Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[O:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:24]2[C@H:28]([OH:29])[C@H:27]([OH:30])[C@@H:26]([CH2:31][Cl:32])[O:25]2)C=CC=CC=1>C(O)C.C1CCCCC1.[OH-].[Pd+2].[OH-]>[OH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH:24]1[C@H:28]([OH:29])[C@H:27]([OH:30])[C@@H:26]([CH2:31][Cl:32])[O:25]1
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4OCc4ccccc4)ncnc32)[C@@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCCCC1
Product: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Reaction time: 6 h
Yield: 41.3 %

Procedure:
The 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol obtained in Example 3 (22 g) was dissolved in ethanol (450 mL) and cyclohexane (200 mL). To this solution was added palladium hydroxide (20 mole %, 1 gram added initially, 1 gram after 6 hours, and 1 gram after 14 hours), and the reaction mixture was refluxed for 18 hours. The reaction mixture was filtered thru celite while still hot, and solvent removed from the filtrate under reduced pressure. The product was triturated with ethanol (20 mL), filtered, and washed with ethanol, to afford 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol as a white powder (7.3 grams).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:24][C:25]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:25]1[C:34]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][C@@H:19]4[CH3:23])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC[C@@H]4C)n3)c3nccn3n2)c1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (124 mg, 0.38 mmol), methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (124 mg, 0.45 mmol), Pd2(dba)3 (22 mg, 0.038 mmol), X-phos (73 mg, 0.152 mmol) and Na2CO3 (121 mg, 1.14 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give (S)-methyl 2-methyl-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (72 mg, 43%) as a yellow solid. LC-MS: [M+H]+, 443.2, tR=1.880 min.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[N:12][C:11]2[N:14]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[BH4-].[Na+]>CCO>[CH:28]1([N:27]2[C:9]3[C:8](=[CH:13][N:12]=[C:11]4[N:14]([S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=5)(=[O:19])=[O:18])[CH:15]=[CH:16][C:10]4=3)[CH2:7][CH2:6][CH2:2]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(CCC4OCCO4)cnc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(cnc32)CCCN4C2CCCCC2)cc1
Temperature: 40 °C
Yield: 75.7 %

Procedure:
To a solution of 5-(2-(1,3-dioxolan-2-yl)ethyl)-N-cyclohexyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-amine (0.209 g, 0.445 mmol) in EtOH (2 mL) was added aqueous HCl (12 N, 0.186 mL, 2.23 mmol) dropwise. The mixture was heated at about 40° C. for about 2 h and then cooled to about 0° C. in an ice bath. Sodium borohydride (0.118 g, 3.12 mmol) was added portionwise and the mixture was warmed to ambient temperature. After about 2 h the solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3 (10 mL each). The aqueous phase was extracted with EtOAc (2×5 mL) and the combined organics were washed with water and brine (5 mL each), dried over anhydrous Na2SO4, filtered and concd under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc in heptane to give 1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]-[1,6]naphthyridine (0.138 g, 75%) as a white solid: LC/MS (Table 1, Method b) Rt=3.01 min; MS m/z: 410 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2nccnc2c1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of quinoxaline-6-carboxylic acid (438 mg, 2.51 mmol) in benzene (16 mL) was added oxalyl chloride (0.26 mL, 3.02 mmol) and anhydrous DMF (0.1 mL). The reaction was stirred at room temperature for 30 minutes after which the mixture was concentrated in vacuo. The resulting yellow solid was azeotroped 3× with toluene and the product was used immediately without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[C:17]1([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:24]([CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:26])=[O:25])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1

Procedure:
Starting materials: sodium hydride 60% (0.240 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (1.01 g), α-toluenesulfonylchloride (1.19 g). Reaction conditions: −30° C., 30 min; −30° C., 2.5 hours.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:10])[NH:8][CH3:9])=[C:5]([NH:11][C:12]([C:14]2[C:19](Br)=[CH:18][N:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[O:13])[CH:4]=[N:3]1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:1][N:2]1[C:6]([C:7](=[O:10])[NH:8][CH3:9])=[C:5]([NH:11][C:12]([C:14]2[C:19]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][N:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[O:13])[CH:4]=[N:3]1
Reactant: Nc1cccnc1
Reactant: CNC(=O)c1c(NC(=O)c2nc(C(C)C)ncc2Br)cnn1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(NC(=O)c2nc(C(C)C)ncc2Nc2cccnc2)cnn1C
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 5-bromo-2-isopropyl-pyrimidine-4-carboxylic acid (1-methyl-5-methylcarbamoyl-1H-pyrazol-4-yl)-amide (40 mg, 105 μmol), 3-aminopyridine (15 mg, 157 μmol) and potassium phosphate tribasic (31 mg, 147 μmol) in toluene (1 ml) was treated with tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (10.9 mg, 10.5 μmol) and xantphos (20 mg, 34.6 μmol) were added and the reaction mixture was stirred at 120° C. for 16 h. The reaction was cooled to r.t., filtrated and the product was obtained after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (10 mg, 25%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([CH:19]=1)[C:15](OC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S([O-])(O)(=O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([CH:19]=1)[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(CO)c1
Yield: 63.7 %

Procedure:
To a solution of methyl 5-tert-butoxycarbonylaminomethyl-2-nitrobenzoate (2.0 g, 6.45 mmol) and sodium borohydride (740 mg, 19.56 mmol) in THF (11 mL) was added dropwise methanol (1.5 mL) over 1.5 h under reflux. After the addition was completed, the excess reagent was decomposed with 5% aqueous potassium hydrogen sulfate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 3:1 to 1:1 hexane/ethyl acetate to give 1.16 g of the title compound (64%).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19]([CH3:29])([CH3:28])[CH2:20][CH2:21][N:22]3[CH:25]([CH3:27])[CH3:26])=[CH:17][C:16]=2[CH3:30])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH:25]([N:22]1[C:23]2[C:18](=[CH:17][C:16]([CH3:30])=[C:15]([N:11]([CH2:12][CH2:13][CH3:14])[C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:31])=[O:3])=[CH:10][CH:9]=3)[CH:24]=2)[C:19]([CH3:29])([CH3:28])[CH2:20][CH2:21]1)([CH3:26])[CH3:27]
Reactant: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C)(C)CCN2C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCN2C(C)C
Temperature: 50 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
A solution 4-[(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-propyl-amino]-benzoic acid ethyl ester (Compound 49, 12.0 mg, 0.0284 mmol) in ethanol (1 mL) was treated with 2N KOH (0.5 mL) and stirred at 50° C. for 2 days. The solvent was removed under reduced pressure and the residue was washed with ethyl acetate and acidified with 2N HCl. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexane, Rf=0.28) to give the title compound (11 mg, 98%) as a white solid: 1H NMR (300 MHz, CDCl3): δ0.95 (t, 3 H, J=7.4 Hz), 1.16 (d, 6 H, J=6.6 Hz), 1.31 (s, 6 H), 1.69-1.80 (m, 4 H), 1.95 (s, 3 H), 3.15 (t, 2 H, J=5.9 Hz), 3.54 (br s, 2 H), 3.97 (sp, 1 H, J=6.6 Hz), 6.47 (d, 2 H, J=8.9 Hz), 7.08 (s, 1 H), 7.88 (d, 2 H, J=8.9 Hz).
Reaction SMILES: [Si:1]([O:8]CC(=O)C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.CNC.[C-]#N.[K+].[CH3:20][N:21]([CH3:29])[C:22]1([C:27]#[N:28])[CH2:26]CC[CH2:23]1>O>[CH3:29][N:21]([CH3:20])[C:22]([CH3:23])([CH2:26][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:27]#[N:28]
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: CN(C)C1(C#N)CCCC1
Agent: CNC
Agent: Cl
Agent: [C-]#N
Solvent: O
Product: CN(C)C(C)(C#N)CO[Si](C)(C)C(C)(C)C
Yield: 45 %

Procedure:
The title compound (2.16 g, 45%) was prepared from 1-(t-butyldimethylsilyloxy)-2-propanone (3.77 g, 0.02 mol), dimethylamine hydrochloride (1.71 g, 0.02 mol) and potassium cyanide (1.37 g, 0.02 mol) in water (50 ml) in a similar manner to that described in D1. An additional purification step was passage of the compound through SCX resin, elution with DCM to remove the starting material and then elution with 1 M ammonia in methanol to elute the title compound. 1H NMR (CDCl3) δ: 0.00 (6H, d), 0.81 (9H, s), 1.38 (3H, s), 2.25 (6H, s), 3.36 (1H, d), 3.78 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:25](=[O:27])[CH3:26])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(C)=O
Yield: 91 %

Procedure:
A solution of 2 (p-methoxybenzyl) 3 methyl 4-hydroxy 5-propyl 7 chlorobenzofuran (0.10 gm, 0.29 mmoles), acetic anhydride (0.5 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxy benzyl)-3-methyl-4-acetoxy-5-propyl 7-chlorobenzofuran, mp. 119°-120° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=2)[N:10]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=2)[N:10]=1
Reactant: N#CCc1ccc(-c2nccc(OCc3ccccc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1ccc(-c2nccc(O)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.3 %

Procedure:
A mixture of 2-(4-(4-(benzyloxy)pyrimidin-2-yl)phenyl)acetonitrile (1.2 g) in 2,2,2-trifluoroacetic acid (15 ml) was stirred at room temperature for 2 h. Then, the solvent was removed under reduce pressure. The product was washed by ether to afford 2-(4-(4-hydroxypyrimidin-2-yl)phenyl)acetonitrile (1.02 g, 85%) as white solid. The title compound was determination by LC-MS (LC-MS (m/z)=212.1 [M+H]+)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[OH:16][CH2:17][C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:19][CH2:18][C:17]([NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)CO)C1

Procedure:
A mixture of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.0 equiv.), 2-hydroxyacetic acid (1.80 equiv.), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.0 equiv.), and N,N-dimethylpyridin-4-amine (0.20 equiv.) was stirred in DCM (0.1 M) at room temperature overnight. The reaction was quenched with water and washed (3×) with water. The combined aqueous fractions were then back-extracted with chloroform (4×) and the combined organics were dried over Na2SO4, filtered, and concentrated. The resulting oil was passed through a pad of SiO2 gel using 5-50% MeOH/DCM and concentrated to yield (R)-tert-butyl 2-((2-hydroxyacetamido)methyl)morpholine-4-carboxylate as an oil. LCMS (m/z) (M+H)=175.1 (-Boc), Rt=0.55 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:15][NH:16][O:17][CH3:18].Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[N:16]([O:17][CH3:18])[CH3:15])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
2-t-butoxycarbonylamino-propionic acid (25 g, 132 mmole) was dissolved in dimethylformamide (DMF, 300 ml). N,O-dimethylhydroxylamine HCl (12.9 g, 132 mmol) was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (26.6 g, 139.0 mmol), HOBT (17.8 g, 132 mmol), and NaHCO3 (44.4 g, 528 mmol). The reaction mixture was stirred under nitrogen for 48 h. The solution was then filtered, and the solvent evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with 2% aqueous HCl, saturated aqueous NaHCO3, and water. The organic layers were dried over sodium sulfate and evaporated under reduced pressure to provide [1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (intermediate XIIIa, 12.84 g, 42%). M+=233.
Reaction SMILES: CN([CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)C.O.C(=O)([O-])[OH:24].[Na+]>Cl.CS(C)=O>[OH:24][CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: O=C([O-])O
Reactant: CN(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c2c3ccccc3c(=CO)c2n2ccnc12

Procedure:
10-Hydroxymethylene-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one may be obtained in the following way: a solution of 1.4 g of 10-dimethylaminomethylene-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one in 35 ml of 5N hydrochloric acid is stirred for 30 minutes at a temperature in the region of 25° C. After addition of 60 ml of water and neutralization with 120 ml of saturated aqueous sodium hydrogen carbonate, the solid formed is isolated by filtration, washed twice with 60 ml in total of water and air-dried. The product obtained (1.1 g) is dissolved in 120 ml of dimethyl sulphoxide and, after addition of 120 ml of water, the solid formed is isolated by filtration, washed twice with 10 ml in total of distilled water and twice with 10 ml in total of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1 g of 10-hydroxymethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained as a 60/40 mixture of the Z and E forms, decomposing without melting at 290° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): a 60/40 mixture of isomers is observed: from 7.20 to 7.40 (mt, 2H: --H7 and --H8); 7.56 and 7.64-8.29 and 8.79 (4 broad s, twice 1H: --H of the imidazole); from 7.80 to 8.15 (mt, 2H: --H6 and --H9); 8.21 and 8.24 (2s, 1H in total: =CH--O--); 12.43 (mult., 1H: --NH--)].
Reaction SMILES: FC(F)(F)S(OC1C=C(OC)C=CC=1CCC1C=CC(OC)=CC=1)(=O)=O.C(OC1C=C(B(O)O)C=CC=1)C1C=CC=CC=1.C([O:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:59]=2[CH2:66][CH2:67][C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=2)[CH:55]=[CH:56][CH:57]=1)C1C=CC=CC=1>>[CH3:65][O:64][C:62]1[CH:61]=[CH:60][C:59]([CH2:66][CH2:67][C:68]2[CH:69]=[CH:70][C:71]([O:74][CH3:75])=[CH:72][CH:73]=2)=[C:58]([C:54]2[CH:55]=[CH:56][CH:57]=[C:52]([OH:51])[CH:53]=2)[CH:63]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2-c2cccc(OCc3ccccc3)c2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2OS(=O)(=O)C(F)(F)F)cc1
Agent: OB(O)c1cccc(OCc2ccccc2)c1
Product: COc1ccc(CCc2ccc(OC)cc2-c2cccc(O)c2)cc1
Yield: 44.3 %

Procedure:
Synthesized from 5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl trifluoromethanesulfonate and 3-benzyloxyphenylboronic acid according to an analogous synthetic method to Example 24, 3′-benzyloxy-5-methoxy-2-[2-(4-methoxyphenyl)ethyl]biphenyl (527 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (184 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].CCCCCC.Br[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32]>CN(C)C=O.O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:4]=[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]2[C:2]=1[NH:1][CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32]
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccccc1-c1nc2c3ccccc3ccn2c1NC(C)c1ccccc1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of 5 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 30 ml of dry N,N-dimethylformamide was added dropwise to a solution of 1.2 g of sodium hydride in oil (prewashed with hexane) in 10 ml of dry N,N-dimethylformamide over 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, a solution of 4.1 g of (1-bromoethyl)benzene in 30 ml of dry N,N-dimethylformamide was added dropwise. When addition was complete, the mixture was stirred at room temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, and recrystallized from benzene/hexane to give 5.3 g of the title compound as colorless needles.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11](CC(O)=O)[CH:12]=[CH:13][CH:14]=1.CN(C=O)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:1][C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
An excess of oxalyl chloride was added dropwise to a stirred mixture of 3-methoxyphenylacetic acid (33.2 g), DMF (4 ml) and methylene chloride (800 ml) and the mixture was stirred at ambient temperature for 65 hours. The mixture was evaporated to leave 3-methoxyphenylacetyl chloride (39.6 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=2)[NH:10][CH:9]=1>[Pd].O>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=2)[NH:10][CH:9]=1
Reactant: CCC(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd]
Solvent: O
Product: CCC(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1

Procedure:
Obtained from the title compound of Example 51 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a gum. Rf 0.70 (SS 7). [α]D25 +105° (c=0.1, C3OH). Found: C,73.04; H,8.66; N,8.97. C19H26N2O; 0.75 H2O requires C,73.15; H,8.88; N,8.98%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-[3-(1-pyrrolidinyl)propyl]-9H-purin-6-amine (49 mg, 0.141 mmol) was dissolved in methanol (5 ml) and 4M hydrogen chloride in 1,4-dioxane (0.879 ml, 3.52 mmol) was added and the mixture stirred at room temperature for 5 hours. The solvent was removed in vacuo to give a cream solid which was dissolved in methanol and loaded onto an aminopropyl SPE cartridge (2 g) and eluted with methanol. The solvent was evaporated to give the title compound as a white solid (43 mg).