Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14](N)[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>>[N:16]1[CH:14]=[C:13]2[C:19]([N:10]=[CH:11][NH:12]2)=[N:18][CH:17]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Product: c1ncc2[nH]cnc2n1
Reaction time: 0.5 h

Procedure:
The optimum pH was determined by high-performance liquid chromatography with adenosine, guanosine and inosine substrates. The reaction solution (200 μl) contained 0.5 mM of adenosine or inosine or 0.25 mM of guanosine as the substrate, 50 mM of the buffer solutions described below and a sufficient amount of enzyme, and the reaction was conducted at 50° C. for 30 minutes. The results are shown in FIGS. 2, 3 and 4.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[C:17]1([C:23]2[N:24]=[CH:25][C:26]([NH:29][C:30](=O)[O:31]C3C=CC=CC=3)=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CS(C)=O.CN(C)CC1C=CC=CC=1>C(#N)C.O>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:30]([NH:29][C:26]3[CH:25]=[N:24][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:28][N:27]=3)=[O:31])[CH2:3][CH2:4]2)[O:8]1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: CN(C)Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CS(C)=O
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (515 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (583 mg) were dissolved into dimethyl sulfoxide (2.6 mL), followed by dropwise addition of dimethylbenzylamine (0.33 mL). The temperature of the resultant mixture was raised up to 50° C., and the mixture was stirred for one hour. The reaction mixture was cooled to room temperature, and acetonitrile/water (1:2) mixture solution (7.8 mL) was dropwise added. At the time when 0.2 mL of the mixture solution was added, seed crystal was added. The resultant mixture was stirred at room temperature for 6 hours. The yielded colorless crystals were collected by filtration, washed with acetonitrile/water (1:1) and dried in vacuum at room temperature for 15 hours to obtain the above-identified compound (793 mg) as crude colorless crystals. Crude crystals (26 g) prepared by the repetition of the above procedure were suspended in water-saturated isopropyl acetate (143 mL). The mixture was seeded with seed crystal and stirred at room temperature for 18 hours. The yielded crystals were collected by filtration, washed with isopropyl acetate (20 mL) and dried in vacuum at 30° C. for 15 hours to obtain the above-identified compound in the crystal form D (25.2 g) as colorless crystals (melting point; 206° C. measured without correction by the use of Melting Point B-545 distributed by Buchi Company).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(CC)C.[CH3:21][O:22][P:23](Cl)(=[O:26])[O:24][CH3:25]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[O:15]=[C:12]1[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][N:13]1[P:23](=[O:26])([O:24][CH3:25])[O:22][CH3:21]
Reactant: COP(=O)(Cl)OC
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COP(=O)(OC)N1C[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.13 h

Procedure:
3-[(Phenylacetyl)amino]-2-azetidinone (250 mg)was dissolved in a mixture of dry dimethylformamide (2 ml) and anhydrous tetrahydrofuran (5 ml). The mixture was cooled to -78° C., sec-butyllithium (0.83 ml of 1.4 N in cyclohexane) was added, stirring was continued for 8 minutes dimethylphosphorochloridate (187 μl) was added, and the mixture was stirred for 45 minutes at -78° C. After dilution with saturated aqueous sodium chloride and two extractions with ethyl acetate, the combined extracts were dried (sodium sulfate), filtered, and solvent was removed in vacuo yielding an oil. Thin-layer chromatography on plates developed in ethyl acetate gave the product as an oil which crystallized from ether. The solid was recrystallized from ethyl acetateether-pentane, triturated with ether, and dried in vacuo yielding 283 mg of the title compound as a powder, melting point 77.5°-81.5° C.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]([OH:22])[CH3:1])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc2ncccc2nc1-c1ccccc1F
Solvent: C1CCOC1
Product: CC(O)c1cc2ncccc2nc1-c1ccccc1F

Procedure:
Methyl magnesium bromide (2M in diethyl ether, 2.38 mL, and 4.76 mmol) was added dropwise to the solution of 2-(2-fluorophenyl)-1,5-naphthyridine-3-carbaldehyde (600 mg, 4.76 mmol) in THF (60 mL) at −0° C. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution and ethyl acetate, and then filtered through Celite™. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give an oily mass. The oily mass was then purified by silica gel column chromatography using 30% of ethyl acetate and hexane as eluent to give 1-(2-(2-fluorophenyl)-1,5-naphthyridin-3-yl)ethanol as a yellow oil: 1H-NMR (CDCl3) δ: 1.3 (s, 3H), 5.0 (brs, 1H), 7.7-7.2 (m, 5H), 8.4 (d, 1H), 8.8 (s, 1H), 9.0 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CC(O)=O.O>>[NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1nc(C2CCC3(CC2)OCCO3)ccc1N
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)c1nc(C2CCC(=O)CC2)ccc1N
Temperature: 75 °C

Procedure:
A mixture of 3-Amino-6-(1,4-dioxaspiro[4.5]dec-8-yl)-N-methylpyridine-2-carboxamide (Compound 232C, 0.160 g, 0.549 mmol) in AcOH (1.0 mL, 18 mmol) and H2O (0.2 mL, 10 mmol) was warmed to 75° C. for 2.5 hours, after which, the reaction was cooled and concentrated in vacuo. The residue was taken up in water and basified with a saturated aqueous solution of K2CO3. This mixture was extracted three times with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated to a brown tar. This was taken up in DCM, treated with silica and concentrated and loaded into a sample cartridge. The product was isolated after purification on an ISCO Combiflash unit (eluting with 0-4% MeOH/DCM) as 53 mg of a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 1.97-2.13 (m, 4H), 2.26 (dt, J=14.40, 2.02 Hz, 2H), 2.52-2.59 (m, 2H), 2.77 (d, J=5.05 Hz, 3H), 3.05 (tdd, J=11.43, 3.79, 3.66 Hz, 1H), 6.65 (s, 2H), 7.09 (d, J=8.30 Hz, 1H), 7.20 (d, J=8.30 Hz, 1H), 8.42 (d, J=4.80 Hz, 1H). MS (ES+): m/z=247.87 (90) [M+1]. HPLC: tR=2.95 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(Br)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Br)c3)nc2n(CC)c1=O
Yield: 51.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.52 g (11.1 mmol) of 3-bromocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 2.01 g (yield 37%) of Compound 154 as pale green plates.
Reaction SMILES: [CH3:1][I:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]=2[CH:22]=1)#[N:4]>C(#N)C>[I-:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=3[CH3:1])[C:9]=2[CH:22]=1)#[N:4]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C#N)ccc2O1
Reactant: CI
Solvent: CC#N
Product: C[n+]1ccccc1C1=NC(C)(C)Oc2ccc(C#N)cc21
Product: [I-]

Procedure:
Methyliodide (2 ml) was added to a solution of 6-cyano-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.20 g) in acetonitrile (14 ml) and the mixture was heated under reflux for 7 hours. After air-cooling, the solvent was distilled off under reduced pressure and the residue was crystallized from diethyl ether to obtain 2-(6-cyano-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)-1-methylpyridinium iodide (0.29 g) (Compound 18).
Reaction SMILES: C(#N)C([CH2:4][C:5]#[N:6])O.[H-].[Na+].[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:28]=[C:21]3[C:22]([O:24][C:25](=O)[NH:26][C:20]3=[CH:19][CH:18]=2)=O)[CH2:13][CH2:12]1.C[N:30](C)C=O>O>[NH2:30][C:25]1[C:4]([C:5]#[N:6])=[C:22]([OH:24])[C:21]2[C:20](=[CH:19][CH:18]=[C:17]([N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]3)[CH:28]=2)[N:26]=1
Reactant: CN(C)C=O
Reactant: CN1CCN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC1
Reactant: N#CCC(O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2 g of malonitrile is dissolved in 30 mL of dimethylformamide. To the solution, in several portions, 1.3 g of 60% oily dispersion of sodium hydride are added. To the clear solution 6.5 g of 5-(4-methylpiperazino)isatoic acid anhydride is added and the mixture is stirred at room temperature for 10 hours. The reaction mixture is diluted with 70 mL of water and extracted with 2×30 mL of ethyl acetate. The aqueous phase is evaporated in vacuum, the solid residue is dissolved in 20 mL of water, the pH is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water. After drying 5.2 g of the title compound is obtained, m.p.: 156° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5](Br)=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH:5]([N:1]=[N+:2]=[N-:3])=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCC=CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCC=CN=[N+]=[N-]
Temperature: 80 °C
Yield: 56.4 %

Procedure:
To do this, sodium azide (2.781 g, 43 mmol) was dissolved in 170 ml of dimethylformamide (DMF). 5 ml of undecenyl bromide (36 mmol) were added, with stirring, to the reaction medium, which was subsequently heated at 80° C. for 24 hours. The mixture was left to cool to ambient temperature, and then 100 ml of water were added portionwise. An extraction with ethanol (3×100 ml) was subsequently carried out, and the organic phase was then washed with water (3×100 ml) and dried over sodium sulfate (Na2SO4). Finally, the solvent was evaporated off and 2.58 g of undecenyl azide (20.3 mmol; yield 60%) were isolated in the form of a pale yellow-colored transparent oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][OH:8])[CH2:3][C:4]([NH2:6])=[O:5].CN(C)C=O.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Ca+2].[Cl-]>O1CCCC1.N1C=CC=CC=1>[OH:1][CH:2]([CH2:7][O:8][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][C:4]([NH2:6])=[O:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[C@H](O)CO
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
11.9 g (0.10 mol) (S)-3,4-dihydroxy-butyramide was dissolved in 50 ml of tetrahydrofuran and 50 ml of dimethylformamide and 10 ml of pyridine followed by 30.6 g (0.11 mol) of trityl chloride was added to the flask. A drying tube filled with calcium chloride was used to exclude moisture. The reaction mixture was stirred at room temperature for 36 hours. After this period of time, it was filtered to remove the solid. The liquid was concentrated under reduced pressure to remove most of the solvent. The solution was poured into ice water, stirred for half an hour and the water layer was removed from the trityl protected amide. The product which was obtained as a semicrystalline liquid was dried under vacuum. The excess trityl chloride was washed away by trituration with hexane. The yield was 33.0 g (91%). Physical data: m.p. 59.0-60.0° C. (from solvent dichloromethane:hexane:acetone=6:3:0.5) [α]25D=−53.5° (c=0.5,, methanol). 1H NMR (300 MHz, CDCl3) δppm, 7.50-7.20 (m, 15 H), 6.17 (s, 1H), 5.62 (s, 1H), 4.19 (m, 1H), 3.17 (d, 2H, J=5.7 Hz), 2.41 (m, 2H). 13C NMR (75 MHz, CDCl3) δppm, 174.8, 143.5, 128.3, 127.5, 126.7, 86.3, 67.4, 39.2. FTIR cm−1 3345, 1667, 1600, 1490, 1448, 1218, 1074, 763, 703.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[C@@H:9]1([NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH2:25][N:26]4[C:30]5=[N:31][CH:32]=[C:33]([F:35])[CH:34]=[C:29]5[N:28]=[CH:27]4)[CH:22]=[CH:21][C:19]=3[N:20]=2)CCCC=[CH:10]1.[CH2:36]1[CH2:40][O:39][CH2:38][CH2:37]1>C(O)(C)(C)C.O.O=[Os](=O)(=O)=O>[F:35][C:33]1[CH:34]=[C:29]2[N:28]=[CH:27][N:26]([CH2:25][C:23]3[CH:22]=[CH:21][C:19]4[N:20]=[C:16]([NH:15][C@@H:9]5[CH2:10][CH2:38][CH2:37][C@H:36]([OH:5])[C@@H:40]5[OH:39])[S:17][C:18]=4[CH:24]=3)[C:30]2=[N:31][CH:32]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Reactant: Fc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@H]3C=CCCC3)sc2c1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: O[C@H]1[C@@H](O)CCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 2 %

Procedure:
To a stirred mixture of NMO in tert-butanol (5 mL), THF (1.5 mL), H2O (0.5 mL), and a 4% wt solution of OsO4 in H2O (10 μL, 0.3 mmol) at rt was added portionwise (R)—N-(cyclohex-2-en-1-yl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine (142 mg, 0.4 mmol) from Example 176. After the mixture was stirred at rt for 18 h, it was partitioned between EtOAc (200 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified twice by reverse-phase preparative HPLC eluting with a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1S,2R,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (7 mg, 2%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.40 (m, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.21 (dd, J=1.6, 8.2 Hz, 1H), 5.47 (s, 2H), 4.45-4.70 (m, 2H), 3.88 (br s, 1H), 3.76 (m, 1H), 3.43 (m, 1H), 1.40-1.62 (m, 5H), 1.25 (m, 1H); LCMS (ESI) m/z 414 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[NH:4][C:5]([CH:23]([F:25])[F:24])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10].[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[F:26][CH:2]([F:1])[C:3]1[N:4]([CH3:27])[C:5]([CH:23]([F:24])[F:25])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)N(C)C(C(F)F)=C3C#N)cc12
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.277 mmol) 2,6-bis(difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 13) in DMF (1.5 ml) was cooled to 0° C., and 108 mg (0.33 mmol) caesium carbonate were added at this temperature. After stirring for 30 min, 21 μl (0.33 mmol) methyl iodide were added dropwise at room temperature, and the mixture was stirred at rt overnight. After this, additional methyl iodide (20 μl) was added, and stirring at rt was continued for further 48 h. The reaction mixture was then filtered, and the filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA isocratic 40:60 v/v) to give 12 mg (11% of th.) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:28]2=[CH:29][N:30]=[C:31]([CH:33]=O)[CH:32]=[C:27]2[CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:55].CO>C(N(CC)CC)C>[ClH:55].[O:23]1[C:28]2=[CH:29][N:30]=[C:31]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[CH:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:6][CH2:7]3)[CH:32]=[C:27]2[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCCC2
Reactant: ClC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cl
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCCC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (for a preparation see Example 5(j)) (51 mg, 0.14 mmol) in chloroform:methanol (9:1, 3 ml) at rt under argon was treated with triethylamine (0.06 ml) and stirred at rt for 10 min. The solution was then treated with 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (21 mg, 0.133 mmol) and stirred for a further 2 h. The solution was then treated with NaBH(OAc)3 (87 mg) and stirred at rt for 2 h. The reaction was then treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×50 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (20 mg, 32%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][NH:41][CH3:42]>C1COCC1>[ClH:36].[ClH:36].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][N:41]([CH3:42])[C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:13]=2)[CH:16]=1
Reactant: CNCCN(C)C
Reactant: CCOC(=O)Cl
Reactant: Cc1csc(Nc2cc(Oc3cccc(C(=O)O)c3)ccn2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc(C(=O)N(C)CCN(C)C)c3)ccn2)n1
Product: Cl
Yield: 61.1 %

Procedure:
Using the method of Example 32, 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl carbonochloridate (0.03359 mL, 0.3513 mmol), and N1,N1,N2-trimethylethane-1,2-diamine (0.1191 mL, 0.9164 mmol) were reacted in THF (2 mL) to provide N-(2-(dimethylamino)ethyl)-N-methyl-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzamide dihydrochloride (0.052 g, 35.14% yield) as off white solid. 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.50 (m, 1H), 7.45 (m, 1H), 7.34 (bs, 1H), 7.19 (d, 1H), 6.69 (m, 2H), 6.39 (s, 1H), 4.05 (t, 2H), 3.31 (m, 2H), 3.19 (s, 3H), 2.91 (s, 6H), 2.38 (s, 3H); Mass spectrum (esi) m/z=412 (100) (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][OH:20].[CH3:21][CH2:22][OH:23]>[Pd].C(O)=O>[CH3:21][C:22]([O:20][CH2:19][C:2]1[C:3]2[C:14](=[CH:7][CH:6]=[CH:11][CH:4]=2)[C:18]([CH2:17][O:16][C:14]([CH3:3])=[O:15])=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2)=[O:23].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CO
Reactant: CCO
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Agent: [Pd]
Solvent: O=CO
Product: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1

Procedure:
According to Scheme A, ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (VIII) is obtained in four steps from commercially available synthetically accessible m-anisidine (II). m-Anisidine is combined with diethyl ethoxymethylenemalonate at temperatures ranging from 100° C. to about 125° C., preferably 125° C. for a period of 1 to 5 h, preferably about 3 h to provide diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) is obtained by heating Dowtherm™ at a temperature of 257° C. and diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate for a period of 15 minutes to 2 h. Compound (IV) ethyl 7-methoxyquinoline-3-carboxylate is commercially available or synthetically accessible from ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) in two steps. Chlorination of compound (III) under conditions known to one skilled in the art, for example, but not limited to, oxalyl chloride, thionyl chloride, or phosphorus oxychloride, with or without a catalytic amount of DMF, in the presence or absence of a solvent such as DCM or CHCl3, at temperatures ranging from 50° C. to about 70° C., for a period ranging from 2 to 4 h, preferably 2.5 h, provides ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. Subsequent reduction of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate, employing Pd/C under hydrogenation conditions, in a solvent such as MeOH or EtOH, in the presence or absence of an acid such as acetic or formic acid, provides ethyl 7-methoxyquinoline-3-carboxylate (IV). Commercially available or synthetically accessible ethyl 7-methoxyquinoline-3-carboxylate (IV) is reacted under demethylation conditions, for example, HBr in H2O or HOAc, at temperatures ranging from 80° C. to about 110° C., preferably 105° C. for a period of 0.5 h to 24 h, preferably about 2 h, to provide 7-hydroxyquinoline-3-carboxylic acid. Ethyl 7-hydroxyquinoline-3-carboxylate (V), where R3 is H, is obtained by esterification of 7-hydroxyquinoline-3-carboxylic acid, employing methods known to one skilled in the art, for example, but not limited to, reaction of 7-hydroxyquinoline-3-carboxylic acid with an acid such as H2SO4, and the like, in a solvent such as EtOH, at temperatures ranging from 60° C. to about 80° C., preferably 75° C. for a period of about 12 to 24 h, preferably 20 h.