Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1>CC(N(C)C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.968 g, 8.79 mmol) in DMA (15 mL) was treated with potassium tert-butoxide (0.987 g, 8.79 mmol), stirred at RT for 3 h, treated with 4-chloro-N-methylpicolinamide (1.5 g, 8.79 mmol) and stirred at RT for 2 days. The mixture was concentrated to dryness, treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford 4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (1.3 g, 61%). 1H NMR (400 MHz, DMSO-d6): δ 8.75 (m, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.9 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.10 (dd, J=5.6, 2.7 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.07 (s, 2H), 2.77 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 245.1 (M+H+).
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CC1.C1([Mg]Br)C=CC=CC=1.[C:19]1([C:25]2(O)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:19]1([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC1(c2ccccc2)CCc2ccccc21
Agent: Br[Mg]c1ccccc1
Agent: O=C1CCc2ccccc21
Solvent: CCOCC
Product: C1=CC(c2ccccc2)c2ccccc21
Reaction time: 16 h
Yield: 95.9 %

Procedure:
1-Indanone (13.30 g, 0.1006 moles) was stirred in diethylether (300 mL) at -78° C. as PhMgBr (0.150 moles, 50.00 mL of 3.0M solution in diethylether) was added. The mixture was then allowed to slowly warm to 20°-25° C. and then stirred 16 hours. After the reaction period the mixture was poured on ice and then extracted with aqueous solutions of 1M HCI (1×100 mL), 1M NaHCO3 (1×100 mL), andthen H2O (1×100 mL). The organic layer was then dried over MgSO4. Filtration followed by removal of the volatiles resulted in the isolation of a yellow oil which by NMR was seen to still contain some 1-phenyl-1-indanol. This oil was then distilled under vacuum to yield the desired product as a pale yellow oil (18.56 g, 95.9 percent).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]>Cl>[OH:3][C:2]1[N:1]=[C:4]([CH3:11])[CH:5]=[C:6]([OH:10])[C:7]=1[C:8]#[N:9]
Reactant: Cc1cc(=O)c(C#N)c(N)o1
Agent: Cl
Product: Cc1cc(O)c(C#N)c(O)n1
Yield: 83.3 %

Procedure:
A suspension of 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile (6.0 g, 40 mmol) in 10% hydrochloric acid (60 mL) was heated under reflux for 4 hours. The precipitate was collected by filtration and washed with water, and then recrystallized from methanol to give 2,4-dihydroxy-6-methylnicotinonitrile (5.0 g, 80%) as a brown solid. 1H NMR (300 MHz, CD3OD): δ 12.44-12.46 (m, 1H), 11.69 (s, 1H), 5.85 (s, 1H), 2.15 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[O:8][CH:9]=[CH:10][N:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[O:8][CH:9]=[CH:10][N:11]=1)=[O:4]
Reactant: Nc1ncco1
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1ncco1
Reaction time: 16 h

Procedure:
A solution of bromoacetyl bromide (0.44 mL) in dry CHCl3 (5 mL) was added dropwise to a suspension of 2-amino-1,3-oxazole (0.39 g) and triethylamine (0.96 mL) in dry CHCI3 (92 mL) at room temperature. The brown mixture was allowed to stir for 16 h, then quenched with H2O (2 mL) and stirred for 20 mins before concentrating under reduced pressure to a light brown solid. The crude product was purified by silica gel chromatography eluting with 1-3% MeOH/dichloromethane to give the title compound (0.56 g) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([CH3:10])[CH:3]=1.[OH-:11].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:19]>>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([C:10]([OH:19])=[O:11])[CH:3]=1
Reactant: Cc1cc(Br)sc1C(=O)O
Reactant: [OH-]
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1cc(Br)sc1C(=O)O
Temperature: 80 °C

Procedure:
A suspension of 5-bromo-3-methyl-thiophene-2-carboxylic acid (177 g, 0.80 mol), example 1-b, and sodium hydroxide (720 g, 18 mol) in 3 L of water was heated to 80° C. Potassium permanganate (513 g, 3.25 mol) was added in 25 g portions to the warm solution over 2-3 hours. The resultant suspension was heated to reflux temperature for 2 hours and then cooled to room temperature. The solid was filtered off and washed twice with 1 N NaOH and twice with water. The aqueous solution was acidified to pH <3 with concentrated sulfuric acid. The resulting white precipitate was collected on a medium fritted glass filter, washed twice with cold water, and dried under high vacuum to produce 112 g of a white solid. MS: (−) m/z 248.91, 250.98 (M−1, 79Br/81Br)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]#[C:23][CH2:24][N:25]3[CH2:30]COC[CH2:26]3)=[CH:17][CH:18]=2)[C:13]1=[O:31].CO.C(OCC)(=O)C>C(O)C.[Pd]>[CH3:30][N:25]([CH3:26])[CH2:24][CH2:23][CH2:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:13]2=[O:31])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(C#CCN4CCOCC4)cc3c2=O)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(CCCN(C)C)cc3c2=O)c1
Yield: 91.2 %

Procedure:
Methyl 4-methyl-3-[7-(3-morpholin-4-ylprop-1-yn-1-yl)-1-oxoisoquinolin-2(1H)-yl]benzoate (292 mg) and 10% Pd/C (30 mg) were stirred in a mixture of ethanol (2 ml)/methanol (4 ml)/ethyl acetate (2 ml) under an atmosphere of hydrogen at room temperature for 17 hours. The catalyst was removed by filtration through a microfibre filter and the filtrate was concentrated to yield an oil. The oil was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to yield methyl 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate as a brown oil (242 mg); NMR Spectrum: (DMSOd6) 1.79 (m, 2H), 2.14 (s, 3H), 2.28-2.36 (m, 6H), 2.77 (t, 2H), 3.57 (m, 4H), 3.86 (s, 3H), 6.72 (d, 1H), 7.30 (d, 1H), 7.59 (d, 1H), 7.67 (m, 2H), 7.83 (s, 1H), 7.98 (d, 1H), 8.08 (s, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:26][CH:25]([N:27]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:28][C@H:29]([OH:46])[CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:33]=3)[CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH2:47]([N:27]([CH2:28][C@H:29]([OH:46])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:37]=1)[CH:25]1[CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][S:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)(=[O:14])=[O:13])=[CH:22][CH:21]=2)[CH2:26]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Nc1ccc(N2CC(N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(N3CC(N(Cc4ccccc4)C[C@H](O)COc4ccc(OCc5ccccc5)cc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Butoxybenzenesulfonyl chloride (0.20 g, 0.79 mmol) was added to a solution of (2S)-1-{[1-(4-amino-phenyl)-azetidin-3-yl]-benzyl-amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol (which was obtained in Example 401) (0.37 g, 0.727 mmol) and triethylamine (0.56 mL, 3.99 mmol) in anhydrous methylene chloride (7 mL). The reaction was stirred at room temperature overnight. The solution was then treated with water (30 mL) followed by extraction with ethyl acetate (3×30 mL). The organic extract was dried with anhydrous sodium sulfate, filtered and concentrated to afford a crude solid. The desired product was isolated using silica gel flash chromatography to give 90 mg of an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.99(t, 3H, J=5.04 Hz), 1.47(m, 2H), 1.78(m, 2H), 2.69(m, 2H), 3.08(brs, 1H), 3.65(m, 3H), 3.78(m, 2H), 3.87(m, 4H), 3.95(t, 2H, J=6.45 Hz), 5.01 (s, 2H), 6.01(s, 1H), 6.29(d, 2H, J=8.73 Hz), 6.86(m, 10H), 7.35(m, 8H), 7.56(d, 2H, J=8.94 Hz). MS (ES) m/z: 722.1 (MH+); Anal. Calcd. for C42H47N3O6S: C, 69.88; H, 6.56; N, 5.82. Found: C, 68.91; H, 6.38; N, 5.55.
Reaction SMILES: [Br:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH3:16])=[CH:7][C:8](C)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:4].CC1C=CC(C(O)=O)=CC=1>>[Br:1][CH:2]([CH3:17])[C:3]([C:5]1[CH:14]=[C:9]([CH:8]=[CH:7][C:6]=1[CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[O:4]
Reactant: COC(=O)c1cc(C(=O)C(C)Br)c(C)cc1C
Agent: Cc1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(C)c(C(=O)C(C)Br)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.6, except 4-methylbenzoic acid was used in place of 2,4-dimethylbenzoic acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17](Br)[N:18]=2)[N:13]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]=1)=[O:10])[CH3:7].[F:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[N:37][C:38]=2[Sn](CCCC)(CCCC)CCCC)[CH:35]=1>CN(C=O)C.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.[Cu]I>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:38]3[N:37]=[CH:36][N:34]4[CH:35]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=34)[N:18]=2)[N:13]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]=1)=[O:10])[CH3:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(F)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(F)ccc34)nc12)c1ncco1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide (148 mg, 0.32 mmol) and 6-Fluoro-1-tributylstannyl-imidazo[1,5-a]pyridine (380 mg, 0.45 mmol) were dissolved in DMF (3 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.016 mmol) and copper (I) iodide (13 mg, 0.068 mmol) were added. The reaction mixture was stirred at 80° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica sel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to afford 109 mg (66%) of 2-(6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxazol-2-yl-ethyl)-amide as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]2[CH3:28])=[N:12][C:13]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:14][C:15]=1[CH3:16]
Reactant: CNc1ccccc1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3[C@H]2C)c1C
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccccc2)nc(N2CCc3ccccc3[C@H]2C)c1C
Product: Cl
Yield: 29 %

Procedure:
After N-methylaniline(1.04 ml, 9.6 mmol) was added to a mixture solution of (R)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) and dimethyl formamide(10 ml), 0.55 g of the title compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10].[CH2:12]=[CH:13][CH2:14][CH3:15].CC(C)C>[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH:13]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH2:14][CH3:15])[CH3:12].[CH:13]([C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:8])[CH3:11])[CH:5]=[CH:6][C:1]=1[OH:7])([CH2:14][CH3:15])[CH3:12]
Reactant: C=C(C)C
Reactant: C=CCC
Reactant: Oc1ccccc1
Agent: CC(C)C
Agent: [Al+3]
Agent: [O-2]
Product: CCC(C)c1cc(C(C)(C)C)ccc1O
Product: CCC(C)c1ccccc1O
Temperature: 220 °C

Procedure:
105 g of phenol and 5.0 g of aluminum oxide catalyst that was calcined in air at a temperature of 450° C. was charged in an autoclave and heated to 220° C. A raffinate stream containing 82.4% isobutylene, 1.3% 1-butene, and 16.3% isobutane was then charged over a period of 3 hours. The amount of raffinate charged was 70 g with an isobutylene to phenol mole ratio of 1.13:1. The yield of OTBP at the end of 6 hours was 50.41%, down from 52% at the 5-hour mark. The amount of 1-butene in the feed that reacted to form 2-sec-butylphenol and 2-sec-butyl-4-tert-butylphenol was 44.5%. The amount of the two sec-butylphenol impurities (2-sec-butylphenol and 2-sec-butyl-4-tert-butylphenol) were 0.44 area percent and 0.15%, respectively.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:14][C:15]2([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: NC1(CO)CCCC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(CO)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.030 g, 0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added 1-amino-1-cyclopentanemethanol (35 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 276 (M+H)+; 1H NMR (DMSO) δ 4.99 (m, 1H), 4.86 (t, 1H), 4.28 (m, 1H), 4.00 (m, 1H), 3.50 (d, 2H), 3.51 (m, 2H), 2.27 (m, 2H), 2.14 (m, 1H), 1.75 (m, 6H), 1.55 (m, 2H).
Reaction SMILES: [NH3:1].C(O[C:5](=[O:29])[CH2:6][N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:15]=[C:14]2[CH3:27])=[CH:9][C:8]1=[O:28])C>CO>[CH3:27][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][N:7]([CH2:6][C:5]([NH2:1])=[O:29])[C:8](=[O:28])[CH:9]=2)[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[N:15]=1
Reactant: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Reactant: N
Solvent: CO
Product: Cc1cccc(C#Cc2cn(-c3ccn(CC(N)=O)c(=O)c3)c(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2 ml of a 7M solution of ammonia in methanol were added 60 mg (0.16 mmol) of [4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester (Example 13). The reaction vessel was closed and the yellow solution was stirred for 16 h at room temperature. The solution was then evaporated to dryness yielding 45 mg of the title compound as a light brown solid, MS: m/e=347.1 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH:22]([OH:35])[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)([CH3:25])[CH3:24])=[N+:18]([O-:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C(C)=CC=CC=1C>ClCCl>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH:22]([O:35][S:2]([CH3:1])(=[O:4])=[O:3])[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)([CH3:25])[CH3:24])=[N+:18]([O-:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(Oc1ccc(C#N)cc1)C(Cc1ccc(OCc2ccccc2)c[n+]1[O-])OS(C)(=O)=O
Reaction time: 4.5 h
Yield: 32.4 %

Procedure:
0.7 g of methanesulphonyl chloride was added to a stirred solution of 2.3 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy -3-methylbutyl]pyridine N-oxide and 1 ml of 2,6-lutidine in 10 ml of dichloromethane. The mixture was stirred for 4.5 hours and then a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added. After 2.5 hours a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added and the mixture was stirred for 16 hours. The mixture was then diluted with 50 ml of dichloromethane and washed in succession with 2M hydrochloric acid, water and 10% sodium bicarbonate solution The organic solution was evaporated and the residue was chromatographed on silica gel using diethyl ether/methanol (9:1) for the elution to give 0.89 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-(methylsulphonyloxy)butyl]pyridine N-oxide in the form of a cream solid of melting point 142° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](Br)[CH:15]=[C:14]([Br:19])[CH:13]=1.C(OCC)C>CN(C=O)C.O>[CH2:1]([O:8][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([Br:19])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a solution of benzyl alcohol (10.8 g, 100 mmol) in dry DMF (40 mL), 60% NaH (4.4 g, 110 mmol) was added portionwise and the mixture was stirred at 55° C. for 10 min. Then, 1,3,5-tribromobenzene (22.0 g, 70 mmol) was added slowly to the reaction mixture and the resulting solution was heated at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was poured into a mixture of diethyl ether (500 mL) and water (200 mL) along with intense stirring. The organic layer was separated and washed with water (2×100 mL), 5% HCl (100 mL), saturated NaHCO3 aqueous solution (100 mL) and brine (100 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica using hexanes-acetone (10:0.5) as eluent to afford 18.5 g (77%) of title compound as an yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.45-7.32 (m, 5H); 7.25 (s, 1H); 7.07 (s, 2H); 5.05 (s, 2H).
Reaction SMILES: CN1C(=O)C(C)([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])C(=O)NC1=O.Cl.[CH3:28][CH:29]1[C:34](=[O:35])[NH:33][C:32](=[O:36])[NH:31][C:30]1=[O:37].N[CH:39]1[C:44](=O)N(C(C)C)C(=O)N[C:40]1=O>>[CH:39]([N:31]1[C:30](=[O:37])[C:29]([CH3:28])([N:9]2[C:10](=[O:23])[C:11]3[C:16](=[C:15]([F:19])[C:14]([F:20])=[C:13]([F:21])[C:12]=3[F:22])[C:17]2=[O:18])[C:34](=[O:35])[NH:33][C:32]1=[O:36])([CH3:44])[CH3:40]
Reactant: CC1C(=O)NC(=O)NC1=O
Reactant: CC(C)N1C(=O)NC(=O)C(N)C1=O
Reactant: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Agent: Cl
Product: CC(C)N1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O

Procedure:
Compound 19c was synthesized in the same manner as described for 19a from 5-amino-1-isopropylbarbituric-5-methylbarbituric acid hydrochloride (0.35 g, 1.50 mmol). The crude product was recrystallized from EtOH (70%) to give 1-isopropyl-5-methyl-5-(tetrafluorophthalimido)barbituric acid (19c) as white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]4[CH2:36][O:35]C(C)(C)[O:33]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]([OH:33])[CH2:36][OH:35])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCC(O)CO)c4ccc(OC(F)F)cc34)nc12
Reaction time: 2 h
Yield: 39 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (1 mL) at room temperature and the reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 38% acetonitrile/62% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 46% acetonitrile/54% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3,4-dihydroxybutyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (30 mg, 39% over two steps) as a white solid. MS: (M+H)+=489.1; 1H NMR (300 MHz, DMSO): δ 12.85 (s, 1H), 9.11 (s, 1H), 8.42 (d, 1H, J=3.0 Hz), 8.24 (d, 1H, J=1.2 Hz), 7.92-7.88 (m, 2H), 7.45 (t, 1H, J=9.2 Hz), 7.23 (t, 1H, J=74.4 Hz), 4.67-4.64 (m, 2H), 3.48-3.26 (m, 4H), 2.16-2.10 (m, 4H), 1.86-1.83 (m, 4H), 1.54 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:26])[C:10]([C@@H:12]1[CH2:16][C:15]([F:18])([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:18][C:15]1([F:17])[CH2:14][NH:13][C@H:12]([C:10]([N:9]([CH3:8])[CH3:26])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11 mL of trifluoroacetic acid was added under ice cooling to a 40 mL chloroform solution of 3.85 g of the compound obtained in step 3-4, and the reaction mixture was stirred for 2 hours at room temperature. The solvent was then distilled off under reduced pressure to obtain 8.02 g of residue (pale yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH2:3].[CH2:25](Br)C=C>>[CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH:3][CH3:25]
Reactant: C=CCBr
Reactant: C=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CC=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 48 %

Procedure:
Following the above procedure for the preparation of 8-(2-propenylmercapto)guanosine (Example 6), but substituting 2-butenyl chloride for allyl bromide, the title compound was obtained in 48 percent yield as a white powder, mp 210° C. (decomp.). NMR (DMSO-d6): δ6.3 (bs, 2H); 5.6 (d, J=5Hz, 1H); 1.6 (d, J=6Hz, 3H). IR (KBr): 1690, 1630, 1600, 1510 and 1365 cm-1.