Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6]([O:17][CH3:18])=[C:7]([CH:12]=[C:13]([Cl:16])[C:14]=1[NH2:15])[C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:8]([C:7]1[C:6]([O:17][CH3:18])=[C:5]2[C:14](=[C:13]([Cl:16])[CH:12]=1)[NH:15][CH2:2][CH2:3][CH2:4]2)([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Cl)c(N)c(CCCO)c1OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c2c(c1OC)CCCN2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the compound of step 4 above (1.4 g), triethylamine (1 ml) and TsCl (1.1 g) in CH2Cl2 is stirred at 25° C. for three days. The mixture is washed with saturated aqueous NaHCO3 and evaporated affording a residue which is dissolved in toluene and refluxed for 21/2 hours. The toluene is evaporated and the residue is dissolved in CH2Cl2 and washed with saturated NaHCO3 (25 mls). The organic layer is dried, evaporated and the residue chromatographed on silica gel affording a gum which crystallizes from HexEt2O to give the desired product (M.P. 105°-108° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:4]([CH2:17][C:18]([CH3:20])=O)[C:3]1=[O:21].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.Cl.C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:4]([CH2:17][CH:18]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH3:20])[C:3]1=[O:21]
Reactant: C1CCNCC1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)N(C)CCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C2=C(CC(C)N3CCCCC3)C(=O)N(C)CCC2)c1

Procedure:
The solution of 8.0 g of 1-methyl-3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 14.2 g of piperidine, 6.4 ml of 5 N methanolic hydrogen chloride and 1.91 g of sodium cyanoborohydride in 100 ml of methanol is refluxed overnight. An additional portion of 1.91 g of sodium cyanoborohydride is added and refluxing continued for another day. The solution is cooled, acidified with a 35 ml of concentrated hydrochloric acid and evaporated. The residue is diluted with 100 ml of water, the aqueous solution washed with benzene, filtered, basified with 65 ml 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue crystallized from petroleum ether and recrystallized from hexane, to yield the 1-methyl-3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 101°-103°.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].[N+](=[CH:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])=[N-]>CCOCC>[CH3:5][C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][CH2:2][O:1][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22]
Reactant: COP(=O)(C=[N+]=[N-])OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Solvent: CCOCC
Product: COP(=O)(COCC=C(C)CCC=C(C)CCC=C(C)C)OC
Temperature: 25 °C

Procedure:
(E,E)-Farnesol, (5.0 mmol, 1.11 g, 1.26 ml) was stirred under argon in 10 ml of dry deoxygenated benzene (10 ml) and treated in one portion with ##STR88## (1.0 mmol, 0.442 g). The dark blue/green solution was stirred at room temperature and a solution of (1.5 g, 10.0 mmol) of dimethyl diazomethylphosphonate (prepared according to D. Seyferth et al, J. Org. Chem., 1971, vol. 36, No. 10, pages 1379 to 1386) in 20 ml of dry, deoxygenated benzene was added dropwise over 4 hours via syringe pump. After addition, the reaction mixture was stirred an additional 45 minutes. The reaction mixture was stripped of solvent and applied as a 75% ethyl acetate/Hexane solution to a flash chromatography column (50 mm diameter, 6" of silica gel) eluted with 75% ethyl acetate/hexane to afford 0.627 g, yield), of the ether as a dark blue/green oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[C:23]([CH:24]=[CH2:25])=[CH:22][S:21][CH:20]=1>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:23]3[C:19]([CH3:18])=[CH:20][S:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cscc1C
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cscc2C)CCN(C)C1
Reaction time: 0.08 h
Yield: 0.3 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 1.255 mmol) in NMP (1 mL), was added powdered KOH (490 mg, 8.75 mmol). After stirring for 5 min, 3-methyl-4-vinyl-thiophene (310 mg, 2.50 mmol) was added into the reaction mixture, which was stirred at 85° C. for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The organic layer was washed with water (6×30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography using silica (100:200) and 2% MeOH-DCM, followed by reverse phase HPLC to yield 1.10 mg of 2,8-dimethyl-5-[2-(4-methyl-thiophen-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (d, 1H), 7.24 (s, 1H), 7.07 (d, 1H), 6.92 (s, 1H), 6.78 (s, 1H), 4.6 (d, 1H), 4.3 (m, 3H), 3.62 (m, 1H), 3.3 (m, 3H), 3.0 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=3)(=[O:42])=[O:41])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: Cc1c(N2CCN(S(=O)(=O)c3cccc(F)c3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and 3-fluorobenzene-1-sulfonyl chloride to give 5,7-difluoro-2-(4-(3-fluorophenylsulfonyl)-piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.96 (br s, 3H), 3.03 (t, J=4.4 Hz, 4H), 3.14 (br s, 4H), 3.34-3.36 (m, 4H), 3.68 (t, J=4.4 Hz, 4H), 6.47 (s, 1H), 7.13-7.19 (m, 1H), 7.25-7.28 (m, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.60-7.65 (m, 3H), 7.71-7.77 (m, 2H,), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=599.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.N1CCCCC1.C(O)(=O)C>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[CH:19][C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)[C:8]2=[O:13]
Reactant: O=Cc1cccs1
Reactant: COc1cccc2c1CCCC2=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cccc2c1CCC(=Cc1cccs1)C2=O
Temperature: 130 °C
Yield: 78.3 %

Procedure:
A mixture of 5-methoxy-1-tetralone (1 g; 5.67 mmol), thiophene-2-carboxaldehyde (800 μl 8.51 mmol), piperidine (168 μl; 1.7 mmol) and acetic acid (97 μl; 1.7 mmol) was heated at 130° C. for 2 hours. The mixture was taken up in CH2C2 and washed in water and in a saturated aqueous solution of NaCl. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (95/5) to give 5-methoxy-2-(2-thienylmethylene)-1-tetralone (1.2 g; 80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][N:4]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[Si:18]([O:11][CH2:10][C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)[OH:12])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COc1ncc([C@@H](O)CO)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COc1ncc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-1-(2-methoxypyrimidin-5-yl)ethane-1,2-diol (3.46 g, 20.3 mmol) and imidazole (3.08 g, 44.7 mmol) was dissolved in methylene chloride (40 mL). The mixture was cooled to 0° C. and tert-butyldimethylsilyl chloride (3.48 g, 22.4 mmol) dissolved in methylene chloride (40 mL) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at room temperature overnight. The mixture was treated with water (200 mL) and extracted with methylene chloride (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]3[C:24](=[O:25])C4C(=CC=CC=4)C3=O)=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[OH2:27].NN.O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CO.C1COCC1.C(OCC)(=O)C>[C:8]([O:27][C:24](=[O:25])[NH:16][CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[S:10][C:6]([CH2:4][OH:5])=[CH:7][C:8]=2[CH:14]=1)([CH3:14])([CH3:9])[CH3:7]
Reactant: CCOC(=O)c1cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2s1
Reactant: O
Agent: NN
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc2sc(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (1.05 g) obtained in Example 120-1 was dissolved in methanol (20 ml) and added with hydrazine monohydrate (1.0 ml), followed by thermal reflux for 3 hours. The solution was added with water and subjected to extraction with chloroform. The resulting organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The dried product was dissolved in DMF (30 ml) and then added with triethylamine (0.60 ml) and di-t-butyl dicarbonate (942.8 mg), followed by stirring overnight at room temperature. After the solvent had been distilled off, the residue was added with water and extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The dried product was dissolved in anhydrous THF (10 ml). The solution was gradually dropped in a solution cooled at 0° C., which was prepared by suspending lithium aluminum hydride (218.6 mg) in anhydrous THF (20 ml), over 5 minutes, followed by stirring at 0° C. for 1 hour. Ethyl acetate and methanol were added to the solution, and the whole was concentrated. The residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (600.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C(=O)(O)[O-].[Na+].Cl[O-].[Na+]>C(OC)(C)(C)C>[CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: COC(C)(C)C
Solvent: CC#N
Product: O=C(COCc1ccccc1)COCc1ccccc1
Temperature: 1.100000023841858 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
1,3-dibenzyloxy-2-propanol(100.0 g, 367 mmol), acetonitrile (1352 mL) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (5.74 g, 36.7 mmol) were placed in a 5,000-mL four-necked flask equipped with a mechanical stirrer and a thermometer under a nitrogen stream, and the mixture was stirred for 5 minutes. Then, 3% aqueous sodium bicarbonate solution (1,028 g, 367 mmol) was added and the mixture was cooled to 1.1° C. using an ice bath. 11.9% aqueous sodium hypochlorite solution (when 10% aqueous sodium hypochlorite solution on the market was titrated, the accurate concentration was 11.9%) (276 g, 441 mmol) was added to the mixture over a period of more than 2 hours while keeping the temperature of the mixture at 5° C. or less (the reaction was a little exothermic), and the mixture was stirred at from 0.5° C. to 2.0° C. for 1 hour. Methyl t-butyl ether (2,700 mL) was added to the reaction mixture, the mixture was stirred for 20 minutes while keeping the temperature at 10° C. or less and allowed to stand for 10 minutes, and the resulting two layers were separated (the water layer weighed 1, 289 g and its pH was 8). The obtained organic layer was washed with 10% aqueous sodium sulfite solution (330 g), 5% saline (200 g) and 20% saline (200 g) in this order. The resulting solution (3,130 g) was analyzed by high performance liquid chromatography and as a result 91.8 g (yield 93%) of the captioned 1,3-dibenzyloxypropanone was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35](NCCC(O)=O)=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CCOC(C)=O>[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35]([NH:3][C@H:4]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH2:5][C:6]([OH:8])=[O:7])=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Reactant: O=C(O)CCNC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](NC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O)c1cccnc1

Procedure:
Following the procedure described for 1-7, but substituting β-alanine ethyl ester hydrochloride (Aldrich) for ethyl 3-amino-3(S)-(3-pyridyl)propionate dihydrochloride, the title compound was prepared. Rf (silica, EtOAc)=0.3. ##STR37## N-{[7-(Piperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone-2-yl]acetyl}-β-alanine (1-14)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH3:22])=[CH:20][S:21][C:15]=2[N:14]([CH3:23])[C:13]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>C(Cl)Cl>[Br:32][C:20]1[S:21][C:15]2[N:14]([CH3:23])[C:13](=[O:24])[N:12]([CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[C:17](=[O:18])[C:16]=2[C:19]=1[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Solvent: ClCCl
Product: Cc1c(Br)sc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.0 g, 8.14 mmol) in DCM (30 mL) at 0° C. was added NBS (1.6 g, 8.95 mmol). The reaction was stirred at 0° C. for 2 h then diluted with DCM (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (1:1) to give 6-bromo-3-(3-(tert-butyldimethylsilyloxy) propyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.4 g, 93.4% yield) as a white solid. LCMS: MH+ 448 and TR=2.917 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7].C(NC(C)C)(C)C.[Li]CCCC.[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O.CCOC(C)=O.CCCCCCC.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[C:10]1([CH:9]2[S:6](=[O:8])(=[O:7])[NH:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cc1ccccc1)NCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S1(=O)NCCCC1c1ccccc1
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of N-(3-bromopropyl)-1-phenylmethanesulfonamide (2.3 g, 7.9 mmol), diisopropylamine (0.28 mL, 2.0 mmol) and 1,10-phenanthroline (3.6 mg, 0.02 mmol) in tetrahydrofuran (26 mL) at −78° C. was added n-BuLi (6.8 mL, 2.5 M in hexanes) dropwise and the reaction was stirred for 16 hours. Saturated NH4Cl was then added and the reaction was diluted with EtOAc, washed with water and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-50% EtOAc/heptane) to 6-Phenyl-1,2-thiazinane 1,1-dioxide (1.3 g, 80% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.35 (m, 5H), 6.98 (m, 1H), 4.12 (dd, 1H), 3.26-3.20 (m, 2H), 2.40-2.30 (m, 1H), 2.16-2.12 (m, 1H), 1.77-1.65 (m, 2H). LCMS (ESI), m/z, 234 [M+Na]+. (Reference: D. Askin, et al. Org. Lett. 2003, 4175.)
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][NH:16][C:17]([C:19]2[O:20][CH:21]=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:18])=[O:14])=[CH:11][C:10]=1[O:38][CH3:39])C1C=CC=CC=1.O1CCOCC1>[C].[Pd].CO>[OH:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][NH:16][C:17]([C:19]2[O:20][CH:21]=[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:18])=[O:14])=[CH:11][C:10]=1[O:38][CH3:39]
Reactant: COc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Reaction time: 6 h
Yield: 60.5 %

Procedure:
A mixture of the compound of Example 68 (0.80 g), dioxane (100 ml), methanol (10 ml) and 10% palladium carbon (0.16 g) was hydrogenated at 40° C. with stirred for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/chloroform=1/9) and recrystallized from ethanol, thereby giving 0.40 g of the desired compound. Melting point: 216-220° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[N:12][C:11]1=2>C(#N)C>[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21]([NH:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:22])[CH:13]=[N:12][C:11]1=2
Reactant: NCc1ccccn1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCc1ccccn1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
0.500 g (4.62 mmol) of 2-(aminomethyl)pyridine and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated together with stirring in a 10 ml round bottom flask at 110° C. for 90 minutes. The solution solidified and was cooled to room temperature. 10 ml of acetonitrile was added and the solid was broken up with a spatula until a fine white precipitate was formed. The solid was collected by Buchner vacuum filtration and the solid was washed with acetonitrile and ether to yield 267 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[(2-pyridinyl)methyl]propanamide (AIT-0063) as a white solid. Yield: 84%.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>O.O1CCCC1>[CH3:19][O:18][C:16]([NH:1][C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])=[O:17]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.9 %

Procedure:
A solution of D-phenylalanine (25.00 g, 0.151 mol) and sodium hydroxide (6.05 g, 0.151 mol) in water (170 ml) and tetrahydrofuran (225 ml) was cooled to −15° C., and a solution of methyl chloroformate (18.6 g, 0.197 mol) in tetrahydrofuran (50 ml) was added dropwise. When the addition was ˜half complete, a solution of sodium hydroxide (9.10 g, 0.227 mol) in water (20 ml) was also added dropwise. When the additons were complete, the mixture was stirred at room temperature for an additonal 2 hours and acidified with 10% hydrochloric acid. The acid was extracted twice with diethylether, and the extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a clear oil (38.38 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][N:11]2[C:20]([C:19]1[CH:18]=[N:17][C:16]([NH2:15])=[CH:24][CH:23]=1)=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2
Reactant: Nc1ccc(C(=O)O)cn1
Product: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2C(=O)c1ccc(N)nc1
Yield: 31 %

Procedure:
Using amide formation method 1, (R,R)-2,5-Diaza-bicyclo[2.2.1]heptane-2-c arboxylic acid tert-butyl ester (1.0 g, 4.26 mmol, 1.0 eq) was combined with 6-Amino-nicotinic acid (588 mg, 4.26 mmol, 1.0 eq) to give 5-(6-Amino-pyridine-3-carbonyl)-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (420 mg, 31% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35-1.40 (m, 3H) 1.40-1.51 (m, 9H) 1.89 (br. s., 2H) 3.31-3.50 (m, 2H) 3.55 (d, J=9.09 Hz, 1H) 3.67 (dd, J=13.14, 6.57 Hz, 1H) 4.50 (br. s., 1H) 4.64 (br. s., 1H) 4.91 (br. s., 1H) 6.51 (d, J=6.57 Hz, 1H) 7.64 (br. s., 1H) 8.24 (br. s., 1H); MS m/z 637.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[K+]>C1COCC1.C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1sc2nccnc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1c(C(=O)O)sc2nccnc12
Yield: 98.2 %

Procedure:
A solution of ethyl 7-aminothieno[2,3-b]pyrazine-6-carboxylate 7 (10 g, 44.8 mmol) and potassium hydroxide (5.0 g, 90 mmol) in THF (50 mL), ethanol (50 mL) and water (20 mL) was stirred at 70° C. for 2 h. Quenched in a cold solution of 2N HCl, and the resulting precipitate was collected to give crude 7-aminothieno[2,3-b]pyrazine-6-carboxylic acid 8 (8.59 g, 98%). 1H-NMR (400 MHz, DMSO-d6) 7.03 (br s, 2H), 8.77 (s, 2H), 12.8 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16]/[CH:15]=[CH:14]\[C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:2]=2[F:1])[CH:11]=1
Reactant: CN(C)CCC=Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)CC/C=C\c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.67 h
Yield: 68.2 %

Procedure:
To a mixture of 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-N,N-dimethylbut-3-en-1-amine (234) (171 mg, 0.44 mmol) and NH4Cl (20 mg, 0.37 mmol) in EtOH (4.4 mL)/water (2.2 mL) at 100° C., Fe (209 mg, 3.75 mmol) was added in one portion and the mixture was heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celiteg, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving title compound 235 as a yellow solid (122.8 mg, 0.3 mmol, 69% yield). MS (m/z): (M+1) 358.1 (100%).