Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc2c(Cl)ccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(Cl)ccnc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (250 mg, 0.74 mmol), (prepared as described for the starting material in Example 1), in suspension in DMF (4 ml) were successively added 4-chloro-7-hydroxyquinoline (133 mg, 0.74 mmol) and potassium carbonate (153 mg, 1 mmol) and the reaction mixture heated to 100° C. More 4-chloro-7-hydroxyquinoline (27 mg, 0.15 mmol) was added after one hour and heating was continued for a further 30 minutes. The product precipitated upon cooling to ambient temperature. The reaction mixture was diluted with water, the product was collected by filtration and washed with more water. The dried solid was triturated with ether and filtered to give 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (166 mg, 47%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 4 h
Yield: 19.7 %

Procedure:
Under a nitrogen atmosphere, 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 2.3 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (0.64 mL, 4.6 mmol) using mild heat and vigorous stirring. The solution was chilled in an ice-water bath and 4-morpholinecarbonyl chloride (0.27 mL, 2.3 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for an additional 4 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (25 mL). The phases were separated and the organic layer was washed with water (3×25 ml), brine (25 mL), dried (Na2SO4), filtered and concentrated to yield a yellow foam. The product was recrystallized from dichloromethane and ethyl acetate. The crystals were triturated with ether (2×5 mL) to remove residual solvent. The final product was dried in a vacuum oven to provide 200 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide as a tan crystalline solid, m.p. 164-166° C.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[C:9]1=[O:39])(C)(C)C>FC(F)(F)C(O)=O.CO.[C].[Pd]>[NH2:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9](=[O:39])[C@@H:10]1[CH2:28][CH2:29][CH2:30][NH2:31])=[O:27]
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)CNC(=O)OCc2ccccc2)[C@@H](CCCNC(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of trifluoroacetic acid was dissolved 500 mg of (S)-4-benzyloxycarbonylaminoacetyl-3-(3-t-butoxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid t-butyl ester. The solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure to leave an oily product, which was dissolved in 10 ml of methanol. To the solution was added 10 mg of 10% palladium-carbon. The mixture was stirred for one hour at room temperature under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to leave a crude product of (S)-4-aminoacetyl-3-aminopropyl-2-oxopiperazine-1-acetic acid. This product was dissolved in a mixture of 10 ml of water and 10 ml of dioxane. To the solution was added 400 mg of sodium hydrogen carbonate. Subsequently, 420 mg of 3-(4-carboxyphenylamino)-1,2,4-oxadiazolin-4H-5-one produced in Reference Example 25 and 250 mg of N-hydroxysuccinimide were dissolved in 5 ml of dimethylformamide. To the solution was added 450 mg of dicyclohexyl carbodiimide. The mixture was stirred for 3 hours at room temperature, then concentrated under reduced pressure to leave an oily substance. This substance was dissolved in 5 ml of dioxane, and added to the solution of (S)-4-aminoacetyl-3-aminopropyl-2-oxopiperazine-1-acetic acid prepared as above. The mixture was stirred for 6 hours at room temperature. The reaction mixture was neutralized with 1N HCl, then concentrated under reduced pressure to give a crude product, followed by purification by means of a sephadex LH-20 column to afford 230 mg of the title compound as a colorless amorphous powdery product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].CC[O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:14](=[O:13])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][NH:5]2)=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2cc(F)c(OC)cc2c1=O
Temperature: 110 °C
Yield: 46.5 %

Procedure:
A mixture of 3-fluoro-4-methoxyaniline (3.00 g, 21.26 mmol) and diethyl ethoxymethylene malonate (4.59 g, 21.26 mmol) is heated at 110° C. for 1 hour then cooled to room temperature. Hexane is added and the solids collected by filtration. This material is suspended in 45 mL of a 3:1 mixture of diphenyl ether:biphenyl and the mixture is heated at reflux for 2 hours to provide a brown solution. The reaction mixture is cooled to room temperature and hexane is added. The resultant solid is collected by filtration washing with hexane to provide 2.62 g of ethyl 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate as a white solid, mp>300° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:28][CH2:29]2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(C4CC4)c(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(OC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 3-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.029 g, 0.068 mmol) in DCM (2 mL) was added TFA (0.35 mL) dropwise and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-yloxy)-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a white solid (0.020 g, 90%). LC/MS (Table 1, Method 5) Rt=2.056 min.; MS m/z: 329 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2([OH:15])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CC2(O)CCNCC2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CC2(O)CCNCC2)cc1
Reaction time: 13 h

Procedure:
6.6 g of Raney nickel is added to a solution of 66.45 g (0.281 mol) of 4-(4-nitrobenzyl)piperidin-4-ol in 660 mL of methanol. The reaction mixture is hydrogenated for 13 hours at ambient temperature and 3 bar hydrogen. The catalyst is filtered off and the filtrate is evaporated down. Yield: 64.5 g (111% of theory); C12H18N2O (M=206.28); calc.: molecular ion peak (M+H)+: 207; found: molecular ion peak (M+H)+: 207.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](=[CH2:11])[C:9]#[N:10])[CH2:3][CH2:2]1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]CC.[Na+].Cl>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[CH2:11][N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:19][C:9]2=[NH:10])[CH2:3][CH2:2]1
Reactant: NNc1ccccc1
Reactant: C=C(C#N)CN1CCOCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C1NN(c2ccccc2)CC1CN1CCOCC1

Procedure:
α-Morpholinomethylacrylonitrile (54g) and phenylhydrazine (37g) were boiled under reflux with a solution of sodium ethoxide (7.5g sodium) in ethanol (250 ml) for two hours. A solid product was formed during the reaction. Dilute hydrochloric acid (160 ml 2N) was added and the solution was evaporated to dryness. The solid residue was extracted with dry ethanol and the product crystallised from the ethanol as colourless plates (melting point 204-5° C).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH2:14]([SH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C(=O)C>[CH2:14]([S:22][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCS
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCSc1ccc(C#N)c(C#N)c1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
While cooling a reaction vessel on a water bath, were mixed 17.3 g (100 mmol) of 4-nitrophthalonitrile, 15.7 g (110 mmol) of 1-octanethiol, 20.7 g (150 mmol) of potassium carbonate and 80 ml of N,N-dimethylacetamide. The resultant mixture was stirred for 7 hours at room temperature and then for 1 hour at 40° C. The thus-obtained reaction mixture was poured into 600 ml of a 3% hydrochloric acid. The resultant precipitates were separated by a filtration under reduced pressure, and then washed with water and dried. Thereafter, by recrystallization from a mixed solvent of methanol (190 ml)/water (9 ml), there was obtained 18.5 g (Yield: 68%) of white powder synthesis intermediate (A-1) (Melting point=37 to 38° C.).
Reaction SMILES: Cl.C(O)(=[O:4])C.[C:6]([C:12]#[N:13])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)(O)[O-].[Na+]>>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6](=[O:11])[C:12]([NH2:13])=[O:4]
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)C(=O)C(N)=O
Yield: 75.1 %

Procedure:
Hydrogen chloride was passed into a mixture of 60 g (1 mole) of glacial acetic acid and 111.0 g (1 mole) of pivaloyl cyanide at 20° to 25° C. and under 8 bars for 5 hours. The reaction mixture was then let down and poured onto an excess of a saturated sodium bicarbonate solution. The mixture was extracted three times with 200 ml of methylene chloride each time. The combined organic phases were washed with 200 ml of water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue which remained crystallized after a short time. Recrystallization from petroleum ether gave 97 g (75.2% of theory) of trimethylpyruvic acid amide of melting point 68° to 69° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1COCC1.N1C=CC=CC=1>[C:1]([O:7][CH2:8][CH3:9])(=[O:6])/[CH:2]=[CH:3]\[CH2:4][CH3:5]
Reactant: CCC#CC(=O)OCC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC/C=C\C(=O)OCC
Yield: 98.5 %

Procedure:
To a slurry of Lindlar catalyst (0.844 g, 0.396 mmol) in THF (100 mL) and pyridine (10.00 mL) was added ethyl pent-2-ynoate (5.22 mL, 39.6 mmol). The reaction mixture was sparged with hydrogen for about 10 min and an atmosphere of hydrogen was maintained via balloon. After about 15 h the reaction mixture was filtered through a pad of Celite®, diluted with Et2O (30 mL) and washed with saturated aqueous CuSO4 (40 mL), followed by water (40 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd in vacuo to provide crude (Z)-ethyl pent-2-enoate (5 g, 98%). 1H NMR (DMSO-d6) δ 1.05 (t, 3H), 1.28 (t, 3H), 2.65 (m, 2H), 4.18 (q, 2H), 5.72 (m, 1H), 6.21 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH3:24].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:24])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Reactant: CNCCOC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCN(C)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Temperature: 140 °C

Procedure:
A suspension of (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (250 mg, 0.7 mmol), N-methoxyethyl-methylamine (99 mg, 1.1 mmol), sodium tert-butoxide (142 mg, 1.5 mmol) and di-μ-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 185812-86-6] (29 mg, 0.04 mmol) in toluene (5 mL) was sealed in a microwave vial and heated for 30 min at 140° C. (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with EtOAc, dried (Na2SO4) and evaporated in vacuo. The crude product was purified by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give the title compound after lyophilization. MS (LC/MS): 347.0 [M]+. tR (HPLC conditions c): 5.23 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)CCC>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH2:2][CH2:3][CH2:4][CH3:5])=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and n-butanol Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C32H35N3O3
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH:14]([F:20])[N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:8]=1>CO.O>[Cl:3][C:4]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:21])[CH:14]([F:20])[N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(F)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(F)n1cncn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
With stirring, 0.6 g of sodium borohydride is added at 5°-10° C. to a suspension of 12.1 g of 1-[4-(2,4-dichlorophenoxy)phenyl]-2-fluoro-2-(1H-1,2,4-triazol-1-yl)ethanone in 100 ml of methanol and 2 ml of water and the resultant mixture is stirred further first for 1 hour at 5°-10° C. and then for 2 hours at room temperature, whereupon a clear solution gradually forms. This solution is then poured into ice-water and extracted twice with dichloromethane. The organic phase is separated, washed twice with water, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography through a column of silica gel eluted with diethyl ether, affording the following three fractions: The first fraction is concentrated by evaporation and the residue is recrystallised from petroleum ether, affording beige crystals with a melting point of 138°-139° C. Analytic and spectroscopic data show the presence of the pure diastereoisomer A. The second fraction is also concentrated by evaporation and the residue is recrystallised from diethyl ether, affording beige crystals with a melting point of 115°-116° C. Spectroscopic data shows that a mixture of both diastereoisomers A and B (approx. 1:1) is obtained. Similar working up of the third fraction affords the third pure diastereoisomer B with a melting point of 107°-108° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:19])[C:10]([N-]N1CCOCC1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([Li])([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1.CCCCC>[CH2:1]([O:8][C@@H:9]([C:10](=[O:11])[CH:20]([CH3:22])[CH3:21])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C(C)C
Reactant: C[C@@H](OCc1ccccc1)C(=O)[N-]N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)C(=O)[C@@H](C)OCc1ccccc1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a stirred solution of (R)-2-benzyloxypropionyl N-morpholinyl amide (10 mmol) in THF (20 mL) under nitrogen atmosphere at −78° C. was added dropwise isopropyl lithium (15 mmol) in pentane. The reaction mixture was stirred at −78 C for 3 h (monitored by tlc). The reaction mixture was poured into saturated ammonium chloride solution and then extracted with ethyl acetate (3×25 mL). The combined extract was washed with water (2×25 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by passing through a short silica gel column using a 0-25% gradient of ether and n-pentane as eluents to give pure 20a as a colorless liquid in 94% yield. 1H NMR (400 MHz, CDCl3): δ 1.08 (3H, d); 1.10 (3H, d); 1.36 (3H, d); 3.02 (1H, m); 4.06 (1H, q); 4.46 (2H, dd); 7.33-7.34 (5H, m). MS (ESI) m/z 207.13 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([NH:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=1
Reactant: Nc1cc(Br)cc2[nH]ccc12
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cc(Br)cc2[nH]ccc12
Yield: 101.8 %

Procedure:
6-Bromo-1H-indol-4-amine (500 mg, 1.97 mmol) was treated with methanesulfonyl chloride (167 μl, 2.16 mmol) according to the method described in Preparation 15b to give 580 mg (91% yield) of the title compound. Purity 89%.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])C1C=CC=CC=1>ClCCl.FC(F)(F)C(O)=O.N.[Pd]>[CH2:31]([O:30][P:25]([CH2:24][O:23][C@@H:10]([CH2:9][OH:8])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])([O:27][CH2:28][CH3:29])=[O:26])[CH3:32]
Reactant: CCOP(=O)(CO[C@@H](COCc1ccccc1)COn1cnc2c(N)ncnc21)OCC
Agent: [Pd]
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(CO[C@@H](CO)COn1cnc2c(N)ncnc21)OCC
Reaction time: 5 h

Procedure:
10% Pd-C (50 mg) was added to a solution of (S)-9-[3-benzyloxy-2-(diethoxyphosphorylmethoxy)propoxy]adenine (0.21 g, 0.45 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (lml) and the mixture hydrogenated at atmospheric pressure and ambient temperature for 5 hours. The mixture was filtered, the filtrate evaporated and the residue obtained dissolved in ethanolic ammonia solution (5 ml). After 15 minutes the solvent was evaporated and the residue chromatographed on silica gel using dichloromethane/methanol 90:10 as eluant. T.l.c. examination of the product indicated traces of a non UV absorbing impurity which was removed by prep. t.l.c. using dichloromethane/methanol 88:12 as eluant. (S)-9-[2-(diethoxyphosphorylmethoxy)3-hydroxypropoxy]adenine was obtained as a colourless gum (0.11 g, 65%). 1H NMR: δH [(CD3)2SO] 1.23 (6H, t, J=7 Hz, (OCH2CH3)2), 3.5-3.65 (2H, m, CH2OH), 3.75-3.85 (1H, m, CH), 3.98-4.15 (6H, m, OCH2P, (OCH2CH3)2), 4.38 (1H, dd, J=6.6 Hz, J=11.3 Hz, NOCHB), 4.54 (1H, dd, J=3 Hz, J=11.3 Hz, NOCHA), 4.88 (1H, t, J=5.5 Hz, D2O exchangeable OH), 7.38 (2H, br.s, D2O exchangeable NH2), 8.15 (1H, s, H-2 or H-8), 8.43 (1H, s, H-2 or H-8). m/z: (FAB+, thioglycerol matrix) 376 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:17][C:16](/[CH:18]=[CH:19]/[C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[N:15][CH:14]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]([CH2:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[N:15][CH:14]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C/c1ncc(-c2cnc(-c3ccccc3)nc2)[nH]1)\c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(-c2ncc(-c3cnc(CCc4cccnc4)[nH]3)cn2)cc1
Reaction time: 120 h
Yield: 106.9 %

Procedure:
The title compound was prepared by subjecting (E)-2-phenyl-5-(2-(2-(pyridin-3-yl)vinyl)-1H-imidazol-5-yl)pyrimidine (Example 15, 7 mg, 0.02 mmol) to hydrogenation using 10% palladium on carbon (dry, 1 mg) in ethanol (3 mL). After five days, the reaction mixture was filtered through Celite using ethanol to rinse. Evaporation provided the title compound as a brown solid (7 mg, quantitative yield); melting point 113° C.; 1H-NMR (400 MHz; CD3OD) δ 9.16 (s, 2H), 8.39-8.44 (m, 4H), 7.64 (s, 1H), 7.52-7.53 (m, 5H)), 3.12-3.19 (m, 4H); LC/MS (ESI+) m/z 328; H-PGDS FPBA IC50: 0.3 μM.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].C(O)(=O)C.[K+].[Br-]>C(O)C>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:23]([C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(C#N)cc3)nc2n(CCC)c1=O
Temperature: 0 °C

Procedure:
1,3-Dipropyl-8-(4-cyanophenyl)xanthine was prepared by treatment of 1,3-dipropyl-5,6-diaminouracil (6.37 g, 28.15 mmol) with 4-cyanobenzaldehyde (3.72 g, 28.37 mmol) in absolute ethanol (175 ml) with acetic acid (5 ml) heated at reflux for 2 hours. The reaction mixture was then cooled to 0° C., and the resulting precipitate collected, and recrystallized from ethanol yielding a white solid (8.1 g, 24.0 mmol, 85%) IR (KBr) 3142 (N--H), 2965 (C--H), 2232 (C=N), 1695 (C=O), 1651 (C=O) cm-1 ; 1H NMR (DMSO d6) δ8.2 (d,J=8 Hz, 6H). Anal. Calcd. for C18H19N4O21, MW. 337.38: C, 64.08; H, 5.68; N, 20.76. Found: C, 64.15, H, 5.69; N, 20.72.