Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:16][C:7]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:23])=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccccc2)c(OCC(=O)OC(C)(C)C)c(-c2ccccc2)c1
Temperature: 70 °C
Yield: 96.2 %

Procedure:
To the phenol from Step 2 (3.50 g, 11.5 mmol) in acetonitrile (40 mL) was added tert-butyl bromoacetate (3.39 mL, 23 mmol) and K2CO3 (1.93 g, 12.65 mmol). The mixture was heated for 2 h at 70° C. then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate/H2O. The organic phase was dried (MgSO4) and concentrated to give crude product. The compound was purified by passing it through a short filter column (SiO2) using hexane as the elutant. Concentration afforded 4.63 g (96%) of product as a clear oil. 1H NMR (DMSO-d6) δ 7.86 (s, 2H), 7.60-7.40 (m, 10H), 3.85 (2s, 5H), 1.19 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:41]([CH2:43][NH2:44])[OH:42]>C(Cl)(Cl)Cl>[OH:42][CH2:41][CH2:43][NH:44][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][CH:27]=[C:17]([N:10]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9]2)[CH:18]=1
Reactant: NCCO
Reactant: O=C(O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1)NCCO
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
In 60 ml of chloroform were dissolved 4.0 g of 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetic acid and 1.3 g of triethylamine. Thereto, 1.4 g of ethyl chlorocarbonate was added at -40° C. The mixture was stirred for 30 minutes. After 0.8 g of ethanolamine was added thereto, the temperature was gradually elevated to room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with chloroform. The organic layer was concentrated. The obtained white crude crystals were recrystallized from dioxane to give 2.4 g of N-(2-hydroxyethyl)-3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]-pyridin-1-yl]phenoxyacetamide, m.p. 161°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12]>S(=O)(=O)(O)O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][CH2:12][CH2:11][C:13](=[O:14])[CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COc1ccc(COCCC(C)=O)cc1
Reaction time: 1 h

Procedure:
Combine 4-methoxybenzyl alcohol (13.8 g, 0.10 mole) with methyl vinyl ketone (8.4 g, 0.12 mole), treat with 5 drops of concentrated sulfuric acid, and stir 1 hour. Dilute with ethyl ether, wash with 1.0 N sodium bicarbonate solution, dry the organic phase over anhydrous sodium sulfate and evaporate in vacuo to obtain the title compound, m.p. 48-9° C.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[C:10]([CH3:48])=[C:11]([CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)[C:12]([O:33][CH3:34])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3C2CCCCO2)[CH3:16])[CH:14]=1.C(Cl)[Cl:50]>>[Cl:8][C:9]1[C:10]([CH3:48])=[C:11]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:12]([O:33][CH3:34])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH:14]=1.[ClH:50]
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.0 M HCl in dioxane (2.0 mL, 8 mmol) was added to a solution of tert-butyl 4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]piperidine-1-carboxylate (250 mg, 0.43 mmol) in methylene chloride (1.0 mL, 16 mmol) and the reaction was stirred at room temperature for 1 hour. The solvent was removed to provide the desired product as HCl salt which was used in the next step without further purification. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2. found: =401.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=O.N1C=C[CH:12]=[CH:11][C:10]=1[CH:15]=[O:16]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[CH:12][CH:11]=[CH:10][CH:15]=[O:16]
Reactant: O=Cc1cnccn1
Reactant: O=Cc1ccccn1
Product: O=CC=CC=Cc1cnccn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 2-pyrazinecarboxaldehyde for the 2-pyridinecarboxaldehyde of Reference Example 5. MS 161 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[NH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:7](=[O:12])[C@@H:6]([CH3:13])[NH:5][C:4]=2[N:3]=1
Reactant: C[C@H]1Nc2nc(Cl)ncc2NC1=O
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1Nc2nc(Cl)ncc2N(c2cccc(C#N)c2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
To a stirred solution of (7R)-2-chloro-7-methyl-7,8-dihydropteridin-6(5H)-one (4.2 g, 21.15 mmol) in dichloromethane (350 mL) was added triethylamine (29.61 ml, 211.5 mmol), cupric acetate (7.69 g, 42.30 mmol) and 3-cyanophenyl boronic acid (6.62 g, 42.30 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 24 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (Yield: 39%). 1HNMR (300 MHz, CDCl3): δ 1.66 (d, J=6.9 Hz, 3H), 4.55 (q, J=5.1 Hz, 1H), 5.98 (br s 1H), 7.16 (s, 1H), 7.50-7.53 (m, 1H), 7.59-7.68 (m, 1H), 7.72 (t, J=7.8 Hz, 1H) and 7.81-7.83 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1cc(F)cc(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C)cc(F)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-5-methylbenzoic acid (1.50 g, 9.73 mmol, Oakwood) in Acetone (40 mL) was added Potassium carbonate (1.34 g, 9.73 mmol) followed by Methyl iodide (0.73 mL, 12 mmol). The reaction mixture was heated to 65° C. for 1 hour, heating discontinued and stirred overnight, then heating resumed at that temperature for a further 2 hours. Additional Methyl iodide (0.5 mL, 8 mmol) was added and heating was continued for 6 hours. Solids were removed by filtration and acetone was removed in vacuo. The residue was partitioned between 1N NaOH and ethyl acetate. The aqueous portion was extracted with a further two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, decanted and concentrated. The product so obtained was used without further purification (1.64 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.66-7.63 (m, 1H), 7.51 (d, 1H), 7.10-7.04 (m, 1H), 3.91 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C@:17]2([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[O:22][C:21](=[O:23])[CH:20]=[C:19]([OH:24])[CH2:18]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C>[Pd].C1COCC1>[CH:25]1([C@@:17]2([CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[O:22][C:21](=[O:23])[CH:20]=[C:19]([OH:24])[CH2:18]2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1C=C(O)C[C@@](CCc2cccc(OCc3ccccc3)c2)(C2CCCC2)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1C=C(O)C[C@@](CCc2cccc(O)c2)(C2CCCC2)O1

Procedure:
The title compound was prepared as described in General Method 4 using (S)-6-[2-(3-benzyloxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (0.64 g, 1.63 mmol) from Example EEEEE, 0. I g of 20% Pd over charcoal and THF (16 mL). Purification by silica gel chromatography, eluting with CH2Cl2 :MeOH (97.5:2.5) gave the title compound. 1H-NMR (DMSO-d6) δ 1.3-1.7 (m, 8 H), 1.85-1.95 (m, 2 H), 2.35 (t, 1 H), 2.4-2.6 (m, 4 H), 4.95 (s, 1 H), 6.55-6.6 (m, 3 H), 7.05 (t, 1 H), 9.25 (s, 1 H), 11.35 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: O=Cc1ccc(Cl)cc1
Product: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1F

Procedure:
Ethyl 4-amino-2-fluorobenzoate (17 g), 4-chlorobenzaldehyde (14 g), and 100 ml of absolute alcohol are heated on a steam bath for 10 minutes. Upon cooling, the mixture is filtered. The residue is dried and then dissolved in 200 ml of hot ethanol and 4 g of sodium borohydride is added in portions with stirring. The mixture is then heated under reflux, with stirring, for 3 hours, cooled, added to ice water and filtered to yield ethyl 4-(p-chlorobenzylamino)-2-fluorobenzoate as a solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:26])OC2C=CC=CC=2)[N:14]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[N:13]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:34]([C:36]1[N:41]=[C:40]([NH:42][C:43]2[CH:48]=[C:47]([CH2:49][O:50][C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:54]([NH:61]C(=O)OC(C)(C)C)=[CH:53][CH:52]=3)[CH:46]=[CH:45][N:44]=2)[CH:39]=[N:38][CH:37]=1)[CH3:35]>C1COCC1>[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:61][C:54]2[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:51]([O:50][CH2:49][C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:40]4[CH:39]=[N:38][CH:37]=[C:36]([CH2:34][CH3:35])[N:41]=4)[CH:48]=3)=[CH:52][CH:53]=2)=[O:26])[N:14]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[N:13]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cncc(Nc2cc(COc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc34)ccn2)n1
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
Triethylamine (0.013 mL, 0.093 mmol) was added to a solution of phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate B) (0.042 g, 0.121 mmol) and N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine (Intermediate D) (0.093 g, 0.250 mmol) in THF (1.5 mL) at 40° C. The reaction mixture was stirred at 40° C. for 40 min then cooled to RT and stirred for 3 days, and then concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g column, 0 to 5% MeOH in DCM) to give an off white-brown solid. The product was re-purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 45-75% MeCN in Water) to afford the title compound 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea as an off white solid (0.029 g, 49%); Rt 2.26 min (Method 1); m/z 627 (M+H)+ (ES+), 625 (M−H)− (ES−); 1H NMR δ: 1.18 (3H, t), 1.28 (9H, s), 2.40 (3H, s), 2.63 (2H, q), 5.36 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.07 (1H, dd), 7.37 (2H, m), 7.45 (2H, m), 7.56-7.67 (3H, overlapping m), 7.94 (1H, m), 7.99 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.39 (1H, m), 8.60 (1H, s), 8.81 (1H, s), 8.92 (1H, s), 10.08 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([C:17]([O:19]CC)=[O:18])=[CH:12]2)=[O:5].[OH-].[Na+]>O1CCCC1>[C:17]([C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:26])([OH:19])=[O:18]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.2 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (300 mg), 1N sodium hydroxide solution (1.95 ml) in tetrahydrofuran (10 ml) was stirred for 6 hours at 50° C. The mixture was concentrated in vacuo, and water was added to the residue. The solution was washed with diethyl ether, and the aqueous layer was adjusted to pH 3 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give 3-carboxy-8-(2,6-dichlorobenzoylamino)quinoline (251.1 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][CH3:7])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCC(C)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1
Product: CCC(C)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 3 was followed for the reaction of 60g (0.5 mole) of 2-methylbutyryl chloride with 67g (0.5 mole) of tert-butylbenzene. Obtained was 98.6g of a clear liquid: ir (film) 3.4 (s), 5.95 (s), 8.2 (m) microns; nmr (CDCl3) 7.66 (4H, d of d) 3.37 (1H, q), 1.77 (2H, m), 1.28 (9H, s), 1.16 (3H, d), 0.88 (3H, t) ppm. A VPC analysis indicated a single pure product.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:12]([OH:14])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[OH-].[Pd+2].CCOC(C)=O.C(O)C>[C:2]1([CH2:1][CH2:9][CH2:10][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[C:12]([OH:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)[C@H](CCCc1ccccc1)NC(=O)C(F)(F)F
Yield: 84.3 %

Procedure:
Reduce the product of Step 1 (9.7 g) with Pearlman's catalyst (3.5 g) in EtOAc (75 ml) and ethanol (25 ml) at 50 psi H2 for 3 hours. Filter, concentrate and wash the resultant residue with 3:1 hexane:diethyl ether to give the title compound (7.8 g).
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17].[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+].C(O)(=O)C>CO>[NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)OCN1C(=O)C2=C(CN)C=NC2=NC1N
Reactant: O=C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)OCN1C(=O)C2=C(CNC3CCCC3)C=NC2=NC1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
In 10 ml of dry methanol were dissolved 251 mg of 2-amino-5-aminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one and 252 mg of cyclopentanone and the mixture was allowed to stand under stirring at room temperature for 30 min. The mixture was then cooled to 0° C. and treated with 38 mg of sodium borohydride for 2 hrs. The excess reagent was decomposed with acetic acid, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 218 mg of 2-amino-5-cyclopentylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. The whole amount of this product was dissolved in 60 ml of 2 N--HCl and, after nitrogen purging, hydrolyzed at 70° C. for 5 hrs. The solvent was then evaporated to dryness under reduced pressure to give 196 mg of the desired compound.
Reaction SMILES: [Br:1]Br.[CH3:3][CH2:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]>C(O)C>[Br:1][CH:4]([CH3:3])[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: CCC(=O)c1cccc2ccccc12
Solvent: CCO
Product: CC(Br)C(=O)c1cccc2ccccc12

Procedure:
53.3 g (0.334 mol) of bromine was added dropwise to a solution consisting of 61.1 g (0.332 mol) of 1-propionaphthone and 180 mL of ethanol at 50 to 55° C. After completion of addition, the ethanol was distilled off in vacuo, and the resulting concentrate was dissolved in 130 mL of toluene, washed with a mixed aqueous solution of sodium bicarbonate and sodium chloride (150 mL×two times), and then dried over sodium sulfate to obtain a toluene solution of 2-bromo-1′-propionaphthone.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[O:23])=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Following a procedure similar to that of Example 1 but using 2.544 g of 4-carbamoylimidazolium-5-olate and 5.922 g of p-benzyloxybenzoyl chloride, there was obtained 5-carbamoyl-1H-imidazole-4-yl p-benzyloxybenzoate.
Reaction SMILES: [Cl:1]C1C=CC(C(O)=O)=C(OCC2C3C(OC(C)(C)O3)C(N3C=NC4C3=NC=NC=4NC(NC3C=CC=CC=3)=O)O2)N=1.Cl[C:43]1[N:51]=[C:50]([O:52][CH2:53][CH:54]2[CH:61]3[CH:57]([O:58][C:59]([CH3:63])([CH3:62])[O:60]3)[CH:56]([N:64]3[CH:72]=[N:71][C:70]4[C:65]3=[N:66][CH:67]=[N:68][C:69]=4[NH:73][C:74]([NH:76][C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)=[O:75])[O:55]2)[CH:49]=[CH:48][C:44]=1[C:45]([OH:47])=[O:46]>>[Cl:1][C:49]1[C:50]([O:52][CH2:53][CH:54]2[CH:61]3[CH:57]([O:58][C:59]([CH3:63])([CH3:62])[O:60]3)[CH:56]([N:64]3[CH:72]=[N:71][C:70]4[C:65]3=[N:66][CH:67]=[N:68][C:69]=4[NH:73][C:74]([NH:76][C:77]3[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=3)=[O:75])[O:55]2)=[N:51][CH:43]=[C:44]([CH:48]=1)[C:45]([OH:47])=[O:46]
Reactant: CC1(C)OC2C(COc3ccc(C(=O)O)c(Cl)n3)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Reactant: CC1(C)OC2C(COc3nc(Cl)ccc3C(=O)O)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Product: CC1(C)OC2C(COc3ncc(C(=O)O)cc3Cl)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1

Procedure:
6-Chloro-2-{2,2-dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (isomer A) & 2-Chloro-6-{2,2-dimethyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-nicotinic acid (isomer B):
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([C:13]3=[O:20])[CH2:11]1)[CH2:17]2.CS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:16]23[CH2:18][CH:12]4[CH2:11][CH:10]([CH2:19][CH:14]([C:13]4=[O:20])[CH2:15]2)[CH2:17]3)[CH:3]=1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: Oc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Product: O=C1C2CC3CC1CC(c1cc(Br)ccc1O)(C3)C2
Temperature: 80 °C
Yield: 78.1 %

Procedure:
The mixture of 4-bromophenol (3.11 g, 17.98 mmol), 5-hydroxy-2-adamantanone (2.49 g, 14.98 mmol), and MeSO3H (7 mL) was stirred with heating at 80° C. (oil-bath) for 5 h. The resulting mixture was quenched with H2O (40 mL) and filtered. The precipitate was washed several times with H2O, 5% NaHCO3, and CH2Cl2 and dried to give 3.76 g (79%) of 5-(5′-bromo-2′-hydroxyphenyl)-2-adamantanone as a white solid, mp 287-289° C. 1H NMR 8 (DMSO-d6) 1.82-2.45 (m, 13H, AdCH and AdCH2), 6.71 (d, J=8.5 Hz, 1H, 3′-ArH), 7.10 (d, J=2.4 Hz, 1H, 4′-ArH), 7.16 (dd, J=2.4 Hz, 8.5 Hz, 1H, 6′-ArH), 9.78 (s, 1H, OH).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:33]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:27]5[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][CH:16]=3)=[N:13][CH:14]=2)O1.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[S:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[N:46]=2)=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1COCC1>[CH:23]1[C:22]2[N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[N:13]=[CH:14][C:9]([C:36]5[CH:41]=[N:40][C:39]([C:42]6[S:43][C:44]7[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=7[N:46]=6)=[CH:38][CH:37]=5)=[CH:10][CH:11]=4)=[CH:16][CH:17]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3s2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2sc(-c3ccc(-c4ccc(-c5ccc(-n6c7ccccc7c7ccccc76)cc5)nc4)cn3)nc2c1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of 7 (0.841 g, 1.89 mmol), 9 (0.549 g, 1.89 mmol), tetrakis(triphenylphosphine)palladium(0) (109 mg, 94.2 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) was degassed with argon for about 20 min while stirring. The stirring reaction mixture was then maintained under argon at about 80° C. for about 18 h. Upon confirming consumption of the starting materials by TLC (SiO2, CH2Cl2), the mixture was cooled to RT and poured over CHCl3 (300 mL). The organics were then washed with sat. NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 100% CH2Cl2 to 49:1 CH2Cl2-acetone) provided 19 (0.72 g, 72%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH:17][CH3:18]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][N:17]([CH3:18])[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1(c2cccc(F)c2)CCCCC1
Reactant: CNC
Product: CN(C)CC1(c2cccc(F)c2)CCCCC1
Yield: 39.1 %

Procedure:
The title compound was prepared from 1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by column chromatography (SiO2, MeOH/CH2Cl2, MeOH from 0% to 15%) to give 1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (46 mg, 39%) as a clear oil. 1H NMR (CDCl3): δ 1.32-1.38 (m 3H), 1.49-1.56 (m, 3H), 1.59-1.66 (m, 2H), 1.99 (s, 6H), 2.05-2.09 (m, 2H), 2.33 (s, 2H), 6.83-6.88 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.23-7.29 (m, 1H). 13C NMR (CDCl3) δ 22.4, 26.8, 34.4, 43.6, 48.6, 72.9, 112.2, 112.4, 114.6, 114.8, 123.2, 129.4, 129.5, 162.0, 164.5.ESI MS m/z 236.