Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH:32][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)CN
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC(=O)c1cccnc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of nicotinic acid (10 g, 81 mmol), p-toluenesulfonyl chloride (17 g, 89 mmol), benzyltriethylammonium chloride (1.85 g, 8.1 mmol), and potassium carbonate (K2CO3, 44.9 g, 320 mmol) in chloroform (CHCl3, 500 mL) was stirred mechanically at 40° C. for 1 h. Glycine methyl ester hydrochloride (10.2 g, 81 mmol) and K2CO3 (11.2 g, 80 mmol) were then added and stirred at 50° C. for 90 minutes (min). The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (2% methanol/ethyl acetate) to give the desired product as an orange gum which solidified upon standing at room temperature (4.7 g, 30%): 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=2.2 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.15 (dt, J=8.1, 1.8 Hz, 1H), 7.42 (dd, J=8.1, 4.8 Hz, 1H), 6.84 (br s, 1H), 4.28 (d, J=5.2 Hz, 2H), 3.87 (s, 3H); ESIMS m/z 195 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.[Br-].[Mg+2].[Br-].[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[O:31])[S:28][CH:29]=1>O1CCCC1.CCCCCC.ClCCl>[Br:24][C:25]1[CH:26]=[C:27]([CH:30]([OH:31])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)[S:28][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=Cc1cc(Br)cs1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2cc(Br)cs2)c1
Temperature: -78 °C
Yield: 48.2 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (30.2 g, 0.105 mol), prepared as in Example 1, was dissolved in 300 mL of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.6M n-butyllithium in hexane (66 mL, 0.105 mol) was added dropwise at a rate to maintain a temperature below -65° C. The reaction was stirred for thirty minutes after the addition was complete and the cold solution was transferred to another vessel containing a room temperature solution of magnesium bromide (20.2 g, 0.11 mol) in 400 mL of dry tetrahydrofuran under nitrogen. The resulting solution was allowed to warm to 15° C. while stirring. After one hour a solution of 4-bromo-2-thiophenecarboxaldehyde (20.0 g, 0.105 mol) in 100 mL of dry tetrahydrofuran was added slowly at a rate to maintain a temperature below 25° C. The resulting solution was stirred for three hours at room temperature, then washed three times with aqueous ammonium chloride, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane:hexane/50:50 gave 20.23 g (48.2%) of α-(4-bromo-2-thienyl)-3-((tert-butyldimethylsilyl)-oxy)benzyl alcohol as a viscous yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])(=O)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>C1COCC1.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])[CH3:2]
Reactant: COc1ccc(C(C)=O)c(O)c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc(OC)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Under a nitrogen atmosphere, 36.70 g (120.4 mmol) of 2-acetyl-5-methoxyphenol (1) was combined with 20.13 ml (144.4 mmol) of triethylamine in 150 mL of anhydrous THF. The reaction mixture was cooled to 0° C., and 13.81 ml (144.4 mmol) of ethyl chloroformate was added dropwise to the reaction mixture over a 30 minute period. The reaction mixture was allowed to stir for an additional 30 minutes. The resultant white solids were filtered. A solution of 13.64 g (361.1 mmol) of sodium borohydride in 200 ml of water was added dropwise to the filtrate over a period of 45 minutes at a temperature of 5-10° C. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The resultant solution was acidified to pH 2 with 1M HCl and extracted with ether (1×250 ml). The ether layer was then extracted with 10% sodium hydroxide (5×100 mL). The combined base extracts were acidified with concentrated HCl and extracted with ether. The combined ether extracts were washed with water (1×100 ml), dil NaHCO3 (1×100 ml) and brine (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield 18.37 g of crude product, 2-ethyl-5-methoxyphenol (2), as a colorless oil. The crude product was used in Preparation 2 below.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:27]([OH:29])=[O:28]>CC(O)C.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:23][CH3:22])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (98 g, 0.31 mol), 3-methoxy-4-aminobenzoic acid (57 g, 0.341 mol) in i-PrOH (1.05 L) and conc. HCl (30 mL) was heated to reflux for a day. The mixture was cooled to room temperature and the solid was filtered, washed with isopropanol and dried to give 96.5 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitroaniline (5 g, 32.2 mmol, 1.0 eq.) and triethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) in dichloromethane (100 ml) is added a solution of 3-trifluoromethylbenzoyl chloride 33.8 mmol, 1.05 eq.) within 30 min. The suspension formed is stirred for 1 h at room temperature. Then, the reaction mixture is diluted with dichloromethane (800 ml) and extracted with water (100 ml), 2M aqueous Na2CO3 (100 ml), 2M HCl (100 ml), water (100 ml). The organic layer is dried over Na2SO4, evaporated to a volume of about 100 ml and diluted with hexanes (100 ml). The precipitate is filtered off, washed with hexanes/dichloromethane 1:1 and hexanes. Vacuum drying over night at room temperatures gives light yellow fine needles: HPLC: tR=6.72 min (purity: >99%, gradient A), ESI-MS: 325.2 [MH]+
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[O:5][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 93 %

Procedure:
o-vanillin (24.20 g) was dissolved in DMF (300 ml) and potassium carbonate (15.4 g) and ethyl 2-bromopropionate (24.8 ml) were added to the solution, followed by stirring the solution at room temperature for 19.5 hours. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was distilled to obtain the desired compound (36.98 g, yield: 93%).
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([Br:13])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.C([Li])CCC>O>[Br:13][C:5]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:2][S:3][CH:4]=1
Reactant: CCCCCCc1c(Br)sc(Br)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1cscc1Br
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Compound 51 (70 g, 0.173 mol) was mixed with dry THF (400 mL). To this mixture, n-butyllithium (138 mL, 2.5M in hexane, 0.345 mol) was added dropwise at −78° C. under argon. The resulting mixture was stirred for 10 minutes, then water (30 mL) was added to quench the reaction. The THF was evaporated and the organic was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), water (70 mL) and dried over MgSO4. After evaporation of the solvent, the resulting crude product was purified by vacuum distillation (72-74° C. at 0.17 mbar) to yield 52 (35.3 g, 82.6% yield). GC/MS: 246 g/mol (M−1). 1H NMR (CD2Cl2): δ 7.22 (s, 1H), 6.96 (s, 1H), 2.57 (t, 2H), 1.61 (m, 2H), 1.32 (m, 6H), 0.88 (t, 3H). 13C NMR: 141.92, 122.87, 120.95, 112.89, 31.88, 30.07, 29.53, 29.20, 22.88, 14.14.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)=O)[CH3:2]>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[NH:15][C:10]2[C:9]([CH:8]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2]
Reactant: CCOC(=O)CC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc2ccccc2[nH]1

Procedure:
A sample of 12.0 gm (0.048M) of ethyl-γ-2-nitrophenylacetoacetate was dissolved in 200 cc. glacial acetic acid. Approximately 21/2 spatulas of 5% Pd/C was added to the solution and the compound was reduced on the Parr hydrogenator. Ethyl-2-indolylacetate was obtained as a dark orangy oily liquid after removal of catalyst and solvent.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[K+]>C(OCC)C.O.N1C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:6][CH2:5][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: OCCc1ccccc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2Br)cc1
Temperature: 18 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A magnetically stirred solution of 2-bromophenethyl alcohol (5.00 g, 24.9 mmol, ex ALDRICH) and 4-methylbenzenesulfonyl chloride (11.20 g, 59.7 mmol) in diethyl ether (50 ml) was cooled to 0° C. (ice-bath) then treated with powdered KOH (3.2 g, 2.4 mole equiv.). The reaction mixture thus obtained was allowed to warm to 18° C., stirred at this temperature for 2.0 h then diluted with water (100 ml). The separated organic phase was washed with water (1×100 ml) then dried (MgSO4), filtered and concentrated under reduced pressure to give a white solid. Since this material contained residual 4-methylbenzenesulfonyl chloride it was dissolved in pyridine (75 ml) and the resulting solution stirred at 18° C. for 0.16 h then diluted with water (500 ml) and extracted with diethyl ether (1×500 ml). The separated organic phase was washed with HCl (1×250 ml of a 5 M aqueous solution) then sodium hydrogen carbonate (1×250 ml of a 0.5 M aqueous solution) before being dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (8.66 g, 98%) as white crystalline masses, m.p. 39-39.5° C. (Found: C, 50.9; H, 4.2; Br, 22.6; S, 8.8. C15H15BrO3S requires C, 50.7; H, 4.3; Br, 22.5; S, 9.0%). nmax (KBr) 1356, 1177, 1021, 980, 962, 895, 812, 769, 752, 665, 557 cm−1. 1H n.m.r. d 7.68, d, J 8.3 Hz, 2H; 7.45, d, J 7.7 Hz, 1H; 7.27, d, J 8.3 Hz, 2H; 7.17, m, 2H; 7.07, m, 1H; 4.25, t, J 7.0 Hz, 2H; 3.09, t, J 7.0 Hz, 2H; 2.43, s, 3H. 13C n.m.r. d 144.5 (C), 135.3 (C), 132.7 (CH), 132.8 (C), 131.3 (CH), 129.7 (CH), 128.5 (CH), 127.6 (CH), 127.4 (CH), 124.2 (C), 68.6 (CH2), 35.5 (CH2), 21.5 (CH3). Mass spectrum m/z 356 (0.7%) 354 (0.7) (M+.); 184 (98) 182 (100) [M—H3CC6H4SO3H)+.]; 171 (49) 169 (51); 155 (45); 103 (32); 91 (80) (C7H7+).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Ca+2].[OH-]>O>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: [OH-]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Agent: [Ca+2]
Solvent: O
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 25 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (purity content 10.82 g, 50.0 mmol) was mixed with calcium hydroxide (3.70 g, 50.0 mmol), and water (60 g), and the mixture was heated to 100° C. and stirred for 3.5 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 25%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>>[C:2]1([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=Cc1ccccc1
Solvent: CCN(CC)CC
Product: C(=Cc1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of iodobenzene (1 mmol), of styrene (1.5 mmol), of PdBr2 or PdSO4 (10 mol %) and of triethylamine (2 mmol) in N,N′-butylmethylimidazolium methyl H-phosphonate (2 g) is brought to 110° C. for 5 hrs. The formed trans-stilbene is extracted with ether (3×10 mL), the structure of which is confirmed by 1H NMR. (yield=100%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.C1COCC1>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 61.2 (0.87 g, 3.40 mmol) in 3:2 MeOH/THF (25 mL) was added NaBH4 (0.13 g, 3.40 mmol) as a solid in one portion. The mixture was stirred for 2 hours at room temperature and concentrated. The residue was suspended in 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to afford 61.3 as a white powder. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 2H), 7.62 (d, 2H), 7.26 (d, 1H), 7.01 (d, 1H), 4.86 (d, 2H), 1.84 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:10][OH:11].O>C(O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: NO
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(=NO)CC1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 4,4-dimethylcyclohexanone (0.511 g, 4.049 mmol) in 95% ethanol (20 ml) was added 50% hydroxylamine in water (2.481 ml, 40.49 mmol), and the reaction was heated to reflux for 2 hours. The reaction was cooled to ambient temperature, and the product was precipitated by the addition of water. The solids were collected by vacuum filtration to yield 202 mg of the title compound (35% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:19].C(Cl)(Cl)Cl>O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn(COCCO)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1

Procedure:
To a solution of 2-amino-9-(2-hydroxyethoxymethyl)adenine (0.22g) in water (30ml) was added a suspension of adenosine deaminase in aqueous ammonium sulfate (0.44ml, containing 4.4mg of the enzyme). The reaction mixture, which initially had a pH of 7.0, was heated at 37° C. for 18 hours, at which time the pH was 8.5 and TLC (silica gel plates developed in 15% methanol -- 85% chloroform) indicated a single product different from starting material. The reaction mixture was thoroughly chilled in an ice bath and the resulting white solid removed by filtration and thoroughly washed with cold water. The product was dried at 100° C./0.1mm Hg for 16 hours to give 0.20g of 9-(2-hydroxyethoxymethyl)guanine. 1/4 H2O, the structure of which was confirmed by m.p., TLC, U.V., NMR and mass spectroscopy analysis. Recrystallization from methanol gave the anhydrous 9-(2-hydroxyethoxymethyl)guanine.
Reaction SMILES: N[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:15][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O>[F:15][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-amino-2-naphthoic acid (3.74 g, 20 mmol) and 48% fluoroboric acid (2.07 g, 30 mmol) in 10 mL of H2O cooled to 0° C. is added dropwise a solution of NaNO2 (2.07 g, 30 mmol) in 15 mL of H2O. The mixture is stirred at 0° C. for 1 hour. The mixture is filtered and the solids washed with cold H2O, then MeOH, then Et2O. The remaining solid is dried in vacuo at 40° C. for 2 days. The solid is suspended in xylene and heated to reflux for 8 hours and then cooled to room temperature. To the mixture is added hexane. The solid is filtered and washed with CH2Cl2, and dried to give 3-fluoro-2-naphthoic acid as a brown solid. A mixture of this solid and 80 mL of 1,4-dioxane is added to DPPA (4.5 mL, 20.9 mmol). Then 3.88 mL (27.9 mmol) of Et3N is added and the mixture is stirred for 2 hours at room temperature-under an atmosphere of nitrogen; Ethanol (8.1 mL, 139 mmol) is added, the mixture is heated to reflux for 2 hours, concentrated in vacuo and the residue diluted with 200 mL of EtOAc. The solution is washed with 5% aqueous Na2CO3 (50 mL), brine (50 mL), dried over MgSO4 and evaporated to dryness to give a solid that is purified by flash chromatography on silica gel (100% CH2Cl2) to give N-(3-fluoro-2-naphthyl)carbamic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][O:12][CH3:13])[CH:3]=1>C(O)(=O)C.[Ni]>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][O:12][CH3:13]
Reactant: COCc1cc(C)[nH]c(=O)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Product: COCc1cc(C)[nH]c(=O)c1CN

Procedure:
6-Methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.000 g, 5.61 mmol) was suspended in acetic acid (150 ml) and the solution passed through an H-cube instrument equipped with Raney-Ni cartridge at a rate of 1 mL/min at 50 psi and 60° C. After 18 h. the acetic acid was removed under reduced pressure and the remaining residue was dissolved in MeOH. The methanolic solution was passed through a 0.2 μm teflon syringe filter. The methanolic filtrate was purified by reverse phase HPLC (Gemini 50×100 5 μm column. Run 1: 3 min, 90-10%. Run 2, 5 min 0-10%. Run 3, 10 min, 0-20%. The product fractions were concentrated to dryness on a Genevac HT-4 instrument to afford 3-(aminomethyl)-6-methyl-4-[(methyloxy)methyl]-2(1H)-pyridinone as a pale grey waxy solid (900 mg, 70.2% yield) LCMS MH+=183.0 1H NMR (400 MHz, DMSO-d6) δ 8.40 (br. s., 1H), 6.10 (s, 1H), 4.39 (s, 2H), 3.66 (br. s., 2H), 3.32 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])[CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (3.000 g; 24.60 mmol), 2-iodopropane (12.528 g; 73.70 mmol), K2CO3 (6.790 g; 49.10 mmol), and Cs2CO3 (1.601 g; 4.91 mmol) in anh. DMF (60 ml) was stirred at rt, under nitrogen, for 17 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-isopropoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 165.24 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10](I)([CH3:12])[CH3:11].C(OC1C=C(CCN)C=CC=1)(C)C>>[CH:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:12])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)I
Agent: CC(C)Oc1cccc(CCN)c1
Product: CC(C)Oc1cccc(C=O)c1

Procedure:
3-Isopropoxybenzaldehyde was prepared from 3-hydroxybenzaldehyde and isopropyl iodide analogous to the procedure described in Example 361. By using the procedure of Example 151 this aldehyde was transformed to 2-(3-isopropoxyphenyl)ethylamine, which was reacted with the product of Example 103, following the procedure of Example 105 to give the titled product.
Reaction SMILES: C(O[C:4]([C:6]12[CH2:12][N:9]([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])C.Cl.[CH3:14][NH:15][O:16][CH3:17].C(N(CC)CC)C>Cl.S(Cl)(Cl)=O>[N:9]12[CH2:12][C:6]([C:4]([N:15]([O:16][CH3:17])[CH3:14])=[O:5])([CH2:7][CH2:8]1)[CH2:11][CH2:10]2
Reactant: CNOC
Reactant: CCOC(=O)C12CCN(CC1)C2
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C12CCN(CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Ethyl-1-azabicyclo[2.2.1]hept-4-ylcarboxylate (D20, 1.75 g, 0.01 mole) in concentrated hydrochloric acid (50 ml) was heated under reflux for 1.5 h. The reaction was then concentrated in vacuo to give a solid which was dissolved in thionyl chloride (30 ml) and heated under reflux for 1.5 h. The mixture was then evaporated to dryness, and freed from residual thionyl chloride by co-evaporation which toluene. The residue was then dissolved in dry acetonitrile (50 ml) and treated with N,O-dimethylhydroxylamine hydrochloride (0.73 g, 0.0075 mole) and triethylamine (4.5 ml, 0.032 mole). The mixture was stirred overnight at room temperature and then filtered to remove most of the triethylamine hydrochloride. The filtrate was evaporated to dryness and saturated potassium carbonate solution was added. The product was then extracted into chloroform (3×100 ml) and the combined extracts were dried (Na2SO4), filtered and evaporated to dryness to give the title compound (D21) as a white solid (0.79 g, 41%).