Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[N+:3]([C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1)([O-])=O>[Fe].O>[NH2:3][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])s1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(N)s1
Temperature: 70 °C
Yield: 254.5 %

Procedure:
3.6 g of iron powder, 1.4 g of FeSO4.7H2O, 25 ml of methanol and 8 ml of water were successively introduced into a three-necked flask. 940 mg (5 mmol) of methyl 5-nitro-2-thiophenecarboxylate were then added and the mixture was heated at 70° C. for eight hours. The reaction medium was filtered on celite, the filtrate evaporated, and taken up in water and ethyl ether. The organic phase was decanted, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane; 2 g (77%) of the expected compound of melting point 110°-112° C. were obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CCCCCCC>CN(C)C=O>[Si:34]([O:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:6][CH2:7]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: O=C(OCc1ccccc1)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a stirred solution of benzyl 2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (60.00 g, 155.2 mmol) in anhydrous N,N-dimethylformamide (160 mL) at r.t. was added 1H-imidazole (32.0 g, 466 mmol) and tert-butyldimethylsilyl chloride (36.2 g, 233 mmol). The reaction mixture was stirred at r.t. for 4 h, quenched with water (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (84 g). The pure product (55.4 g) was obtained by re-crystallization of the crude product from heptane. The mother liquor was concentrated and subjected to purification by flash chromatography on a silical gel column eluting with AcOEt/Haxane to give additional 14.4 g of the product with a total 89.7% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=1.C([O:21][CH2:22][C:23]1[CH:27]=[CH:26][O:25][C:24]=1[C:28](=[O:31])[CH2:29]Br)(=O)C.O>CN(C=O)C>[NH2:9][C:8]1[C:7]2[C:6](=[CH:5][C:4]([Cl:3])=[CH:11][CH:10]=2)[N:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:29]=1[C:28]([C:24]1[O:25][CH:26]=[CH:27][C:23]=1[CH2:22][OH:21])=[O:31]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: CC(=O)OCc1ccoc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(C(=O)c2occc2CO)c(N)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 390 mg, 8.8 mmol) in DMF (20 ml) was added a solution of 4-chloro-2-(ethoxycarbonylamino)benzonitrile (step 1, 2 g, 8.8 mmol) in DMF (5 ml) at 0° C. After stirring for 1 h at 0° C., 3-acetoxymethyl-2-(bromoacetyl)furan (step 1, 2.3 g, 8.8 mmol) was added and the resulting mixture was stirred at room temperature for an additional 6 h. The mixture was poured into water (100 ml), and extracted with ethyl acetate (300 ml). The organic extract was washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), and then dried (MgSO4) and concentrated. The residue was diluted with a mixture of ethanol (20 ml) and water (10 ml), and then potassium carbonate (ca. 2 g) was added. After stirring for 6 h, the mixture was poured into a saturated aqueous ammonium chloride (100 ml) and the mixture extracted with ethyl acetate (300 ml). The organic extract was washed with brine (100 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (2/1) to give 505 mg (16%) of the titled compound as yellow solids. Mass; M+=362
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13]Br>>[Br:13][CH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(C)cc1
Product: CCOC(=O)c1ccc(CBr)cc1

Procedure:
An ethyl 4-methylbenzoate (EMB) solution (1134 g in chlorobenzene (CB), ~43 wt. %, 2.93 mol) was charged into a 2-Liter round bottomed flask equipped with mechanical stirrer (300 RPM stirring rate) and a cooling condenser, and heated. The temperature controller was set at 140° C., and a scrubber was connected to the condenser. Liquid bromine (275 g, 1.72 mol or ~59 mol %, Aldrich, 99.5+%, A.C.S. reagent) was fed via Viton tubings, and the bromine feed rate was adjusted to 1.00 mL/minute for the first 30 mol % of bromine and then to 0.50 mL/minute for the rest of the addition at 140° C. Heating and stirring was continued for a few minutes after all bromine was added and the hot mixture was purged with nitrogen for 20 minutes, then allowed to cool to obtain 1183 g crude reaction mixture (some materials were used for routine analysis). The GC wt. % analysis of the crude reaction mixture indicated the following:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:28][N:29]([CH3:34])[CH:30]1[CH2:33][NH:32][CH2:31]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:32]5[CH2:33][CH:30]([N:29]([CH3:34])[CH3:28])[CH2:31]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN(C)C1CNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CC(N(C)C)C4)c(F)cc3cc2c1=O
Yield: 69.5 %

Procedure:
1-Cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 4, but starting with 1.4 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.04 g of 3-(dimethylamino)azetidine dihydrochloride. After concentration of the combined organic extracts to dryness, the solid obtained is recrystallized in 40 cm3 of ethanol. 1.2 g of 1-cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 225° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([C:19]([O:21][CH3:22])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:4]([C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:6]([C:19]([O:21][CH3:22])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(c1cc(Cc2ccc(F)cc2)cnc1C(=O)OC)C1CC1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of methyl 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (234 mg, 0.78 mmol) and ethyl 3-chloro-3-oxopropanoate (0.13 mL, 90%, 1.0 mmol) was heated at 85° C. for 3 hours. Upon cooling to room temperature, dichloromethane and saturated aqueous sodium bicarbonate were added and the layers separated. The organic layer was washed with brine. The aqueous layers were extracted with dichloromethane and the combined organics dried over sodium sulfate. Filtration and concentration followed by silica gel chromatography provided methyl 3-{cyclopropyl[3-(ethyloxy)-3-oxopropanoyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (285 mg, 88%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:11].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>>[OH:11][C@@H:6]1[C:7]2[C:3](=[C:2]([O:1][C:19]3[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: Oc1cccc2c1CC[C@@H]2O
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(Oc2cccc3c2CC[C@@H]3O)cc1
Yield: 42.7 %

Procedure:
According to the method of (Example 99) <Step 1>, from (1S)-4-hydroxy-2,3-dihydro-1H-inden-1-ol (0.99 g) and (4-(methoxycarbonyl)phenyl)boronic acid (1.31 g) that are commercially available or are obtained according to a known method, the subject compound (0.80 g) was obtained as pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-:3])=[O:2]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Yield: 94.2 %

Procedure:
To a stirred solution of 2-nitrophenol (1) (1.4 g, 10 mM) and ethyl 4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added 2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultant colored mixture is then heated under a nitrogen atmosphere at gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture yields an oil which on flash chromatography (silica gel, ethyl acetate/hexane- or methylene chloride as eluant) yields 2.4 g (96% yield) of the title compound (3) as an oily liquid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([F:33])[CH:24]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>C1COCC1>[F:33][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:9][CH2:8][Si@H:7]([CH2:1][CH3:2])[CH2:12][CH2:11]3)[CH2:14][CH2:15]2)[CH:28]=[CH:27][C:26]=1[O:29][CH:30]([F:31])[F:32]
Reactant: CC[Mg]Br
Reactant: CO[SiH]1CCC([C@H]2CC[C@H](CCCCc3ccc(OC(F)F)c(F)c3)CC2)CC1
Solvent: C1CCOC1
Product: CC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(OC(F)F)c(F)c3)CC2)CC1

Procedure:
130 ml (0.13 moles) of a THF solution of 1M of ethylmagnesium bromide was dropped in a mixed solution of 42.9 g (10 mmols) of 1-methoxy-4-(trans-4-(4-(3-fluoro-4-difluoromethoxyphenyl)butyl)cyclohexyl)-1-silacyclohexane and 30 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of solvent and salts, followed by isolation through chromatography to obtain 37.8 g (yield: 88.6%) of the intended trans isomer product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[NH2:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60]>>[CH2:22]([O:21][N:16]1[C:15]([CH3:30])([CH3:31])[CH2:14][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]3[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:54])([CH3:55])[CH2:38]3)[N:3]=[C:2]([NH:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])[N:7]=2)[CH2:18][C:17]1([CH3:20])[CH3:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: NCCC(=O)O
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(NCCC(=O)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and β-alanine according to the procedure of Example 15.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:10]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:17])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: O=C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCN1
Yield: 90.3 %

Procedure:
Sulfonylation of piperazine-2-one (326.2 mg, 3.3 mmol) with 3,4-dichlorobenzene-sulfonyl chloride (800 mg, 3.3 mmol) was carried out according to a similar procedure described for example 15A using anhydrous dichloromethane (8 mL) as solvent and diisopropylethylamine (1.42 mL, 8.2 mmol) as base. 4-(3,4-dichloro-benzenesulfonyl)-piperazin-2-one was obtained in 90.3% yield (912 mg) as white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.17-3.24 (m, 2H) 3.25-3.30 (m, 2H) 3.59 (s, 2H) 7.79 (dd, J=8.46, 2.15 Hz, 1H) 7.94 (d, J=8.34 Hz, 1H) 8.06 (d, J=2.02 Hz, 1H) 8.08 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH3:11])(OC(=O)C)[CH:5]=[CH2:6]>[Cu]Cl>[C:3]([O:12][CH2:6][CH:5]=[C:4]([CH3:11])[CH:3]([O:2][CH3:1])[O:12][CH3:13])(=[O:2])[CH3:4]
Reactant: C=CC(C)(OC(C)=O)C(OC)OC
Agent: Cl[Cu]
Product: COC(OC)C(C)=CCOC(C)=O
Yield: 80.2 %

Procedure:
1,800 parts of 1,1-dimethoxy-2-methyl-2-acetoxy-but-3-ene and 1 part of copper (I) chloride were heated, with stirring, at 155°-160° C. in a reaction vessel equipped with a stirrer, an internal thermometer and a descending condenser, the degree of rearrangement being determined by examining small samples by gas chromatography. The low-boiling products formed distilled off continuously over the entire reaction time of 6 hours. Subsequent working up of the reaction mixture by distillation gave 1,444 parts of 4,4-dimethoxy-3-methyl-crotyl acetate. This corresponds to a yield of 80.2% of theory.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH2:25][C:26]([CH3:36])([CH3:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([CH3:36])([CH3:35])[CH2:25][OH:24])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)(CO)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(CO)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (23.5 g) and 4-[(3-hydroxy-2,2-dimethylpropyl)amino]-1,3-thiazol-2(5H)-one (7.00 g) in 2-propanol (200 mL) was added piperidinium acetate (10.1 g). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (8.83 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cc([N+](=O)[O-])ccc5n4)cc3CC[C@@H]12
Yield: 53.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (96 mg, 1.14 mmol), 2-chloro-6-nitroquinoline (96 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 88 mg (53%) of the title compound as a tan solid. mp 195°-196°. FDMS: m/e=433. α[D]589 =+64.56 (c =0.78, chloroform).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13]O>>[CH2:1]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CSCc1ccccc1
Reactant: CO
Product: COC(=O)CSCc1ccccc1

Procedure:
S-benzylthioglycolic acid (12.0 g) was dissolved in 250 mL of methanol and sparged with hydrogen chloride gas at room temperature for 20 minutes. The solvent was then removed under vacuum. Methyl S-benzylthioglycolate obtained was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1>>[C:11]12([C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=3[OH:1])[CH:6]=[O:7])[CH2:16][CH:15]3[CH2:4][CH:5]([CH2:8][CH:13]([CH2:14]3)[CH2:12]1)[CH2:6]2
Reactant: Oc1ccc(Br)cc1
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Yield: 56 %

Procedure:
When 4-hydroxybenzaldehyde was substituted for 4-bromophenol in Example 31, Step A, the similar procedure afforded 3-(1-admantanyl)-4-hydroxybenzaldehyde in 56% yield, as a pale white solid. 1H-NMR (CDCl3) 9.84 (s, 1H); 7.78 (d, 1H, J=2.07 Hz); 7.61 (dd, 1H, J=8.13, 2.01 Hz); 6.77 (d, 1H, J=8.16 Hz); 5.88 (bs, 1H); 2.12 (s, 6H); 2.09 (s, 3H); 1.78 (s, 6H). This was methylated by similar procedure as described in Example 31, Step B, to give the title compound in 64% yield, as light yellow solid. 1H-NMR (CDCl3) 9.86 (s, 1H); 7.76 (d, 1H, J=2.07 Hz); 7.7 (dd, 1H, J=8.4, 2.1 Hz); 6.95 (d, 1H, J=8.4 Hz); 3.91 (s, 3H); 2.09 (s, 9H); 1.76 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[O:19])=[C:15]([O:28][CH3:29])[C:14]([O:30][CH3:31])=[C:13]([O:32][CH3:33])[CH:12]=2)=[O:10])=[N:6][CH:7]=1.Cl.[CH3:35][NH:36][CH2:37][CH2:38]N>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:36]([CH3:35])[CH2:37][CH2:38][N:27]=4)=[CH:22][CH:21]=3)=[O:19])=[C:15]([O:28][CH3:29])[C:14]([O:30][CH3:31])=[C:13]([O:32][CH3:33])[CH:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CNCCN
Reactant: COc1cc(C(=O)Nc2ccc(Br)cn2)c(NC(=O)c2ccc(C#N)cc2)c(OC)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)Nc2ccc(Br)cn2)c(NC(=O)c2ccc(C3=NCCN3C)cc2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of the compound of N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}(4-cyanophenyl)carboxamide (680 mg, 1.33 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10 ml) was saturated with hydrogen chloride gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine (0.586 ml, 6.65 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder (240 mg, 32%). MS found for C26H26BrN5O5 M+=568, (M+2)+=570.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:8]([C:22]([O:24]CC)=[O:23])=[CH:7]1)#[N:2].[OH-].[Na+]>CCO>[C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:8]([C:22]([OH:24])=[O:23])=[CH:7]1)#[N:2]
Reactant: CCOC(=O)c1cn(CCCC#N)c(=O)cc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCCCn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 100 %

Procedure:
Ethyl 1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the ester to give 1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid as a white solid (100%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 13.10 (v br s, 1H), 9.72 (br s, 1H), 8.48 (s, 1H), 7.76 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (dd, J=8.4, 0.9 Hz, 1H), 7.30 (t, J=8.5 Hz, 1H), 5.49 (s, 1H), 3.95 (t, J=7.1 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 1.93 (pentet, J=7.2 Hz, 2H). HRMS (FAB+) calcd C16H14FIN3O3 (MH+) 442.0064, found 442.0060.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[N+:17]([CH:20]=[CH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc2cc[nH]c2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of indole-6-carboxaldehyde (2.8 g), nitromethane (30 mL) and ammonium acetate (0.560 g) was stirred at 100° C. for 30 minutes. The excess nitromethane was removed under reduced pressure and the residue washed with water, dissolved in ethyl acetate (500 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to a volume of about 50 mL. This solution was then diluted with petroleum ether and the resulting suspension filtered and dried to provide 3.3 g (91%) of the desired compound.