Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25]2[C:9]3[N:10]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:11]4[NH:12][CH2:13][CH2:14][CH2:15][C:16]=4[C:17](=[O:18])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[C:28]([N:12]1[C:11]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:25]4[CH:26]=[CH:27][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][C:8]=3[C:17](=[O:18])[C:16]=2[CH2:15][CH2:14][CH2:13]1)(=[O:30])[CH3:29]
Reactant: COc1ccc2c(c1)CCc1c-2n(-c2ccccc2)c2c(c1=O)CCCN2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2c1n(-c1ccccc1)c1c(c2=O)CCc2ccccc2-1

Procedure:
Treat 5,6,8,9,10,11-hexahydro-3-methoxy-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one (10 mmoles) with equimolar amounts of acetyl chloride and triethylamine dissolved in CH2Cl2 (10 ml) at 0°-25° C. for 3 days. Wash the resulting solution with aqueous NaHCO3 solution and with water, and dry the organic solution. Evaporate the CH2Cl2, and chromatograph the residue on silica gel. Elute the N-acetylated product with 2% MeOH in CHCl3, and crystallize it from isopropyl acetate/disopropyl ether to provide 11-acetyl-5,6,8,9,10,11-hexahydro-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one, m.p. 178.5°-182° C.
Reaction SMILES: [C:1]1(/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:1]1(/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:8]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:28])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCCCCN
Reactant: O=C(O)/C(=C/c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCNC(=O)/C(=C/c1ccccc1)c1ccccc1
Yield: 84.2 %

Procedure:
To a solution of (2E)-2,3-diphenylacrylic acid (0.32 g, 1.4 mmol) (prepared according to procedure given in example 1) in DMF (5 mL) was added Methyl-7-aminoheptanoate (0.25 g, 1.3 mmol), EDCI (0.55 g, 2.8 mmol) and HOBt (0.19 g, 1.4 mmol). TEA (0.6 mL, 4.3 mmol) was added dropwise with constant stirring to the above reaction mixture and it was stirred for 2 hours at room temperature. Reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×100 mL). The organic layer was washed successively with water (3×50 mL), and brine solution (1×50 mL). The organic layer was dried over Na2SO4 and concentrated to afford the title compound (0.4 g, 61% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C([O-])([O-])=O.[Cs+].[Cs+].O.CC(=O)OCC>CN(C=O)C.[Cu](I)I>[N:12]1[N:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[N:14]=[CH:15][CH:16]=1
Reactant: c1c[nH]nn1
Reactant: O=C(O)Cc1ccccc1I
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-iodophenylacetic acid (500 mg) in DMF (5 mL) was added 1H-1,2,3-triazole (0.214 mL), followed by Cs2CO3 (1.21 g) upon which the temperature increased. The reaction mixture was cooled to RT and copper iodide (17.6 mg) was added. The mixture was stirred at RT overnight and at 110° C. for 1 h30. After cooling down, H2O/EA was added and the phases were separated. The aq. phase was acidified to pH=1 with 1M HCl and extracted with EA. The combined org. phases were dried (Na2SO4) and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA/AcOH 100/1; gradient in % B: 18 for 4CV, 18 to 100 over 10CV, 100 for 2CV) to afford 235 mg of white solid. LC-MS (B): tR=0.60 min; [M+H]+: 204.42.
Reaction SMILES: [ClH:1].Cl.CN1CCN(CC(C2(O)CCCCC2)C2C=CC=C(OC3C=CC=CC=3)C=2)CC1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](=O)[CH:40]([C:54]2([OH:60])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH:40]([C:54]2([OH:60])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]2)[C:41]2[CH:42]=[CH:43][C:44]([O:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:45][CH:46]=2)[CH2:35][CH2:34]1
Reactant: CN1CCN(C(=O)C(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1
Agent: CN1CCN(CC(c2cccc(Oc3ccccc3)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1, step 2 1-[2-(4-methylpiperazin-1-yl)-1-(3-phenoxyphenyl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[2-(4-methylpiperazin-1-yl)-1-(4-phenoxyphenyl)-2-oxoethy]cyclohexanol. MS(ESI) m/z 395 ([M+H]+). Anal Calcd for C25H34N2O22HCl 0.9H2O: C,62.08; H,7.88: N,5.79. Found: C, 62.26; H, 8.11; N,5.70.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH:20][CH3:21].O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:20]([O:19][CH3:18])[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([Pb+3])[CH:19]=1.[C:23]1(=[O:30])[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1.C1(C)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([CH:24]2[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:23]2=[O:30])[CH:19]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)CCCC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-ethylphenyllead triacetate (20.00 g, 35.2 mmol) (described in WO08/071,405) in chloroform (100 ml) is added cyclohexane-1,3-dione (3.94 g, 35.2 mmol) and 4-dimethylaminopyridine (22.36 g, 176 mmol). After stirring the reaction at room temperature for 5 minutes toluene (50 ml) is added and the solution is heated at 80° C. for 4 hours. After cooling to room temperature the mixture is allowed to stand overnight, followed by treatment with 2M aqueous hydrochloric acid. Following filtration of the precipitate the biphasic solution is separated, and the aqueous phase is extracted again with dichloromethane (×2). Organic fractions are combined then evaporated under reduced pressure to yield a crude product which is purified by flash column chromatography (10% ethyl acetate/hexane to 70% ethyl acetate/hexane eluant) to afford 2-(5-bromo-2-ethylphenyl)cyclohexane-1,3-dione as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][CH2:2][C@@H:3]([CH3:4])[N:5]=3)=[CH:12][CH:11]=2)[CH:14]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[N:22][CH:21]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)CO)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
N-[(1R)-2-Hydroxy-1-methylethyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.94 g, 3.85 mmol) synthesized in Example (84a) was dissolved in tetrahydrofuran (35 mL), and anhydrous methanesulfonic acid (1.38 g, 7.70 mmol) and triethylamine (2.15 mL, 15.41 mmol) were added, followed by stirring at 50° C. for 1.5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and the solution was separated with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-75%) to afford the desired compound (1.59 g, yield 85%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:17][C:18](OC)=[O:19])[C:13](OC)=[O:14])=[CH:4][N:3]=1.[BH4-].[Li+].O>C(O)(C)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:17][CH2:18][OH:19])[CH2:13][OH:14])=[CH:4][N:3]=1
Reactant: COC(=O)CC(Cn1cnc2cnc(N)nc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1ncc2ncn(CC(CO)CCO)c2n1
Reaction time: 1 h

Procedure:
To a solution of crude dimethyl (2-aminopurin-9-ylmethyl)succinate (3.2 g, 10.9 mmol), dissolved in tert. butanol (250 ml) at 40° C., was added lithium borohydride (1.3 g, 60 mmol) in portions with stirring. After 1 hour at ambient temperature, water (30 ml) was added slowly and stirring continued over night. Inorganic salts were filtered and the solution evaporated to dryness. Yield of crude product was 1.6 g (50%). Chromatography on silica (chloroform+methanol 7+1) afforded pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.[CH3:22]O>>[ClH:20].[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([O:15][CH3:22])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled suspension of 2(S)-benzyloxycarbonylamino-3-aminopropionic acid (Fluka) (23-1) (10 g, 0.042 mol) in 150 ml of methanol was added 5.47 g (0.046 mol) of thionyl chloride over 20 minutes. The resulting solution was allowed to stir at room temperature overnight. After ~18 hrs, the solvent was removed in vacuo, and the residual solid was stirred with 150 ml of ether for 0.5 hr. The resulting white solid was collected and air dried to give 23-2.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.C[Mg]Cl.CC1(C)CCC[CH:19]([C:23](=[O:25])C)[CH2:18]1.C1(C(O)(C)C)CCCCC1.C(OC(=O)C)(=O)C.C(OC(=O)CC)(=O)CC>>[C:23]([O:11][C:8]([CH:4]1[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]1)([CH3:9])[CH3:10])(=[O:25])[CH2:19][CH3:18]
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: CC1(C)CCCC(C(C)(C)O)C1
Agent: CC(C)(O)C1CCCCC1
Agent: CCC(=O)OC(=O)CC
Agent: C[Mg]Cl
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)OC(C)(C)C1CCCCC1

Procedure:
The following compounds were prepared analogously to the method described in Example 16, except that the alcohol component used was 2-(3,3-dimethylcyclohexyl)-2-propanol, [which can be prepared from methylmagnesium chloride and 1-(3,3-dimethylcyclohexyl)-ethanone by a Grignard reaction] instead of 2-cyclohexyl-2-propanol. The esterification was carried out with acetic anhydride (Example 18) or propionic anhydride (Example 19). Thus, only the spectroscopic data are indicated at this point:
Reaction SMILES: Br[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:9]2[CH2:8][CH2:7][N:6]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:5](=[O:25])[C:4]=2[C:3]=1[CH3:26].[OH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[N:10]1[C:9]2[CH2:8][CH2:7][N:6]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:5](=[O:25])[C:4]=2[C:3]([CH3:26])=[C:2]1[C:31]1[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=1
Reactant: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Temperature: 60 °C
Yield: 86.8 %

Procedure:
2-Bromo-1-(2,4-Dichlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (450 mg, 0.98 mmol), 4-hydroxyphenylboronic acid (150 mg, 1.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (150 mg) were dissolved in DME (20 ml) and 1 M Na2CO3 (5 ml)). The resulting solution was degassed and heated at 60° C. under nitrogen overnight. Water and EtOAc were added after cooling and the aqueous phase extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give a crude product that was purified by flash chromatography (heptane:EtOAc gradient) to afford 0.40 g (87%) of the product as a pale yellow solid.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([OH:5])=O.[C:9]1([C@H:15]2[CH2:19][O:18][C:17](=[O:20])[NH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[Cl-].[Li+]>C(OCC)(=O)C>[CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([N:16]1[C@@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19][O:18][C:17]1=[O:20])=[O:5]
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CC/C=C(\C)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC/C=C(\C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 75 °C
Yield: 89.2 %

Procedure:
A 20 L jacketed reactor was fitted with a reflux condenser and a nitrogen inlet. To the flask was charged 1006 g (8.81 mol) of (E)-2-methyl-2-pentenoic acid, 1250 g (7.661 mol) of (S)-(+)-4-phenyl-oxazolidin-2-one, 2179 g (8.81 mol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 81 g (1.915 mol) of lithium chloride, and 12.5 L of ethyl acetate (EtOAc). The reaction was heated to 75° C. for 20 hours and then cooled to room temperature. The reaction solution was extracted 3× with 4 L aliquots of 1N HCl and 1× with 4 L of 0.2N NaOH. The 20 L reactor was fitted with a distillation head. The organic layer was distilled to remove, in succession: 6.5 L of EtOAc, after which 8 L of heptane was added back to the reactor; 4 L of EtOAc/heptane, after which 4 L of heptane was added to the reactor; and 4 L of EtOAc/heptane, after which 8 L of heptane was added to the reactor. After an additional 2 L of EtOAc/heptane was removed by distillation, the reaction mixture was cooled to an internal temperature of 40° C., and the reactor contents were charged to a filter and filtered under 5 psig of nitrogen washing with 8 L of heptane. The solids were dried under 5 psig of nitrogen overnight to give 1772 g of the titled compound: 1H-NMR (DMSO) 7.363-7.243 (m, 5H), 6.137-6.096 (m, 1H), 5.434-5.394 (m, 1H), 4.721-4.678 (t, 1H, J=8.578), 4.109-4.069 (m, 1H), 2.119-2.044 (m, 2H), 1.703-1.700 (d, 3H, J=1.364), 0.945-0.907 (t, 3H, J=7.603); Anal Calc'd for C15H17N1O3: C, 69.48; H, 6.61; N, 5.40. Found: C, 68.66; H, 6.60; N, 5.60; MS (Ion Mode: APCI) m/z=260 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[O:18][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A solution of 3-benzyloxy-4-nitrophenol (EP application 095121) (6.3 g, 25.7 mmol), t-butyldimethychlorosilane (5.81 g, 38.6 mmol), imidazole (3.5 g, 51.4 mmol), and dimethylaminopyridine (2-3 mg) in DMF (20 mL) is stirred 18 h. The solution is poured into EtOAc and extracted once with water and five times with brine. The organic phase is dried, filtered, and concentrated to afford the title compound: 1H NMR (CDCl3δ 7.73 (d, J=9.1 Hz, 1H), 7.21 (m, 5H), 6.31 (d, J=2.5 Hz, 1H), 6.26 (dd, J=8.8, 2.5 Hz, 1H), 5.02 (s, 2H), 0.78 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>C(Cl)(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([N:11]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH:9]=[N:10]2)=[O:27])[CH:22]=1
Reactant: C1=NNC(c2ccccc2)C1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1N=CCC1c1ccccc1
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
A mixture of 5-phenyl-2-pyrazoline (2.9 g) and triethylamine (4 g) was added dropwise with ice cooling to a suspension of nicotinoyl chloride hydrochloride (4 g) in 20 ml chloroform, the resulting mixture was stirred for 15 minutes, washed with water and concentrated, and the concentrate was purified by silica gel chromatography (chloroform/methanol=100/1), giving 4.3 g (yield: 86%) of pure product. M.p. 100°-102° C.; NMR (CDCl3): 2.9-3.8 (2H, m), 5.61 (1H, dd, J=5, 12 Hz), 7.03 (1H, t, J=2 Hz), 7.31 (5H, s), 7.28 (1H, m), 8.15 (1H, dt, J=8, 2 Hz), 8.68 (1H, dd, J=2, 6 Hz), 9.13(1H, d, J=2 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[K].I[CH2:8][CH2:9][CH2:10][CH3:11].[NH:12]1[C:20](=[O:21])[C:18](=[O:19])[C:16](=[O:17])[NH:15][C:13]1=[O:14].Cl>C(O)C.O1CCCC1>[OH:19][C:18]1([C:2]2[N:1]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=2)[C:16](=[O:17])[NH:15][C:13](=[O:14])[NH:12][C:20]1=[O:21]
Reactant: CCCCI
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: c1cc[nH]c1
Agent: Cl
Agent: [K]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCn1cccc1C1(O)C(=O)NC(=O)NC1=O
Yield: 64.1 %

Procedure:
Potassium pyrrole (3.0 g., 0.03 mole), 1-iodobutane (9.2 g., 0.05 moles) and 10 ml. of tetrahydrofuran were combined and refluxed for 1.5 hours by which time the reaction mixture had become a thick mass. The reaction mixture was diluted with 30 ml. of water and extracted with 35 ml. of ether. The ether was backwashed with water, then added to a solution of anhydrous alloxan (4.8 g., 0.03 mole) obtained by heating in 50 ml. of ethanol. The ether was distilled away, 6N hydrochloric acid (5 ml., 0.03 mole) was added, and the mixture refluxed for 3 minutes, cooled, evaporated to a gum, and triturated with water to afford title product [5.1 g.; m.p. 135 (dec); m/e 265].
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24](OC(C)=O)=[O:25]>ClCCl>[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:24](=[O:25])[CH3:23])[CH2:12][CH2:11]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenyl(piperidin-4-yl)methanone hydrochloride (743 mg, 3.29 mmol) in dichloromethane (13.2 mL) and triethylamine (1.10 mL, 7.90 mmol) was treated with Ac2O (0.373 mL, 3.95 mmol) dropwise over 1 minute in an ice bath under argon, and the resulting translucent mixture was immediately removed from the ice bath and stirred at room temperature overnight. The reaction was then extracted with 1 M aqueous HCl (1×8 mL) and 1 M aqueous NaOH (1×8 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the title compound as a translucent beige oil that crystallized upon standing.
Reaction SMILES: S1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.O[O:9][S:10]([O-:12])=O.[K+].C([O-])(O)=O.[Na+]>CC#N.O>[O:9]=[S:10]1(=[O:12])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCSCC1
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tetrahydrothiopyran-4-one in CH3CN (50 mL) and H2O (35 mL) at 0° C. was added in portions over 1 hour a mixture of oxone (70.5 g, 115 mmol) and NaHCO3 (29.9 g, 356 mmol). The reaction mixture was then stirred at room temperature for 1 h, diluted in CH3CN (250 mL) and filtered. The filtrate was concentrated, suspended in acetone and filtered. 1,1-Dioxo-tetrahydrothiopyran-4-one (6.3 g, quantitative yield) was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1)([CH3:5])[CH3:4])#[N:2].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CCOC(=O)c1csc(C(C)(C)C#N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C#N)c1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.6 %

Procedure:
To a solution of ethyl 2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylate (0.9 g, 4.0 mmol) in tetrahydrofuran/methanol/water (=12 mL/4.0 mL/4.0 mL) was added lithium hydroxide monohydrate (330 mg, 8.0 mmol), and the reaction mixture was stirred at room temperature for 10 hr. The mixture was concentrated under reduced pressure, and the obtained aqueous solution was adjusted to pH 5 by adding 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (256 mg, 53%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]=[CH:7][C:8]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:9]=3[C:10](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[CH:3]=1.C1C(=O)N([Br:31])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]3[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C1c2ccc(C)cc2C=Cc2ccc(F)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C1c2ccc(CBr)cc2C=Cc2ccc(F)cc21

Procedure:
Compound 4-a (0.24 g) was dissolved in 20 ml of carbon tetrachloride, and 0.14 g of NBS and catalytic amount of benzoyl peroxide were added to the solution, followed by heating under reflux for 4 hours. After cooling, insoluble matters were filtered off and the filtrate was diluted with dichloromethane. The dilution of the filtrate was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained product was unstable and subjected to the subsequent reaction without particular purification.