Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:12][CH2:13]N(C(C)C)C(C)C.Cl.Cl.[NH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33][S:34]([C:37](F)(F)F)(=[O:36])=[O:35])[CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:10]=1)[C:5]([NH:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33][S:34]([CH:37]2[CH2:13][CH2:12]2)(=[O:36])=[O:35])[CH2:27][CH2:26]1)=[O:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(CCNS(=O)(=O)C2CC2)CC1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-dichlorobenzoic acid (23 mg, 0.12 mmol) in DMF (2 mL) was added DIPEA (0.1 mL, 0.6 mmol), N-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide dihydrochloride salt (40 mg, 0.12 mmol) and HATU (60 mg, 0.15 mmol). The reaction mixture was stirred at room temperature overnight. The organic layer was washed with sat. NaHCO3 aq. (8 mL), dried over Na2SO4, and concentrated to give crude product which was subsequently purified by High Throughput Purification System (HiTOPs).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH2:5][NH2:6]
Reactant: CCCOc1ccc(C#N)cc1O
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: CCCOc1ccc(CN)cc1O
Yield: 48 %

Procedure:
This compound was prepared by reduction of 3-hydroxy-4-propyloxybenzonitrile according to procedure described in preparation of 3,5-dibenzyloxybenzylamine. Yield was 48%: MP 110-113° C. (dec.); 1H NMR (CDCl3, 400 MHz) δ 6.86 (s, 1H), 6.77 (d, 1H, J=8.4 Hz), 6.74 (d, 1H, J=8.1 Hz), 3.95 (t, 1H, J=6.6 Hz), 3.74 (s, 2H), 2.01 (br, 2H), 1.82 (m, 2H), 1.02 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8](=[O:15])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].BrCCCC=C.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[CH:35]=CC=[C:32]([C:36]([O:38]O)=O)[CH:31]=1>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[C:8](=[O:15])[N:7]([CH2:35][CH2:30][CH2:31][CH:32]2[O:38][CH2:36]2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2C
Agent: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCC2CO2)c(=O)c2c1ncn2C
Temperature: 100 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
33.3 g (0.15 mole) of 3-butyl-7-methylxanthine, 24.3 g (0.16 mole) of 1-bromo-4-pentene and 22.1 g (0.16 mole) of potassium carbonate in 500 ml of dimethylformamide were heated with stirring at 100° C. for 15 hours. After cooling down, the reaction mixture was evaporated under reduced pressure, the residue was taken up in methylene chloride, filtered and the filtrate was extracted by shaking with 1N sodium hydroxide solution, the organic phase was washed with water to neutrality, dried over sodium sulfate and solvent was removed in a rotary evaporator. This produced 42.2 g (97% of theory) of crude, crystalline 3-butyl-7-methyl-1-(4-pentenyl)xanthine ##STR32## which was dissolved in 550 ml of chloroform, 35.6 g (0.175 mole) of 3-chloroperbenzoic acid (85% pure) were added and the mixture, after covering with an atmosphere of nitrogen, was stirred at room temperature for 67 hours. Extraction by shaking with 10% strength sodium dithionite solution until disappearance of the iodine-starch reaction, washing, initially with 10% strength sodium bicarbonate solution and then with water, drying over sodium sulfate and evaporation under reduced pressure provided 37.7 g (84.7% of theory) of crude 3-butyl-1-(4,5-epoxypentyl)-7-methylxanthine, ##STR33## which was subjected to hydrolytic opening of the oxirane ring without intermediate purification. For this purpose, the 37.7 g of epoxide was dissolved in a mixture of 200 ml of tetrahydrofuran and 135 ml of water, and 0.61 ml of perchloric acid (70% strength) was added dropwise with stirring within about 10 minutes at room temperature. After stirring at room temperature for 14 hours, the mixture was neutralized with saturated sodium bicarbonate solution and evaporated under reduced pressure. The remaining oily crude product (100% of theory) could be purified by column chromatography on silica gel with chloroform/methanol (volume ratio 10/1) as the eluting agent and subsequent recrystallization from ethyl acetate with the addition of petroleum ether at the boiling point until cloudy.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH2:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[N:4][C:5]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)=[CH:6][C:7]=1[NH:8]C(=O)OC(C)(C)C.[N:34]([O-])=O.[Na+].[OH-].[Na+].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C>[CH3:21][N:19]1[CH:20]=[C:16]([C:5]2[N:4]=[C:3]3[N:22]([CH2:23][C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:34]=[N:1][C:2]3=[C:7]([NH2:8])[CH:6]=2)[CH:17]=[N:18]1
Reactant: Cn1cc(-c2cc(NC(=O)OC(C)(C)C)c(N)c(NCc3ccc4ncccc4c3)n2)cn1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1cc(-c2cc(N)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
tert-Butyl 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate (890 mg, 2 mmol) was added to a solution of acetic acid (5 mL) and water (5 mL) at 0° C., followed by the addition of NaNO2 (300 mg, 4 mmol) in H2O (0.5 mL). The reaction was stirred at 0° C. for 1 h, then basified with 30% NaOH to pH=8. The resulting mixture was filtered to afford a solid. The solid was treated with TFA (3 mL), and then stirred at room temperature for another 0.5 h, before treated with aqueous Na2CO3 to adjust the pH to 8. The resulting mixture was purified by chromatography to afford the title compound (190 mg). MS: 358 (M+1)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].C1COCC1.Cl[C:16]1[CH:21]=[N:20][CH:19]=[C:18]([C:22]#[N:23])[N:17]=1>O.C(OCC)(=O)C>[C:22]([C:18]1[CH:19]=[N:20][CH:21]=[C:16]([S:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[N:17]=1)#[N:23]
Reactant: CN(C)CCS
Reactant: N#Cc1cncc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCSc1cncc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
2-Dimethylaminoethanethiol hydrochloride salt (1.46 g, 10.0 mmol) and sodium hydride (60% in oil, 0.88 g, 22.0 mmol) were added to THF (50 ml), and 2-chloro-6-cyanopyrazine (1.40 g, 10.0 mmol) was added thereto. The mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (1.00 g, 48%) as pale yellow crystals.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][CH2:9][CH2:10][N:11]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH3:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH2:32]>CO>[CH3:7][S:8]([CH2:9][CH2:10][N:11]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][CH2:22][CH3:23])(=[O:19])=[O:20])=[CH:16][CH:17]=1)(=[O:1])=[O:32]
Reactant: O=S([O-])OO
Reactant: CCNS(=O)(=O)c1ccc(N(CCSC)Cc2ccc(F)cc2)cc1
Reactant: O
Agent: [K+]
Solvent: CO
Product: CCNS(=O)(=O)c1ccc(N(CCS(C)(=O)=O)Cc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of Oxone® (0.54 g, 0.88 mmol) in H2O (2 mL) was added to a 0° C. solution of 4-[(2-methylthio-ethyl)-(4-fluoro-benzyl)-amino]-N-ethyl-benzenesulfonamide (0.13 g, 0.34 mmol) in MeOH (8 mL) resulting in an immediate precipitate. After 1 h, the mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layer was dried (Na2SO4), filtered, and evaporated in vacuo to afford 0.14 g (100%) of 4-[(2-methylsulfonyl-ethyl)-(4-fluoro-benzyl)-amino]-N-ethyl-benzenesulfonamide as a pale glass; (m+H)+ 415.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1[CH:30]=[CH:29]N=C1)=O.C1C[O:39]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:19]([O:21][CH2:22][CH2:23][OH:39])=[O:20])=[C:10]([CH3:18])[NH:11][C:12]([CH3:17])=[C:13]2[C:14]([O:16][CH2:29][CH3:30])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCO)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.4 g (10 mmol) of 4-(3-chlorophenyl)-3-(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid and 2 g (10 mmol) of carbonyldiimidazole are stirred overnight at room temperature in 50 ml of abs. THF. The mixture is evaporated, the residue is taken up in 50 ml of ethyl acetate and the mixture is washed twice with 50 ml of water each time. After drying over Na2SO4, the solvent is distilled off and the residue (3.55 g) is dissolved in 10 ml of abs. THF. After addition of 100 ml of ethylene glycol and 100 mg of NaH, the mixture is stirred at room temperature for 3 h, mixed with 100 ml of ethyl acetate and extracted twice by shaking with 100 ml of water each time. After drying over sodium sulphate, the extract is evaporated. The residue is homogeneous in the TLC and is further processed directly. Yield: 2.95 g (83% of theory)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:26](OC(C)(C)C)(=[O:31])[CH2:27][C:28]([O-])=[O:29].C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:22]([C:21]4[CH:24]=[CH:25][C:18]([N:15]5[CH2:16][CH2:17][CH:12]([OH:11])[CH2:13][CH2:14]5)=[CH:19][CH:20]=4)[C:28](=[O:29])[CH2:27][C:26]3=[O:31])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc2[nH]cnc2c1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCC(O)CC2)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.970 g, 7.3 mmol), 4-(4-hydroxypiperidin-1-yl)benzaldehyde (1.5 g, 7.3 mmol), mono-tert-butyl malonate (1.17 g, 7.3 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (1.15 g, 7.3 mmol) and sodium tert.-butoxide (1.5 g, 14.6 mmol) according to method 5.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:24])=O>ClCCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([Cl:24])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Solvent: ClCCCl
Product: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Yield: 100.7 %

Procedure:
In 100 ml of 1,2-dichloroethane, 57 g (0.19M) of 3,4,5-triacetoxybenzoic acid and 34 g (0.29M) of thionyl chloride were reacted at 60° C. for 2 hours. The excess thionyl chloride and 1,2-dichloroethane were distilled off under reduced pressure. Thus, 61 g of the desired compound was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[C:11]([OH:15])(=[O:14])[CH:12]=O.[C:16]1(/[CH:22]=[CH:23]/B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:7]([CH:2]([NH:1][C@@H:12]([CH:23]=[CH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([OH:15])=[O:14])[CH2:3][CH:4]([CH3:6])[CH3:5])([OH:9])=[O:8]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Product: CC(C)CC(N[C@@H](C=Cc1ccccc1)C(=O)O)C(=O)O
Reaction time: 24 h
Yield: 111.3 %

Procedure:
A mixture of L-leucine (100 mg, 0.762 mmol), glyoxylic acid monohydrate (70 mg, 0.762 mmol) and (E)-2-phenylethenyl boronic acid (113 mg, 0.764 mmol) in water (8 mL) was stirred vigorously for 24 hours at 50 C. The precipitate was isolated by filtration, washed with methanol (10 mL) and dried under vacuum to give (E)-2-[(S)-N-(-1′-carboxy-3′-methylbutyl)-amino-4-phenyl-3-butenoic acid (247 mg, 85% yield, 94% de). 1H-NMR (360 MHz, d6-DMSO) δ 7.2-7.5 (m, 5H), 6.62 (d, J=15.3 Hz, 1H), 6.18 (dd, J=15.3 Hz, 8.1 Hz, 1H), 3.82 (d, J=8.1 Hz, 1H), 3.32 (m, 1H), 1.7 (m, 2H), 1.4 (m, 1H), 0.85 (d, 6.8 Hz, 6H).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([F:17])=[C:15]([F:16])[C:9]=2[O:8][CH2:7]1)(=O)C.C(O)C.[OH-].[K+].C(O)(=O)C>O1CCCC1>[F:17][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][CH:6]([CH2:5][OH:4])[CH2:7][O:8][C:9]=2[C:15]=1[F:16]
Reactant: CC(=O)OCC1COc2c(ccc(F)c2F)N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCC1COc2c(ccc(F)c2F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 135 ml of tetrahydrofuran was dissolved 3.03 g of a 3,5-dinitrobenzoyl derivative of (-)-3-acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine, and 135 ml of ethanol and 30 ml of 1.0N potassium hydroxide were added to the solution. After the reaction mixture was stirred at room temperature for 30 minutes, 3 ml of acetic acid was added thereto for neutralization. The mixture was concentrated under reduced pressure, and the concentrate was dissolved in 400 ml of chloroform, washed successively with a sodium bicarbonate aqueous solution and water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The solid was subjected to column chromatography using 40 g of silica gel and eluted with chloroform/methanol (50/1 by volume) to obtain 1.17 g of (-)-7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4H-[1,4]benzoxazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-])=O)[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]=2[CH3:27])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:10]([CH3:27])[N:11]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: [H][H]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(N)cccc21

Procedure:
A solution of [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indol-1-yl]acetic acid, ethyl ester (1.99 kg, 4.92 mol) in ethyl acetate (24.2 kg) was hydrogenated in the presence of a 1% Pt/C catalyst paste (1.39 kg 44% w/w) under 4 bar A hydrogen pressure. After 2 hours hydrogen uptake had ceased so the reaction mixture was inerted then filtered through Celite (2.60 kg). The solids were washed with ethyl acetate (3×8 kg) and the combined filtrates distilled until a volume of 26 L remained to leave a solution of [4-amino-3-(4-chlorophenylsulfanyl)-2-methylindol-1-yl]acetic acid, ethyl ester in ethyl acetate. This solution was cooled to 4° C. then triethylamine (0.50 kg, 4.94 mol) added, followed by an ethyl acetate line wash (0.82 kg). A solution of acetyl chloride (0.39 kg, 4.97 mol) in ethyl acetate (3 kg) was added followed by an ethyl acetate line wash (0.76 kg). The reaction mixture was heated at 40° C. for 17 hours then water (16.9 kg) added. The reaction mixture was distilled down until 24.6 kg of distillate had been removed then cooled to 20° C. The solid product was collected by filtration, washed with water (1.9 kg) followed by acetonitrile (1.6 kg) then dried in a vacuum oven at 40° C. to afford [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid, ethyl ester, 1.69 kg (82%) as an off white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH:18]3[N:19]=[C:20]4[C:25]([N:17]3[N:16]([CH3:32])[C:15]2=[O:33])=[C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[CH:22][N:21]4[NH2:31])(=O)=O)=CC=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[NH2:31][N:21]1[C:20]2[C:25]([N:17]3[N:16]([CH3:32])[C:15](=[O:33])[N:14]([CH2:13][CH2:12][N:48]4[CH2:49][CH2:50][N:45]([C:42]5[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][O:35][CH3:34])=[CH:44][CH:43]=5)[CH2:46][CH2:47]4)[CH:18]3[N:19]=2)=[C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[CH:22]1
Reactant: COCCOc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCN2C(=O)N(C)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccc(N2CCN(CCN3C(=O)N(C)N4C5=C(c6ccco6)N=CN(N)C5=NC34)CC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
A mixture of 2-[5-amino-8-(2-furyl)-1-methyl-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl 4-methylbenzenesulfonate obtained in step 7 (0.25 g, 0.533 mmol), 1-[4-(2-Methoxy-ethoxy)-phenyl]-piperazine (0.188 g, 0.799 mmol) and DIPEA (0.27 ml, 1.599 mmol) were taken in DMF (5 ml) and stirred at 80° C. for 16 hours. To the reaction mixture water (100 ml) was added and solid obtained was filtered off. The crude product was purified by column chromatography to obtain 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (0.135 g, 47%) as an off white solid
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.55 g, 3.93 mmol), phenylboronic acid (0.575 g, 4.72 mmol), potassium carbonate (1.79 g, 13.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.028 g, 0.039 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere and then heated at reflux for 61 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by chromatography according to the method described in Example 59. The resulting foamy solid (1.55 g) was concentrated twice from acetonitrile and then triturated with acetonitrile (25 mL) to provide a solid. The solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 887 mg of 1-[4-amino-2-(ethoxymethyl)-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 158-159° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:10]([OH:12])[OH:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:15]1COCC1.CI>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:10]([OH:12])[OH:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1ccc2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of indole-6-boronic acid (0.100 g, 0.615 mol), sodium hydride (0.07 g, 20 mmol) and THF (5 mL, 60 mmol) was stirred at rt for 20 min. then methyl iodide (100 uL, 20 mmol) was added and the mixture was allowed to stir at rt for 3 hours. The reaction was quenched with sat. NH4Cl solution, washed with brine and dried over Na2SO4, then the solvent was removed in vacuo. The crude product was purified by chromatography over silica gel eluting with 1:9 EtOAc/hexane and 1% MeOH, yielding the desired product. 1H NMR (400 MHz, CDCl3) δ ppm 3.99 (s, 3H), 6.58 (m, 1H). 7.23 (m, 1H), 7.81 (m, 1H), 8.08 (m, 1H) and 8.34 (m, 1H). MS (ES+): m/z 176.15 [MH+].
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH:17]=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CNN=CC(C)=O
Reactant: Cc1cc(C)cc(C(=O)C=O)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
2-Oxopropanal methylhydrazone (7.29 mmol, 730 mg) and (3,5-dimethylphenyl)(oxo)acetaldehyde (7.29 mmol, 1.18 g) synthesized in Reference Synthetic Example 10 were dissolved in acetic acid (25 mL) and stirred at 100° C. for 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) and then by silica gel thin layer chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as an orange liquid (93 mg, yield 5%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:7]([N+:17]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(COC)OC.[H][H]>[Pd].CO>[NH2:17][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)c1ccc(N2CCOCC2)c(N)c1
Reaction time: 3 h
Yield: 97.8 %

Procedure:
4-(4-tert-Butyl-2-nitrophenyl)morpholine (15 g.; 57 mmoles) was dissolved in a mixture of 150 ml. of monoglyme and 150 ml. of methanol. The mixture was then hydrogenated in the presence of 1.4 g. of Pd on carbon catalyst (10%) with an initial pressure of 39 p.s.i. hydrogen. After 3 hours, the resultant mixture was filtered to remove the catalyst and the filtrate evaporated to dryness to give the product (13 g.; 97.8% yield) as tan crystals, m.p. 165°-166° C.
Reaction SMILES: [CH2:1]([O:8]C1C=C(OCC2C=CC=CC=2)C(C(C)C)=CC=1C(O)=O)C1C=CC=CC=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[CH2:56][NH:55][CH2:54]2>CN(C=O)C>[Cl:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[CH2:56][N:55]([CH:1]=[O:8])[CH2:54]2
Reactant: Clc1ccc2c(c1)CNC2
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=CN1Cc2ccc(Cl)cc2C1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropyl-benzoic acid (Preparation B10) (0.451 g, 1.2 mmol), EDC (0.276 mg, 1.44 mmol), HOAt (0.196 mg, 1.44 mmol), triethylamine (0.5 ml, 3.6 mmol) and 5-chloro-2,3-dihydro-1H-isoindole (0.187 g, 1.2 mmol) (Preparation C3) in DMF (5 ml) was stirred at room temperature for 16 hours, then evaporated under vacuum. The crude material was dissolved in ethyl acetate and extracted twice with saturated NaHCO3, organics washed with water three times, then evaporated under vacuum to give 0.5 g of 2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-chloro-1,3-dihydro-isoindol-2-yl)-methanone. MS: [M+H]+ 512