Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:4]4[C:5]([F:9])=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=4)[CH2:18]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc2c(c1)CNCC2
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)CN(c1nc(Cl)ncc1F)CC2

Procedure:
In a like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1,2,3,4-tetrahydroisoquinoline were reacted to provide 2-chloro-N4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.08 (d, 1H, J=3.0 Hz), 7.95 (d, 1H, J=6.0 Hz), 7.50-7.42 (m, 2H), 7.21 (d, 1H, J=8.4 Hz), 6.96-6.90 (m, 1H), 4.95 (s, 2H), 4.04 (t, 2H, J=5.7 Hz), 2.99 (t, 2H, J=5.7 Hz); 19F NMR (282 MHz, CDCl3): −42555, −44573; LCMS: purity: 98%; MS (m/e): 410 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:12])[N:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH3:11][N:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:12]
Reactant: BrCc1ccccc1
Reactant: Cn1ccc(O)c([N+](=O)[O-])c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(OCc2ccccc2)c([N+](=O)[O-])c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To the title compound of step 1 (300 mg, 1.7 mmol) in CH3CN (15 mL) was added K2CO3 (726 mg, 5.2 mmol) at 25° C. under N2. After stirring for 30 min, benzyl bromide (450 mg, 2.6 mmol) was added, and the mixture was heated at 50° C. for 20 h. Following CH2Cl2 extractive work up, the residue was triturated with PE:EA (3:1) to give the title compound (250 mg, 54%) as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.43-7.29 (m, 6H), 6.12 (d, J=7.2 Hz, 1H), 5.27 (s, 2H), 3.57 (s, 3H). LCMS: 261.0 (M+1)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.917 min, m/z=444.4; 1H NMR (CDCl3) 1.51 (d, 3H), 1.92 (m, 1H), 2.13-2.32 (m, 5H), 2.44 (m, 1H), 2.82 (s, 3H), 2.93 (m, 1H), 5.50-5.68 (m, 3H), 7.06 (d, 2H), 7.19-7.35 (m, 5H), 7.39 (d, 2H), 7.58 (s, 1H), 7.65 (d, 1H), 8.74 (d, 1H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1([Cl:24])[CH2:19][C:18]1([CH3:23])[C:20](O)=[O:21].[F:25][C:26]([F:38])([F:37])[CH:27]([CH3:36])[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[Cl:16][C:17]1([Cl:24])[CH2:19][C:18]1([CH3:23])[C:20]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:35]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH:27]([CH3:36])[C:26]([F:25])([F:37])[F:38])=[CH:30][CH:31]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)=[O:21]
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(Oc1ccc(N2CCC3(CCN(C(=O)C4(C)CC4(Cl)Cl)CC3)C2=O)cc1)C(F)(F)F

Procedure:
Off-white crystalline solid. MS (ESI): 493.2 (MH+). This example was prepared in analogy to example 13 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2,2-dichloro-1-methyl-cyclopropanecarboxylic acid, 4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1>[Br-:13].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ccnc2)cc1
Reactant: CCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCn1cc[n+](-c2ccc(F)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 3.09 mmol (0.500 g) 1-(4-fluorophenyl)imidazole and 3.09 mmol (0.509 mg) of 1-bromoheptane are dissolved in 5 ml THF and heated for 12 h to 120° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][Cl:30]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:28][CH2:29][Cl:30])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl

Procedure:
Using 1.5 g of N-(trans-4-methylcyclohexyl)-2-(4-hydroxy-3-methoxyphenyl)acetamide (Example 127), 100 ml of methylisobutylketone, 5 g of potassium carbonate, and 4 ml of 1-bromo-2-chloroethane, a reaction similar to that conducted in Example 106 was carried out. As a result, 1.38 g of N-(trans-4-methylcyclohexyl)-2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetamide (a compound of the present invention) was obtained as a pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[O:16]([C:23]1[CH:24]=[C:25]([NH:29][CH2:30][CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Zn+2].[I-].[I-].C1(C)C=CC=CC=1>[O:16]([C:23]1[CH:24]=[C:25]([N:29]2[CH2:30][CH:31]([C:32]([F:33])([F:34])[F:35])[O:11][CH:10]2[C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=2)[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: [I-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: FC(F)C(F)(F)Oc1cccc(C2OC(C(F)(F)F)CN2c2cccc(Oc3ccccc3)c2)c1
Yield: 91.7 %

Procedure:
A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.45 g, 2.0 mol) and N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0 mmol) was refluxed in the presence of molecular sieves and ZnI2 (˜5 mg) for 18 h under N2. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 0.92 g (92%) of the desired 3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl) oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ10) in the 1H NMR spectrum. HRMS calcd. 502.1253 [M+H]+, found: 502.1220.
Reaction SMILES: [Cl:1]OC(C)(C)C.[CH2:7]=[CH:8][C:9](=[CH2:11])[CH3:10].[C:12]([OH:15])(=[O:14])[CH3:13]>>[Cl:1][CH2:11][C:9]([CH3:10])=[CH:8][CH2:7][O:14][C:12](=[O:15])[CH3:13]
Reactant: CC(=O)O
Reactant: CC(C)(C)OCl
Reactant: C=CC(=C)C
Product: CC(=O)OCC=C(C)CCl

Procedure:
1-Chloro-2-methyl-4-acetoxy-2-butene was prepared in accordance with the process described in J. Am. Chem. Soc. 72 4610 (1950) by reacting t-butyl hypochlorite with isoprene in an acetic acid medium.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].I[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>[Cu].O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C(=O)O)c1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(Oc2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
Potassium hydroxide (3.4 g.) was fused at 180°C. with water (1 ml.), and 2,4-difluorophenol (5.2 g.) added. 2-(4-Iodophenyl)propionic acid (5.5 g.) and copper bronze (0.2 g.) were then added to the melt, and the resulting mixture was stirred at 160°-170°C. for 2 hours. The cooled solid was extracted with methylene chloride containing a little dilute hydrochloric acid, filtered, and the solution extracted with dilute potassium carbonate solution. The aqueous extract was washed with ether and acidified with dilute hydrochloric acid; the resulting oil was isolated in ether and evaporated to dryness. The resulting solid was purified by preparative layer chromatography using 5% acetic acid/petroleum ether b.p. 62°-68°C. and eluting with ethyl acetate; recrystallization from petroleum ether b.p. 80°-100°C. gave 2-[4-(2,4-difluorophenoxy)phenyl] propionic acid, m.p. 105°-106°C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:13]2[CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2CC2)ccc1N
Temperature: 100 °C
Yield: 88.3 %

Procedure:
In a schlenck tube, a mixture of methyl 2-amino-5-bromobenzoate (43.47 mmol, 10 g), cyclopropylboronic acid (112.92 mmol, 9.700 g), K3PO4 (144.16 mmol, 30.6 g), Pd(AcO)2 (3.47 mmol, 0.780 g), P(Cy)3 (7.85 mmol, 2.2 g) in toluene (170 ml) and water (10 ml) was heated for 2 hours at 100° C., under nitrogen atmosphere. The reaction mixture was filtered through celite and the organic phase was separated and evaporated affording 7.34 g (yield 77%) of the expected product.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(C)(C)C.[NH2:12][CH2:13]CCO.C=O.P(=O)(O)(O)O>C(O)C.O>[OH:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[CH2:13][NH2:12]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: NCCCO
Agent: C=O
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: NCc1ccccc1O

Procedure:
An o-hydroxybenzylamine compound of the present invention composition is prepared according to the procedure of Example 1, except that 50 g of 4-t-butylphenol is employed in place of the Bisphenol-A, 25 g of 3-aminopropanol is employed in place of the 2-(methylamino)ethanol and that heating of the reactants was only begun after the formaldehyde addition was completed. A 0.5 g sample of the product is dissolved in 500 ml of ethanol/water (1:4 by volume) and the pH of the solution is adjusted to 3.0 with phosphoric acid.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[N:8]=[C:7]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=1.[Br:29]Br.S(S([O-])(=O)=O)([O-])(=O)=O>O.C(O)(=O)C>[Br:29][C:6]1[C:7]([NH:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[N:10][C:5]=1[Cl:4]
Reactant: BrBr
Reactant: N#Cc1ccc(Nc2nc(Cl)cc(NC(=O)c3ccccc3)n2)cc1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(Nc2nc(Cl)c(Br)c(NC(=O)c3ccccc3)n2)cc1
Reaction time: 11 h

Procedure:
1500 ml of dichloromethane and 150 g of N-[6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide were added to a reaction vessel and to this was added 750 ml of acetic acid and 44.2 mL of liquid bromine solution at 27±3° C. and stirred for 11 hrs. After completion of the reaction, to the reaction mixture was added 375 ml of water under stirring and maintained for 45 mins. To the reaction mixture was further added metabisulphate solution (60 g in 375 ml of water) and stirred further for 30 mins. The solid was filtered and washed with 300 ml of water and suck dried. The wet cake and 1500 ml of water were charged into a clean RB and adjusted pH 9.0±0.5 with 50% potassium carbonate solution. The reaction mass was stirred and filtered; the solid was washed with 150 ml of water followed by 150 ml of dichloromethane. The obtained solid was dried under vacuum at 73±2° C. to yield the title compound.
Reaction SMILES: C(OC(C=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=O)C.I([O-])(=O)(=O)=[O:19].[Na+].CN1CCOCC1>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:7]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:19]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)C=Cc1ccc(CC(=O)O)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: O=Cc1ccc(CC(=O)O)cc1
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a stirred solution of the title compound of Example 1 (46.9 g, 200 mmol) in dioxane (500 mL) and water (500 mL) was added osmium tetroxide (0.5 g, 4% in water), followed by sodium periodate (85.56 g, 400 mmol). The reaction mixture was monitored by HPLC, stirred for 1 hour and N-methylmorpholine (1.0 g) was added, followed by additional osmium tetroxide (1.0 g) after another 16 hours. After 4 hours stirring at room temperature, additional sodium periodate (40 g) was added, the reaction stirred for 21 hours, filtered, and the filter cake washed with ethyl acetate (500 mL). The phases were separated, the aqueous layer extracted with ethyl acetate (500 mL), the remaining aqueous layer acidified with hydrochloric acid (30 mL), extracted with ethyl acetate (500 mL), and the combined organic phases washed with water (500 mL), saturated sodium chloride solution (250 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The wet solid was triturated with methyl tert-butyl ether (50 mL) and to the resulting slurry was added pentane (100 mL). The slurry was filtered, the solid product was washed with pentane (2×25 mL) and dried to give the title compound (12.4 g, 38%). HPLC: 2.19 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). 1H NMR (d6-DMSO): δ 9.99 (s, 1H), 7.85-7.87 (d, 2H), 7.49-7.51 (d, 2H); 3.72 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][OH:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](O)(=O)[CH3:30]>C(OCC)=C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][O:28][CH:29]=[CH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Agent: C=COCC
Product: C=COCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-2(S)-(2-hydroxyethyl)-4-naphthoylpiperazine (0.50 g, 1.3 mmol) was dissolved in freshly distilled ethyl vinyl ether (20 mL) under argon. To this solution was added mercuric acetate (0.436 g, 1.37 mmol) and the reaction refluxed overnight. The reaction was cooled to room temperature, acetic acid added (0.035 mL, 0.58 mmol) and stirred 2 h. The reaction mixture was extracted with ethyl acetate and 5% aqueous sodium hydroxide, and the organic phase further extracted with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5](O)[C:6](=[O:9])[O:7][CH:8]=1)[CH2:2][CH3:3].C(OCC)(=[O:13])C>[Pd]>[OH:13][C:8]1[O:7][C:6](=[O:9])[CH2:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCC1=COC(=O)C1O
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCCC1=C(O)OC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-hydroxy-4-propyl-5H-furan-2-one 373 (15 g, 0.1 mol), ethyl acetate (260 ml) and Pd/C 5% are placed in a Parr apparatus. The mixture is degassed, and hydrogen is introduced at a pressure of 35 psi. This mixture is then stirred vigorously at 25° C. for 2 h. After filtration on celite, the solvent is removed under reduced pressure at 50° C. to give the 5-hydroxy-4-propyl-furan-2-one as a crude product (100% yield). LC/MS: 145 (MH+).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[NH2:25]N.O.Cl>CO>[NH:25]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccn[nH]1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (2.70 g, 8 mmol) and NH2NH2.H2O (1.94 mL, 40 mmol) in MeOH (25 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from AcOEt to give the title compound (0.969 g, 40% yield) as an off-white solid: mp 192-194° C.; NMR (300 MHz, CDCl3): δ ppm 6.82 (1H, d, J=7.9 Hz), 7.03 (1H, d, J=1.9 Hz), 7.69 (1H, d, J=1.9 Hz), 7.72-7.76 (2H, m), 7.83-7.89 (1H, m), 7.91-7.93 (1H, m), 8.33 (1H, d, J=7.9 Hz), 12.85 (1H, brs). LC-MS (ESI) m/z 307 [M+H]+. Anal. Calcd for C14H9F3N4O: C, 54.91; H, 2.96; N, 18.29. Found: C, 54.92; H, 2.99; N, 18.33.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=1
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 39.4 %

Procedure:
A mixture of 10.0 g (0.06 mol) of 3,5-dihydroxybenzoic acid methyl ester, 12.3 ml (0.06 mol) of 1-bromodecane and 8.2 g (0.06 mol) of potassium carbonate in 200 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours. After the usual workup, purification by HPLC using 15% ethyl acetate-hexane gave 7.3 g (34% yield, mp 92°-94°) of 3-(decyloxy)-5-hydroxybenzoic acid methyl ester. The nmr spectra was consistent with the structure.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH:64]([S:81][S:82][CH:83]([CH3:85])[CH3:84])[CH2:65][C@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67](OCC#N)=[O:68])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH:64]([S:81][S:82][CH:83]([CH3:85])[CH3:84])[CH2:65][C@@H:66]([NH:73][C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[C:67]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:68])=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)SSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)SSC(CN=[N+]=[N-])C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 40.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h, 43.6 mg, 0.069 mmol) in water (0.3 mL) and a solution of (2S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 45) (83 mg, 0.206 mmol) in tetrahydrofuran (0.2 mL) were added to buffer A (12 mL), and the mixture was stirred at room temperature for 55 minutes. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 46) (27.7 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1.O=[C:29]([CH3:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[NH2:27][C:26]1[C:3]2[C:2](=[CH:25][CH:24]=[CH:23][C:4]=2[O:5][CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[N:1]=[C:29]([CH3:36])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCN(C(=O)OCc2ccccc2)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCNCC3)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 35c) and ethyl 3-oxobutanoate as an orange solid (25%). 1H NR (400 MHz, DMSO-d6) δ 1.29-1.37 (m, 5H), 1.77-1.80 (m, 2H), 2.07 (brs, 1H), 2.53 (s, 3H), 2.55-2.65 (m, 3H), 3.06-3.09 (m, 2H), 4.06 (d, J=8.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 344 (MH+).
Reaction SMILES: [O:1]([C:8]1[C:9]2[NH:16][C:15](/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[C:28]([O:20][CH2:19]/[CH:18]=[CH:17]/[C:15]1[NH:16][C:9]2[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH:14]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1)c1ccccc1

Procedure:
(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propen-1-ol (1.0 g) was suspended in tetrahydrofuran (20 mL), and triethylamine (0.651 mL) and benzoyl chloride (0.86 mL) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, diluted with ethyl acetate (200 mL) and washed with water (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (1.08 g) as crystals.