Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11]1)(=O)[NH2:8].[OH-].[Na+]>C1COCC1>[NH2:8][CH2:7][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11]1
Reactant: NC(=O)C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1Cc2ccccc2N1
Reaction time: 6 h
Yield: 89.4 %

Procedure:
To a suspension of LiAlH4 (6.0 g, 0.157 mol) in THF (200 mL) was added dropwise a suspension of 2-carbamoylindoline (17.0 g, 0.105 mol) in THF (700 mL) over 50 min. The mixture was refluxed for 5 h and then LiAlH4 (6.0 g) was added further. The reflux was continued additionally for 6 h and the mixture was treated with 10% aqueous THF after being cooled with ice bath. Aqueous 1N NaOH was added and the mixture was extracted with a mixture of diethyl ether and THF. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give 13.91 g of 2-aminomethylindoline (90%): 1H NMR (270 MHz, CDCl3) δ7.11 (dd, 1H, J=7, 1 Hz), 7.01 (dt, 1H, J=1, 7 Hz), 6.68 (dt, 1H, J=1, 7 Hz), 6.61 (d, 1H, J=7 Hz), 3.84 (m, 1H), 3.11 (dd, 1H, J=16, 9 Hz), 2.86 (dd, 1H, J=13, 5 Hz), 2.70 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:17][C:18]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[ClH:2].[F:17][C:18]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH:20][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Nc1cc(O)c(F)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(O)c(F)cc3F)c2cc1OC
Yield: 75.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline hydrochloride (300 mg, 1.15 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 2,4-difluoro-5-hydroxyaniline (184 mg, 0.90 mmol) in isopropanol (10 ml) were heated at reflux for 2 hours. The reaction mixture was then allowed to cool, the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(2,4-difluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (250 mg, 65%)
Reaction SMILES: B([O-])([O-])[O-].[Si+4].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Si+4].[Si+4].[F:20][C:21]([F:50])([F:49])[CH2:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[CH:35]([C:40]2[CH:45]=[C:44]([Cl:46])[C:43]([Cl:47])=[C:42]([Cl:48])[CH:41]=2)[C:36]([F:39])([F:38])[F:37])=[CH:29][CH:28]=1)=[O:24]>CS(C)=O>[F:49][C:21]([F:20])([F:50])[CH2:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]\[CH:35]([C:40]2[CH:41]=[C:42]([Cl:48])[C:43]([Cl:47])=[C:44]([Cl:46])[CH:45]=2)[C:36]([F:37])([F:38])[F:39])=[CH:29][CH:28]=1)=[O:24]
Reactant: O=C(CC(F)(F)F)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Agent: [O-]B([O-])[O-]
Agent: [Si+4]
Solvent: CS(C)=O
Product: O=C(CC(F)(F)F)NCc1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Yield: 8.1 %

Procedure:
A silicon borate vial was charged with (E)-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (133 mg, 0.269 mmol) and dimethyl sulfoxide (DMSO; 10 mL). The mixture was placed within 0.6 to 1 meter (m) of a bank of eight 115 watt Sylvania FR48T12/350BL/VHO/180 Fluorescent Tube Black Lights and four 115 watt Sylvania (daylight) F48T12/D/VHO Straight T12 Fluorescent Tube Lights for 72 h. The mixture was concentrated in vacuo and purified by reverse phase chromatography to give the title compound as a colorless oil (11 mg, 8%): 1H NMR (300 MHz, CDCl3) δ 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.89 (d, J=11.4 Hz, 1H), 6.07 (br s, 1H), 6.01 (m, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J=7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 162.44, 137.20, 135.38, 135.23, 134.82, 134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63, 76.70, 47.33 (q, J=28 Hz), 43.59, 42.12 (q, J=30 Hz); ESIMS m/z 504 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:26]2[CH2:27][CH2:28][N:23]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:24][CH2:25]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)nn1
Yield: 75.2 %

Procedure:
A stirred mixture of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide (0.113 g, 0.5 mmol), 1-benzylpiperazine (90 mg, 0.5 mmol), tetrabutylammonium bromide (27 mg, 0.084 mmol) and 1,8-diazabicylco[5.4.0]undec-7-ene (152 mg, 1.0 mmol) was heated under reflux in dioxane (10 mL) overnight. The solvent was evaporated. Residue was treated with 2% methanol in water (25 mL). The solid, which precipitated, was filtered off and dried in vacuo to give 138 mg (0.376 mmol) of the title compound in 75% yield. 1H NMR (300 MHz, CDCl3) δ 7.98, 7.87, 7.36-7.32, 6.94, 3.76-3.74, 3.57, 3.50-3.46, 2.60-2.58, 1.74-1.68, 1.52-1.48, 0.94. MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[Cl:23]N1C(=O)CCC1=O>C(O)(=O)C.C(#N)C.O>[Cl:23][C:12]1[S:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:11]=1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C:2]([F:1])([F:22])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1csc(-c2ccccc2)c1)N1CCCC(F)(F)CC1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: O=C(c1cc(-c2ccccc2)sc1Cl)N1CCCC(F)(F)CC1
Yield: 25.5 %

Procedure:
(4,4-Difluoro-azepan-1-yl)-(5-phenyl-thiophen-3-yl)-methanone (0.104 g, 0.33 mmol) and N-chlorosuccinimide (0.445 g, 0.33 mmol) in acetic acid (2 mL) were heated by microwave irradiation to 140° C. for 4 minutes. The mixture was diluted with acetonitrile and water and purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as a gum (0.03 g). LCMS m/z 356.13 [M+H]+ R.T.=12.26 min (Analytical Method 2).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH3:8][C:9]1[C:14](/[CH:15]=[CH:16]/[N+:17]([O-])=O)=[CH:13][CH:12]=[CH:11][C:10]=1[O:20][CH3:21].CO>C1COCC1>[CH3:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][NH2:17]
Reactant: COc1cccc(/C=C/[N+](=O)[O-])c1C
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(CCN)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To lithium borohydride (2M in THF; 2.0 ml; 4.0 mmol) (cloudy) at room temperature was added dropwise over 0.5 min chlorotrimethylsilane (1.02 ml; 8.00 mmol). A precipitate was formed and after ca. 3 min, 2-methyl-1-(methyloxy)-3-[(E)-2-nitroethenyl]benzene (Preparation 9, 193 mg; 1.0 mmol) in THF (4 ml) was added dropwise via syringe over 5 min, making sure that the temperature remained at ca. 25° C. (using a water cold bath). The solution was stirred at room temperature overnight. The mixture was cooled with an ice bath, methanol was added slowly, and the solvent removed in vacuo. The residue was partitioned between 25% aqueous sodium hydroxide and dichloromethane. The aqueous phase was separated and extracted three times with dichloromethane and the combined organic layers evaporated. Purification of the residue by solid phase extraction (SCX column), eluting with methanol followed by 2N ammonia in methanol, followed by evaporation of the ammonia containing fraction gave the title compound (80 mg).
Reaction SMILES: [NH:1]([C:3](=[NH:29])[C:4]1[N:5]=[C:6]([NH:16][C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[NH2:2].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>O1CCOCC1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6]([NH:16][C@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18]1)=[N:5][C:4]([C:3]1[NH:29][C:35](=[O:36])[NH:2][N:1]=1)=[CH:13]2
Reactant: COc1cccc2cc(C(=N)NN)nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: COc1cccc2cc(-c3n[nH]c(=O)[nH]3)nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Yield: 18.8 %

Procedure:
To a mixture of (S)-tert-butyl 3-((3-(hydrazinyl(imino)methyl)-8-methoxyisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (400 mg, 1.0 mmol) in dioxane (10 mL) was added CDI (245 mg, 1.5 mmol). The resulting mixture was heated to reflux for 2 hours and then concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (80 mg, 18% over 2 steps). ESI-MS m/z [M+H]+ 427.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.Cl.[NH:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1)=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1Cl
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCOCC2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 241.4, 150 mg, 0.47 mmol) in N,N-dimethylformamide (3 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 91 mg, 0.47 mmol), EDC.HCl (180 mg, 0.94 mmol), 4-dimethylaminopyridine (114 mg, 0.93 mmol) were added to the reaction. The reaction mixture was stirred for 3 h at 25° C., then diluted with 80 mL of EtOAc. The organic layer was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and ACN (25.0% ACN up to 39.0% in 8 min, hold 39.0% in 1 min, up to 100.0% in 3 min, down to 25.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 133.3 mg (62%) of the title compound as a light yellow solid. m/z (ES+) 461 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH2:30]([O:29][C:27]([CH:26]1[C:11](=[O:14])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C

Procedure:
To 10.0 g (50.18 mmol) 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in 60 mL anhydrous ether maintained between −25° C. and −30° C. were added, over 20 minutes, solutions of 8.2 mL (65.23 mmol) boron trifluoride diethyl etherate in 17 mL anhydrous ether, followed by 6.85 mL (65.23 mmol) ethyl diazoacetate in 17 mL anhydrous ether, and the reaction was maintained between −25° C. and −30° C. for 1 hour. The mixture was allowed to warm to room temperature, 30 mL 30% potassium carbonate solution was added and the mixture extracted with EtOAc (3×30 mL), the organic layers were combined and dried with MgSO4. After filtration, the solvent was evaporated to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[CH:6]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:11][C:9]1[CH:8]=[C:7]2[C:3](=[C:2]([F:1])[CH:10]=1)[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(F)cc(F)cc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2cc(F)cc(F)c2C1
Yield: 85.2 %

Procedure:
According to Scheme 3, step 3: A mixture of 4,6-Difluoro-2-methyl-indan-1-ol (8a) (0.65 g, 3.53 mmol) and para-toluene sulfonic acid monohydrate (30 mg, 0.18 mmol) in toluene was heated at reflux for 1 h. The solution was washed with aqueous saturated NaHCO3 and brine, dried over MgSO4 and solvents evaporated. The crude product was purified by silica gel chromatography (eluting with 0% to 100% ethyl acetate in heptane to give 0.50 g of 5,7-Difluoro-2-methyl-1H-indene (9a) which was used immediately in the next step.
Reaction SMILES: NO.[Si:3](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:31][NH:32][OH:33]>ClCCl.O>[CH3:31][N:32]([Si:3]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:33]
Reactant: CNO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(O)[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
One possible synthetic scheme for hydroxylamine derivatives involves adding tert-butyldiphenylsilyl chloride and N,N-diisopropylethylamine to a suspension of N-methyl hydroxylamine hydrochloride in dry dichloromethane. The reaction mixture was stirred followed by the addition of water. The two layers were separated and the aqueous layer was extracted with methylene chloride. The organic solutions were then combined, dried with magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting product was purified by liquid chromatography on silica gel using a mixture of hexane and ethyl acetate to elute the desired product. The purification process gave N-Methyl,N-(tert-butyldiphenylsilyl)hydroxylamine (27).
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[CH2:5]([O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](Cl)[C:10]=1C#N)[CH3:6]>CCO>[CH2:5]([O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH3:15])[N:1]=[C:2]([SH:3])[C:10]=1[C:11]#[N:12])[CH3:6]
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1C#N
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc(S)c1C#N
Yield: 50.4 %

Procedure:
Thiourea (339 mg, 4.46 mmol) was added to a solution of 2-chloro-3-cyano-6-methyl-isonicotinic acid ethyl ester (500 mg, 2.23 mmol) in EtOH (25 mL) at room temperature. The mixture was heated to reflux for 24 h. The mixture was cooled (crystallization began upon cooling) to room temperature. The solid was collected by vacuum filtration giving 3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester (250 mg, 50%) as a yellow orange solid.
Reaction SMILES: [CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])O[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH3:26]>>[CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:26][C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCc1c(C)oc(C)cc1=O
Reactant: N
Product: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)cc1=O
Temperature: 25 °C

Procedure:
Compound 2 (0.02 g, 30.6 mmol) was heated at 100° C. with aqueous ammonia in a high pressure tube for 18 h. After the mixture was cooled to room temperature, the crude was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 5:1 ethyl acetate/methanol gave 3-hexadecyl-2,6-dimethylpyridin-4(1H)-one (4) as a brown solid; yield 0.01 g (51%); silica gel TLC Rf 0.25 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.88-0.89 (m, 3H), 1.28-1.32 (m, 28H), 2.28 (s, 3H), 2.34 (s, 3H), 2.44-2.47 (m, 2H) and 6.18 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24]>ClCCl>[OH:1][C:2]1[C:3]([C:8]([NH:24][CH2:23][C:22]([O:21][CH3:20])=[O:25])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1O
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1nccnc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
In 6 mL of dichloromethane is suspended 0.30 g of methyl 3-hydroxy-2-pyrazinecaroxylate obtained according to the method described in literature [J. Heterocycl. Chem., 34, 27 (1997)]. To the suspension are successively added 0.54 ml. of triethylamine and 0.29 g of glycine methyl ester hydrochloride. The resulting mixture is stirred at ambient temperature for 5 hours. After cooling, the solvent is distilled off under reduced pressure. The residue is purified by reverse phase column chromatography (eluent: water) to obtain 0.16 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)-carbonyl] amino}acetate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:41][C@@H:42]1[C@@H:46]([CH2:47][O:48][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[S:45][CH:44]([N:66]2[CH:73]=[CH:72][C:70]([NH2:71])=[N:69][C:67]2=[O:68])[C@H:43]1[F:74])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[F:74][C@H:43]1[C@H:42]([OH:41])[C@@H:46]([CH2:47][OH:48])[S:45][CH:44]1[N:66]1[CH:73]=[CH:72][C:70]([NH2:71])=[N:69][C:67]1=[O:68]
Reactant: CC(C)(C)[Si](OC[C@H]1SC(n2ccc(N)nc2=O)[C@@H](F)[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
0.24 mL of 0.1 mol/L tetrabutyl ammonium fluoride/tetrahydrofuran solution was added to a solution of 43 mg of ((3S,4S,5R)-4-((tert-butyldiphenylsilyl)oxy)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluorotetrahydrothiophen-2-yl)cytosine in 1.0 mL of tetrahydrofuran. The obtained mixture was stirred at room temperature for 2 hours, and was then left overnight. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 2/1), so as to obtain 14 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:21])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14](O)=[C:9]2[CH:8]=[CH:7]1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[I-:47].[Na+].Cl.C([O-])(O)=O.[Na+].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:21])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([I:47])=[C:9]2[CH:8]=[CH:7]1
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1O
Reactant: [I-]
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of ethyl 1-(3,4-difluorobenzyl)-4-hydroxy-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5.0 g, 13.7 mmol) in acetonitrile (100 mL) was added pyridine (1.3 mL, 15.77 mmol) and the mixture was cooled to 0° C. and triflic anhydride (2.55 mL, 15.09 mmol) was added dropwise in ˜10 min. The mixture was stirred at RT for 1 h then charged with sodium iodide (10.28 g, 68.6 mmol) in one portion followed by dropwise addition of hydrochloric acid (7.54 mL, 15.09 mmol) (2 M/water). The mixture was stirred at 60° C. for 2 h. Saturated NaHCO3/water was carefully added and the mixture was concentrated and then partitioned between EtOAc and water. The organic phase was washed with satd. Na2S2O3/water, saturated NaHCO3/water, brine, dried (Na2SO4), concentrated to provide ethyl 1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (6.5 g, 12.68 mmol, 92% yield) as a dark oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (t, J=7 Hz, 3 H), 2.65 (s, 3 H), 4.48 (q, J=7 Hz, 2 H), 5.39 (s, 2 H), 6.39 (d, J=3.71 Hz, 1 H), 6.86-7.14 (m, 3 H), 7.17 (d, J=3.71 Hz, 1 H); LCMS (m/z) ES+=457 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[OH:17].[Cl:18][C:19]1[N:20]=[C:21](Cl)[C:22]2[NH:27][N:26]=[N:25][C:23]=2[N:24]=1>>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[O:17][C:21]1[C:22]2[NH:27][N:26]=[N:25][C:23]=2[N:24]=[C:19]([Cl:18])[N:20]=1
Reactant: Clc1nc(Cl)c2[nH]nnc2n1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2nn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.2 eq) is added to 2,6-dimethyl-4-(pyridin-4-yl)phenol (prepared according to literature procedures, see Combellas et al., Tetrahedron Letters, 1992, 33, 4923) (1.2 eq) in 1-methyl-2-pyrridone (2 ml/mmol) at 0° C. The reaction mixture is stirred at room temperature for 30 min and a solution of 5,7-dichloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine (see Helvetica Chimica Acta, 1951, 34, 835) (1 eq) in 1-methyl-2-pyrridone (1 ml/mmol) is added. The resulting mixture is heated to 100° C. for 16 h, cooled to room temperature, poured into ice water and extracted with CHCl3 (×3). The combined organic layers are washed with water and brine, dried (Na2SO4), concentrated to dryness and purified by silica gel chromatography.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][C:6]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:5]1.Cl>O.O1CCCC1>[OH:3][CH:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][C:6]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:5]1
Reactant: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a stirred solution of 78 mg (2.1 mmol) of NaBH4 in 2 ml of water at 0° C. is added over 3 minutes a solution of 250 mg (0.515 mmol) of the title product of Example 17 in 3 ml of tetrahydrofuran (THF). After 30 minutes at 0° C., the mixture was permitted to warm to room temperature, and a further 2 ml each of water and of THF were added. After one hour, the reaction mixture was acidified with 3N hydrochloric acid, and the mixture was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), the drying agent removed by filtration, and the solvent removed under reduced pressure. Crystallization of the residue from 50% ethyl acetate/hexane gave the title compound (150 mg), m.p. 131.5°-132.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[CH2:4][C:5]1[N:6]=[CH:7]O[CH:9]=1.C([NH2:17])=O>O>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[CH2:4][C:5]1[N:6]=[CH:7][NH:17][CH:9]=1
Reactant: NC=O
Reactant: Clc1cccc(Cl)c1Cc1cocn1
Solvent: O
Product: Clc1cccc(Cl)c1Cc1c[nH]cn1
Temperature: 180 °C
Reaction time: 4 h

Procedure:
A mixture of 10 g of 4-(2',6'-dichlorobenzyl)oxazole and 30 ml of formamide is stirred at 180° C. for 4 hours. The mixture is cooled and diluted with water. The reaction product is thereafter isolated in the same manner as described in Example 49(d).