Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](Br)[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(OCc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OCc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzyloxy-6-bromo-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:32]([CH3:33])[CH3:31])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (105 mg, 0.25 mmol) obtained in Example 12 in methylene chloride (3 ml), dimethylamine hydrochloride (23 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.061 ml, 0.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 3 hours at room temperature, water was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elusion with hexane:ethyl acetate=3:2 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration, to obtain the title compound (77 mg, 0.17 mmol, 69%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[NH:14][C@@H:15]1[CH2:20][CH2:19]CC[C@H:16]1[NH:21][CH3:22].BrC1C=C(N)C=NC=1>[Cu](I)I.O.CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:19]2[CH:20]=[C:15]([NH2:14])[CH:16]=[N:21][CH:22]=2)[CH:6]=1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: Cc1cn[nH]c1
Agent: I[Cu]I
Agent: Nc1cncc(Br)c1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cnn(-c2cncc(N)c2)c1
Yield: 86.1 %

Procedure:
4-Methyl-1H-pyrazole (114 mg), cesium carbonate (753 mg), trans-N,N′-dimethylcyclohexan-1,2-diamine (164 mg), and copper iodide (110 mg) were added to a DMAc (5 ml) solution containing 5-bromopyridin-3-amine (200 mg) in a nitrogen atmosphere, followed by microwave irradiation (Initiator™, 170° C., 0.5 hours, 2.45 GHz, 0-240 W). Water was added to the reaction solution and the reaction solution was filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layers were washed with saturated saline and dried over sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 0:1). 5-(4-Methylpyrazol-1-yl)pyridin-3-amine (173 mg) was thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)(O)[O-].[Na+]>CN(C=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(O)c2cccc(OCc3ccccc3)c2n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)COc1cc(C)nc2c(OCc3ccccc3)cccc12
Temperature: 80 °C
Yield: 68.6 %

Procedure:
To a mixture of give 8-(benzyloxy)-2-methylquinolin-4-ol (2.34 g, 8.83 mmol) and potassium carbonate (1.83 g, 13.2 mmol) in anhydrous DMF (50 mL) was added ethyl bromoacetate (1.77 g, 10.6 mmol) with stirring under nitrogen. The mixture was heated at 80° C. for 1 h, cooled, mixed with a saturated aqueous sodium bicarbonate and extracted with EtOAc. Evaporation gave a crude product that was dissolved in dichloromethane and precipitated by the addition of a mixture of Hex/EtOAc (10/1). The precipitate was filtered and dried to give ethyl 2-((8-(benzyloxy)-2-methylquinolin-4-yl)oxy)acetate (2.13 g, 69%). A mixture of ethyl 2-((8-(benzyloxy)-2-methylquinolin-4-yl)oxy)acetate (0.70 g, 1.99 mmol), Pd/C (10%, 0.07 g) in EtOH/dioxane (20 mL/20 mL) was placed under hydrogen atmosphere with stirring overnight. The mixture was filtered and evaporated to give ethyl 2-((8-hydroxy-2-methylquinolin-4-yl)oxy)acetate (0.24 g, 46%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=1)=[O:7].[NH2:22][CH:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]3[N:36]([CH3:37])[N:35]=[N:34][N:33]=3)[CH2:28][S:29][C@H:24]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)Cl.O>[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([NH:22][CH:23]2[C:41](=[O:42])[N:25]3[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]4[N:36]([CH3:37])[N:35]=[N:34][N:33]=4)[CH2:28][S:29][C@H:24]23)=[O:18])[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1cccc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(NC=O)n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
Phosphoryl chloride (0.998 g.) was added to N,N-dimethylformamide (5 ml.) and stirred at 40° C. for 30 minutes. To the solution was added a solution of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (1.125 g.) in N,N-dimethylformamide (5 ml.) at -15° C., and stirred at -10° to -8° C. for 50 minutes [solution A]. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.007 g.) and trimethylsilylacetamide (7.22 g.) were dissolved in methylene chloride (20 ml.) at 40° C. and cooled. To the cool solution was added the above solution A at -20° to -15° C. and stirred at the same temperature for 40 minutes. The resultant solution was poured into a solution of a saturated aqueous solution of sodium bicarbonate (30 ml.) and water (40 ml.) under ice cooling. The aqueous layer was separated, washed with ethyl acetate, and then ethyl acetate (50 ml.) was added to the aqueous layer. The solution was adjusted to pH 3 with 10% hydrochloric acid, and extracted with ethyl acetate twice. The extract was washed with water and concentrated to a small amount under reduced pressure. The appeared precipitates were collected by filtration, washed with ethyl acetate and dried to give 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (873 mg.). The same product (126 mg.) was recovered from the mother liquor. Total yield was 999 mg.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([OH:10])[CH:9]=1.[CH3:14]I.O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([O:10][CH3:14])[CH:9]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (1.3 g) in dimethylformamide (10 ml) was added a solution of 5-fluoro-2-nitrophenol (5.0 g) in dimethylformamide (20 ml)under ice-cooling. This reaction mixture was stirred at room temperature for 1 hr. To this solution was added methyl iodide (2.0 ml) and the mixture was left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a red solid. This solid was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (4.3 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[S:10][C:9](=[Se:11])[N:8]([C@@H:12]3[O:25][C@H:24]([CH2:26][O:27]C(=O)C4C=CC=CC=4)[C@@H:14]([O:15]C(=O)C4C=CC=CC=4)[C@@H:13]3[F:36])[C:6]=2[N:7]=1.O(C)[Na]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[S:10][C:9](=[Se:11])[N:8]([C@@H:12]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:14]([OH:15])[C@@H:13]3[F:36])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=[Se])n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)[nH]1
Agent: CO[Na]
Solvent: CO
Product: Nc1nc2c(sc(=[Se])n2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-Amino-3-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-7-oxothiazolo[4,5-d]pyrimidine-2(3H,6H)-selone (0.3 g, 0.5 mmol), NaOCH3 (0.055 g) and anhydrous MeOH (60 mL) was stirred at room temperature for 16 h with the exclusion of moisture. The reaction mixture was neutralized with Amberlite IR-120(H+) ion-exchange resin. The resin was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in MeOH (5 mL), adsorbed onto silica gel (5 g) and loaded on top of a prepacked (in CH2Cl2) silica gel column (2.8×15 cm). The column was flash eluted with CH2Cl2 :MeOH (9:1), the homogeneous product was isolated and crystallized from an acetone:toluene mixture; 0.15 g (0.383 mmol, 76%), mp 178-180° C. Ir (KBr): ν3200-3370 (OH, NH2), and 1630 (C=Se) cm-1. Uv, λmax (nm) (ε×10-3): pH 1, 376 (5.6), 286 (3.0), 220 (3.7); pH 7, 374 (5.5), 280 (3.9), 218 (3.8); pH 11, 374 (5.4), 280 (4.8), 234 (4.3). 1H nmr (DMSO-d6): δ3.76 (m, 3H, C5'H2 and C4'H), 4.72 (s, 1H, C5'OH), 4.91 (m, 1H, C3'H), 5.28 and 5.42 (tt, JH,F =55.6 Hz, JH,H =6.0 Hz, 1H, C2'H), 5.59 (d, 1H, C3'OH), 6.98 (s, 2H, NH2), 7.20 (t, J1',2' =7.6 Hz, 1H, C1'H), and 11.58 (s, 1H, NH). Anal. Calc'd for C10H11FN4O4SSE.0.11 toluene (391.41): C, 33.07; H, 3.06; N, 14.31. Found: C, 32.79; H, 3.06; N, 13.98.
Reaction SMILES: [C:1]1(=[O:15])[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3>[Pd].C1(C)C=CC=CC=1>[C:7]1([CH2:6][C:6]23[C:1](=[O:15])[NH:2][CH2:3][CH2:4][N:5]2[C:13](=[O:14])[C:12]2[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NCCN2C(=O)c3ccccc3C12
Agent: [Pd]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C2(Cc3ccccc3)C(=O)NCCN12

Procedure:
3,4-Dihydropyrazino[2,1-a]isoindole-1,6(2H, 10bH)-dione (described in Example 6, 10 g, 0.049 mol) is added portionwise to a stirring mixture of 10% palladium on carbon (10 g) in 375 ml of dry toluene. The mixture is refluxed for 20 hr and filtered through Celite (diatomaceous earth). The filtrate is evaporated. The residue is chromatographed on silica gel using acetone-benzene (1:1) and the eluates are evaporated. The residue (5.0 g) is crystallized from acetone-petroleum ether to obtain 10b-phenylmethyl-3,4-dihydropyrazino[2,1-a]isoindole-1,6(2H, 10bH)-dione, mp 202°-204° C., Anal. Calc'd. for C18H16N2O2 : C, 73.95% H, 5.52% N, 9.59% and Found: C, 74.18% H, 5.72% N, 9.57%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([O:27][CH3:28])=[CH:17][C:10]=3[N:11]([CH3:16])[C:12](=[O:15])[CH2:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]#[CH:31]>>[C:36]([O:35][C:33](=[O:34])[NH:32][CH2:29][C:30]#[C:31][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:9]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:18]([O:27][CH3:28])=[CH:17][C:10]=3[N:11]([CH3:16])[C:12](=[O:15])[CH2:13][N:14]=2)[CH:3]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1cc2c(cc1-c1ccccc1)C(c1cccc(Br)c1)=NCC(=O)N2C
Reactant: C#CCNC(=O)OC(C)(C)C
Product: COc1cc2c(cc1-c1ccccc1)C(c1cccc(C#CCNC(=O)OC(C)(C)C)c1)=NCC(=O)N2C
Yield: 22 %

Procedure:
Prepared from 5-(3-bromo-phenyl)-8-methoxy-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one Example 62 using the same method described for Example 35 using propargyl Boc-amine instead of hex-1-yne. The title compound (51 mg) was obtained as a beige solid, (yield=22%).
Reaction SMILES: [CH2:1](I)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][S:8](=[S:11])([O-:10])=[O:9].[Na+].[Al].[I-]>O.CN(C=O)C>[CH3:7][S:8](=[S:11])([O:10][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:9]
Reactant: CS(=O)([O-])=S
Reactant: CC(C)(C)CI
Agent: [Al]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COS(C)(=O)=S
Temperature: 90 °C

Procedure:
The reaction mixture of neopentyl iodide (3.054 g, 0.0154 mol), sodium methanethiosulfonate (2.272 g, 0.0170 mol) and dry DMF (4 mL) was heated at 90° C. for 90 hr. The reaction flask was wrapped with aluminum foil to avoid direct sunlight to the reaction mixture, since the iodide was sensitive to sunlight. At the end of the heating, the reaction mixture was red-brown in color. At room temperature, water (15 mL) was added and the mixture was extracted with ether (3×30 mL). The combined ether extracts were washed twice with brine, dried, concentrated and the residue was subjected to column chromatography on silica gel with EtOAc-hexanes (1:2) to afford a colorless oil which slowly solidified (1.2395 g, 44%). The product was recrystallized from 95% EtOH. mp: 28.5-29.0° C.; IR (CH2Cl2 cast): 3021 (m), 2956 (m), 2868 (m), 1467 (m), 1433 (m), 1321 (st), 1310 (st), 1125 (st), 951 (m), 757 (m) and 724 cm−1 (m); 1H NMR (200 MHz, CDCl3): δ 3.32 (s, 3H, CH3SO2S), 3.13 (s, 2H, SCH2C), 1.05 (s, 9H, CMe3); 13C NMR (50 MHz, CDCl3): δ 50.23, 50.09, 32.14, 28.79, MS (El): 182 (M+), 57 (base peak, CMe3+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[CH3:24])=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:25]([C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[CH3:24])=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10])#[N:26]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1-c1nnc(-c2ccc(OC(C)C)c(I)c2)s1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Br)ccc1-c1nnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 120 °C

Procedure:
2-(3-Iodo-4-isopropyloxyphenyl)-5-(4-bromo-2-methyphenyl)-1,3,4-thiadiazole (0.78 mmol; 0.4 g, from Step A), zinc cyanide (0.47 mmol, 0.55 g), tris(dibenzylideneacetone)-dipalladium(0) (0.039 mmol, 0.036 g) and 1,1′-bis(diphenylphosphino)-ferrocene (0.094 mmol, 0.052 g) were dissolved in DMF (5 mL) and heated at 120° C. for 3 h. The reaction was concentrated in vacuo. Silica gel chromatography eluting with 10% EtOAc/hexanes yielded 0.25 g of the desired product. ESI-MS (m/z) 416.1; HPLC A: 4.22 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2.C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:46][S:47]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:18]=1)=[C:7]([O:29][S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2)(=[O:49])=[O:48]
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(O)ccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Yield: 98.3 %

Procedure:
Suspend trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (12.5 g, 24 mmol) in dry methylene chloride (100 ml). Add diisopropylethylamine (8.3 mL, 48 mmol). Slowly add methanesulfonyl chloride (2.7 mL, 36 mmol). Pour reaction into saturated aqueous sodium bicarbonate after 20 minutes and extract with methylene chloride. Wash the organic layer with water, dry with sodium sulfate, filter and concentrate in vacuo to yield 14.2 g (99%) of the title compound.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CC(C)C>>[CH2:2]1[C@H:1]([N:10]2[C:11](=[O:12])[NH:13][C:14](=[O:15])[CH:16]=[CH:17]2)[O:9][C@H:6]([CH2:7][OH:8])[C@H:4]1[OH:5].[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:2]1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CC(C)C[C@H](N)C(=O)O
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
Urd-uridine; Leu-L-leucine.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3)CC2)cc1-c1ccc(F)cc1

Procedure:
134 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-phenylpiperazine (0.055 mL, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]3)[CH:11]=1)=O.[ClH:26]>>[ClH:26].[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]3)[CH:9]=[N:8][CH:7]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(NC(=O)C(C)(C)C)c3)ccc21
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(N)c3)ccc21
Temperature: 90 °C
Yield: 69 %

Procedure:
A suspension of 2,2-dimethyl-N-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yl]-propionamide (0.195 g, 0.578 mmol) in 1N aqueous HCl (5.78 mL) was heated to 90° C. over night. The reaction mixture was evaporated to dryness and the resulting solid material was triturated in MeOH, filtered off and further dried in a the high vacuum to give the title compound (0.115 g, 69%) as an off white solid as the HCl salt. MS: 254.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]CC1C=CC=CC=1)[N:9]=[C:8]1[N:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:23][C:24](=[O:25])[C:7]1=[CH:6]2.CCOCC>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[C:8]1[N:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:23][C:24](=[O:25])[C:7]1=[CH:6]2
Reactant: CCOC(=O)c1nc2nc3cc(OCc4ccccc4)c(OC)cc3cc2c(=O)[nH]1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2nc3cc(O)c(OC)cc3cc2c(=O)[nH]1
Yield: 6 %

Procedure:
A solution of ethyl 7-methoxy-8benzyloxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate (198 mg., 0.488 mmole) in trifluoroacetic acid (4 ml.) is stirred at room temperature for 8 days. Ether (15 ml.) is added and the yellow precipitate which forms separated by filtration. It is taken up in chloroform and the solution filtered through diatomaceous earth to remove a small amount of insoluble material. The filtrate is decolorized with charcoal and concentrated under reduced pressure to small volume. The solid which forms is filtered and dried; 9 mg., 6% yield; m.p. 265°- 266° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][CH2:34]O)=[CH:31][CH:30]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][CH2:34][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[CH:31][CH:30]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Oc1ccccc1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
2-Bromophenol (3.46 g) was mixed with tetrahydrofuran (60 ml) and triphenylphosphine (6.3 g) was added along with 4-fluorophenethyl alcohol (4.2 g). The mixture was cooled in an ice bath before dropwise addition of diisopropyl azodicarboxylate (4.85 g). The mixture was allowed to warm to room temperature over 18 h. The mixture was evaporated and diethyl ether (100 ml) was added. Stirring was continued for 3 h, the mixture was filtered and the filtrate was evaporated. The product was purified by column chromatography eluting with ethyl acetate/hexane mixtures to give a yellow oil (4.47 g).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:15]([CH3:24])[C:16](=[O:23])[C:17]4[S:22][CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:15]1[C:16](=[O:23])[C:17]2[S:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:14]1[S:13][CH2:12][C:11]1[CH:25]=[CH:26][C:8]([C:6](=[O:7])[C:5]2[CH:27]=[CH:28][C:2]([O:1][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Cn1c(SCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccsc2c1=O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(OCCN4CCCCC4)cc3)cc2)nc2ccsc2c1=O
Yield: 90.7 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (408 mg), 1-(2-chloroethyl) piperidine hydrochloride (202 mg) and potassium carbonate (414 mg) in DMF (10 ml) was stirred at 60° C. for 15 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (471 mg).