7.64 (dd, J=7.4, 0.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.00 (dd, J=7.1, 7.1 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.73 (s, 1H), 4.72 (br s, 1H), 3.09 (s, 3H). MS=381 (MH)+. 26b) A suspension of 4-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol (50.0 mg, 0.131 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (27.0 mg, 0.145 mmol) and potassium carbonate (36.0 mg, 0.260 mmol) in acetonitrile (1 mL) was heated at 70° C. for 18 hours. The mixture was cooled to room temperature, diluted with acetonitrile (10 mL), filtered through a plug of diatomaceous earth and evaporated to an orange resin. The residue was purified via chromatography utilizing an ISCO automated purification apparatus with silica gel column (12 g) and 0%→10% methanol:dichloromethane solvent gradient. The title compound, [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine, was isolated as a yellow foam (0.047 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.5 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.3 Hz, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.51-7.46 (m, 2H), 7.00 (t, J=7.0 Hz, 1H), 6.96-6.90 (m, 2H), 6.73 (s, 1H), 4.12 (t, J=5.8 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.80 (t, J=5.6 Hz, 2H), 2.62-2.55 (m, 4H). MS=494 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.Cl>C(O)(=O)C.[Pd]>[ClH:1].[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][NH+:3]=[CH:2][CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc[nH+]cc1
Reaction time: 4 h

Procedure:
A solution of 2-chloro-4-trifluoromethylpyridine (11.6 g) in glacial acetic acid (70 ml), containing 10% palladium on carbon (2.4 g, 21% (w/w)) was hydrogenated at 40 psi for 4 h. Concentrated hydrochloric acid (20 ml) was added and hydrogenation continued for a further 1 h. The catalyst was filtered off and the filtrate evaporated in vacuo to afford 4-trifluoromethylpyridinium hydrochloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:32](=[O:33])[C:31]([CH3:34])=[CH:30][N:12]([C@@H:13]2[O:20][C@H:17]([CH2:18][OH:19])[C@@:15]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([OH:16])[CH2:14]2)[C:11]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.P(=O)(O)(O)[OH:52]>CS(C)=O>[CH2:1]([O:8][CH2:9][N:10]1[C:32](=[O:33])[C:31]([CH3:34])=[CH:30][N:12]([C@@H:13]2[O:20][C@H:17]([C:18](=[O:52])[OH:19])[C@@:15]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([OH:16])[CH2:14]2)[C:11]1=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](CO)O2)c(=O)n(COCc2ccccc2)c1=O
Reactant: O=P(O)(O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: Cc1cn([C@H]2C[C@@](O)(COCc3ccccc3)[C@@H](C(=O)O)O2)c(=O)n(COCc2ccccc2)c1=O

Procedure:
A solution of 3-benzyloxymethyl-3′-benzyloxymethylthymidine (14.5 g, 30 mmol) in DMSO (200 ml) was treated with DCC (33 g, 160 mmol) and phosphoric acid 85% (2.0 g) for 16 h. The reaction mixture was filtered and concentrated in vacuo. The resultant oil was chromatographed on silica gel (EtOAc/hexane, 7/3) to afford the product as a viscous oil, 11 g (76%). 1H NMR (CDCl3) 1.92 (s, 3H, C5-CH3), 2.20-2.52 (m, 2H, C2′H), 4.09 (m, 1H, C4′H), 4.49 (m, 1H, C3′H), 4.62 (s, 2H, NCH2O), 6.28 (t, 1H, C1′H) 7.24-7.51 (M, 11H, ArH, CH═), 9.65 (s, 1H, CHO). Anal. Calcd. for C26H28N2O7: C, 64.99; H, 5.87; N, 5.83. Found: C, 64.68; H, 5.95; N, 6.01.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].Cl>[OH-].[Na+]>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
To a well stirred solution of L-proline (1.15 g; 0.01 mole) in 2N aq. NaOH (5 ml), 4N aq. NaOH (2.5 ml) and iso-valeryl chloride (1.4 ml; 0.012 mole) were added simultaneously dropwise maintaining the temperature near 0°-4° C. After 15 minutes, the mixture was acidified (pH 2-3) with 1N HCl and extracted with CHCL3. The combined organic extract was dried using MgSO4, and the solvent was removed. N-iso-valeryl-L-proline was obtained as an oil. Yield 0.85 g, Rf =0.66 (Silica gel, n-C4H9OH-AcOH-H2O, 5:1:2); [α]D20 -129.3° (c 0.6; CHCl3).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25](C)[C:26](=O)OC(C)(C)C)[S:14]2)[C@H:10]1[F:34])C1C=CC=CC=1.B(Cl)(Cl)Cl>>[F:34][C@@H:10]1[C@H:11]2[N:12]=[C:13]([NH:25][CH3:26])[S:14][C@H:15]2[O:16][C@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[C@H:9]1[OH:8]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OCc3ccccc3)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Product: CNC1=N[C@@H]2[C@@H](F)[C@H](O)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1

Procedure:
The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.200 g, 0.394 mmol), was deprotected with BCl3 using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:15), (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.114 g, 91%). 1H NMR (400 MHz, CD3OD) δ 6.29 (d, J=6.8 Hz, 1H), 5.05-4.93 (m, 1H), 4.55-4.51 (m, 1H), 4.15-4.08 (m, 1H), 3.73 (d, J=8.6 Hz, 1H), 2.85 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 164.35 (d, J=2.7 Hz), 127.35 (q, J=284.3 Hz), 93.14 (d, J=175.8 Hz), 89.65, 75.73 (q, J=27.3 Hz), 73.40 (d, J=27.2 Hz), 72.90, 68.88 (d, J=25.6 Hz), 30.85, 16.75 (q, J=1.3 Hz); MS, (ES, m/z) [M+H]+ 318.1.