Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[O:31])=[CH:17][CH:16]=1
Reactant: CN(C)CCCNC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCNC(=O)COc1ccc(CCCCN)cc1
Yield: 79.6 %

Procedure:
A suspension of 3 (377 mg, 0.85 mmol) and 10% palladium on carbon (0.30 g, 50% wet) in methanol (15 mL) was stirred at room temperature for 2 h under atmospheric pressure of hydrogen. The mixture was then filtered through a Celite pad and the solvent was evaporated to provide 4 (208 mg, 80%) as a white solid. The crude product was directly used in the next step without purification. 1H NMR (300 MHz, CD3OD) δ 1.61 (m, 6H), 2.11 (s, 6H), 2.32 (m, 2H), 2.65 (m, 4H), 3.28 (m, 2H), 4.45 (s, 2H), 6.90 (d, 2H), 7.19 (d, 2H). m/z (ESI) 308.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:7]([Sn:11]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12]I)[CH2:8][CH2:9][CH3:10].CN(C)C=O>O1CCCC1>[CH2:18]([Sn:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][O:4][CH:1]([CH3:3])[CH3:2])[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)O
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
To a mixture of isopropanol (2 mL) and tetrahydrofuran (2 mL) was added sodium hydride (66%, 58 mg, 1.6 mmol) on an ice bath, then, the solution was stirred for 20 minutes at room temperature. To the reaction solution was added a solution of tributyl-iodomethyl-stannane (230 mg, 0.53 mmol), synthesized according to the document (Synthetic Communications, Vol. 24, No. 8, pp. 1117-1120), in tetrahydrofuran (1 mL) dropwise on an ice bath, then, N,N-dimethylformamide (0.5 mL) was added thereto, followed by stirring overnight at room temperature. The reaction solution was partitioned into water (20 mL) and diethyl ether (50 mL). The organic layer was separated, washed with brine, and then, evaporated in vacuo. The residue was purified by neutral silica gel column chromatography (heptane:ethyl acetate=30:1), and the title compound (63 mg, 0.17 mmol, 32%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1>>[CH3:29][O:28][C:25]1[N:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Br)cn1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cn1
Yield: 37.3 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (210 mg, 0.765 mmol) synthesized in Reference example 61 and 5-bromo-2-methoxypyridine (216 mg, 1.15 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 109 mg (yield 37%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC.O>O1CCCC1.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>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3cccs3)cc12
Yield: 45.4 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-thienyl)tin (0.32 ml, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in tetrahydrofuran (20 ml) was refluxed for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.22 g, 45.8%) as crystals.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][NH:24][OH:25])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1>O1CCOCC1>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][N:24]([OH:25])[C:3]([NH:2][CH3:1])=[S:4])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CN=C=S
Solvent: C1COCCO1
Product: CNC(=S)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A solution of methyl isothiocyanate (1.36 g, 18.56 mmol) in 2 ml of dioxane is added dropwise to a suspension of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine (2.01 g, 5.84 mmol) in 60 ml of dioxane and 60 ml of H20 at 0° C. The ice bath is removed. After one hour 0.5 g (6.84 mmol) additional methyl isothiocyanate is added and the reaction mixture is stored in a freezer overnight. The solids are collected by filtration and recrystallized from THF/hexane, rinsed with ether, and dried under high vacuum over P2O5 to give pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)thioxomethyl]-lH-indole-3-methanamine (1.32 g, 54%); mp 198°-198.5° C. (dec).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16]>CO>[C:1]1([N:7]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=C1CCN(c2ccccc2)CC1
Yield: 91.9 %

Procedure:
A mixture of 1-phenyl-piperidin-4-one (180 mg, 1.03 mmol) and hydroxylamine hydrochloride (142 mg, 2.06 mmol) in methanol (10 mL) was heated at reflux for 6 h. The solvent was evaporated and the residue diluted with water. The mixture was extracted with ethyl acetate then the organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to afford 1-phenyl-piperidin-4-one oxime (0.18 g, 92%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:13]([CH2:23][O:24]CC3C=CC(OC)=CC=3)=[N:12][C:11]=2[CH:34]([CH3:36])[CH3:35])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)C.Cl>CO>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:13]([CH2:23][OH:24])=[N:12][C:11]=2[CH:34]([CH3:36])[CH3:35])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CCc2ccccn2)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)c1nc(CO)n(CCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To 1.43 g of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1-(2-(2-pyridyl)ethyl)-1H-imidazole was added 20 ml of ethanol and 40 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1)to give 571 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-hydroxymethyl-1-(2-(2-pyridyl)ethyl)-1H-imidazole (112a)(yield 51%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[F:11])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 94.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-fluorobenzoic acid (8.76 g) and piperazine-1-carboxylic acid tert-butyl ester (8.2 g), the title compound (14.7 g) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH2:11].[C:12](O)(=[O:16])[C:13](O)=[O:14].Cl>>[Cl:10][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][C:7]=1[CH3:9])[NH:2][C:13](=[O:14])[C:12](=[O:16])[NH:11]2
Reactant: Cc1cc(N)c(N)cc1Cl
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Yield: 81.1 %

Procedure:
A mixture of 1,2-diamino-4-chloro-5-methylbenzene hydrochloride (1.90 g, 9.84 mmol), oxalic acid (1.24 g, 13.8 mmol) and 4M aqueous hydrochloric acid solution (49 mL) was heated under reflux for 4.5 hours. After being cooled, the solid precipitate was collected by filtration, washed well with water and dried under reduced pressure at 80° C. to afford 6-chloro-7-methyl-2,3(1H, 4H)-quinoxalinedione (1.68 g, 81%) as a dark grey solid, mp >330° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30](B(O)O)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[C:28]5[C:33](=[CH:32][CH:31]=4)[N:25]([CH3:24])[CH:26]=[CH:27]5)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccc5c(ccn5C)c4)c(C(=O)O)s3)c2cc1OC
Yield: 11.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and N-methylindole-5-boronic acid (26.2 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(1-methyl-1H-indol-5-yl)-thiazole-5-carboxylic acid (5.1 mg, 12%) as a white solid. MS 435 m/z (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=3)[CH2:22]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc2c(c1)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 31.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (3.7 g), 1,2,3,4-tetrahydro-7-methoxyisoquinoline (2.7 g; Daniel J. Sall and Gary L. Grunewald, J. Med. Chem. 1987, 30, 2208-2216) and potassium carbonate (6.7 g) in isopropanol (150 ml) was stirred under reflux for 48 h. The mixture was evaporated to dryness, and the residue was extracted with dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was then purified by column chromatography elating with dichloromethane/methanol (99:1) to give the title compound (1.6 g) as an orange solid, MP: 92°-94°. NMR includes signals at d 3.6 (2H,m,N--CH2Ar), 3.7 (3H,s,OCH3).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[C:20]1([Li])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[C:4](/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: [Li]c1ccccc1
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Product: CCc1cccc(-c2ccccc2)c1/C=N/C(C(C)C)C(C)C

Procedure:
(E)-[1-(3-Ethyl-biphenyl-2-yl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3 a) and phenyl lithium in analogy to procedure Example 5 a): colourless liquid: MS (ISP): 308.1 ((M+H)+.), 192.9 (((M-((iPr2)2CHNH2))+.), 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]([OH:16])=[C:6]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+](C1C=C(S(O[CH2:47][C@@H:48]2[CH2:50][O:49]2)(=O)=O)C=CC=1)([O-])=O>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])=[CH:4][C:5]([O:16][CH2:47][CH:48]2[CH2:50][O:49]2)=[C:6]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:7]=1
Reactant: CC(C)[Si](Oc1cc(O)c(NC(=O)C2CCCC2)cc1Cl)(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1cc(OCC2CO2)c(NC(=O)C2CCCC2)cc1Cl)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 17.8 %

Procedure:
N-{5-chloro-2-hydroxy-4-[(triisopropylsilyl)oxy]phenyl}cyclopentanecarboxamide (140 mg, 0.3 mmol) was dissolved in 1,4-dioxane (20 mL). Caesium carbonate (170 mg, 0.5 mmol) was added, followed by (2S)-oxiran-2-y-methyl 3-nitrobenzenesulfonate (90 mg, 0.3 mmol). After stirring over night at room temperature the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and concentrated. Purification by HPLC on C18 (Xterra, 5 um, 19×50 mm; acetonitrile/water 60/40 to 100/0 over 15 min) yielded 25 mg (17%) of the titled intermediate compound.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16].[C:18]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:18]([N:26]1[CH2:31][CH2:30][C:29]2([CH2:16][C:15](=[O:17])[C:8]3[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=3[O:6]2)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)O2
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
Pyrrolidine (8.35 ml, 7.11 g, 0.1 mol) was added to a suspension of 2'-hydroxy-5'-methoxyacetophenone (16.62 g, 0.1 mol) in methanol (100 ml). The mixture was stirred for 10 minutes, then 1-benzoyl-4-piperidone (20.32 g, 0.1 mol) was added and the mixture was heated under reflux for 7 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (400 ml) was added and the mixture was extracted with ethyl acetate (3×400 ml). The combined organic fractions were evaporated under reduced pressure and the residue was recrystallized from methanol to give the ketone as a pale yellow solid (29.54 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=[O:15])[CH2:7][CH2:6]2.[N+:16]([C:19]1[C:24]([CH:25]=O)=[CH:23][C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[CH:23][C:24]=1[CH:25]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:15])([O-:18])=[O:17]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Product: COc1cc(C=C2C(=O)CCc3cc(OC)c(OC)cc32)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 6,7-Dimethoxy-2-tetralone and 6-nitroveratraldehyde; mp 65-66° C.; IR (Nujol): 2855,1720, 1540; 1H NMR: δ2.71 (2H, t), 2.98 (2H t), 3.35 (3H, s), 3.66 (3H, s), 3.89 (3H, s), 3.97 (3H,s), 6.41 (1H, s), 6.62 (1H, s), 6.73 (1H, s), 7.74 (1H, s), 7.91 (1H, s); 13C NMR: δ28.4, 39.7, 56.5, 56.6, 56.8, 56.9, 107.7, 108.6, 111.2, 113.1, 128.1, 129.3, 130.3, 132.2, 133.3, 148.9, 149.0, 150.0, 153.3, 200.7.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (220 mg, 1.0 mmol), tert-butyl [(trans-4-aminocyclohexyl)methyl]carbamate (250 mg, 1.1 mmol) and triethylamine (0.43 mL, 3.1 mmol) in isopropyl alcohol (8 mL) was heated at 90° C. for 2 h. The solvent was removed and the resulting residue was purified by flash chromatography (0-80% EtOAc/Hexanes) to give the desired product (0.32 g, 77%). LCMS calculated for C19H27N4O4S (M+H)+: m/z=407.2. Found: 407.0.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 72 h
Yield: 67 %

Procedure:
Dibenzylamine (4.1 ml, 21.24 mmol, 1 eq) was added to a solution of tert-butyl 4-(2-(methyl-sulfonyloxy)ethyl)piperidine-1-carboxylate (6.5 g, 21.24 mmol, 1 eq) and triethylamine (3.2 ml, 23.36 mmol, 1.1 eq) in toluene (100 ml), and refluxing was carried out for 72 h. Then the reaction solution was concentrated and the residue was taken up in dichloromethane (300 ml), washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% ethyl acetate in hexane), a yellow solid was obtained. Yield: 67% (5.8 g, 14.21 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH2:24][NH:25][OH:26]>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH2:24][N:25]1[C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[C:6](=[O:7])[O:26]1
Reactant: ONCc1cc(Cl)ccc1Cl
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)ON(Cc2cc(Cl)ccc2Cl)C1=O
Reaction time: 16 h
Yield: 39 %

Procedure:
To a stirred solution of 4.1 grams (0.024 mole) of dimethylmalonyl chloride and 3.8 grams (0.048 mole) of pyridine in 100 ml of dry toluene at 0° C., 4.7 grams (0.024 mole) of N-(2,5-dichlorophenylmethyl)hydroxylamine (Intermediate D) was added dropwise over 30 minutes, while the temperature was maintained at 0°±5° C. The reaction mixture was allowed to rise to ambient temperature and was stirred about 16 hours. A white solid was separated and washed with toluene. Filtrate and washings were combined, washed with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. Sodium sulfate was separated, and the liquid was concentrated under reduced pressure to a viscous liquid, and ultimately to a solid. Recrystallization from hexane-ethyl acetate yielded 2.7 grams of solid product; mp 78°-80° C. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: CO.[CH3:3][C@@H:4]1[CH:11]=[CH:10][CH2:9][C:6]2([CH2:8][CH2:7]2)[C@@H:5]1[C:12](=[O:14])[CH3:13].[NH4+].[Cl-]>CCCCC>[CH3:3][C@@H:4]1[CH:11]=[CH:10][CH2:9][C:6]2([CH2:7][CH2:8]2)[C@H:5]1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)[C@@H]1[C@H](C)C=CCC12CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: CO
Product: CC(=O)[C@H]1[C@H](C)C=CCC12CC2
Temperature: 80 °C
Yield: 56.8 %

Procedure:
Na (22.7 mg, 0.987 mmol) was added to MeOH (24 ml). The resulting solution was treated at 25° C. with rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (1.62 g, 9.97 mmol, prepared in example 11), and heated at 80° C. for 64 h. The resulting solution was cooled, diluted pentane and poured into a saturated aqueous NH4Cl solution. The aqueous phase was extracted twice with pentane and the combined organic phases were washed with a saturated aqueous NaCl solution, dried (Na2SO4) and concentrated. FC (250 g SiO2, pentane/Et2O 10:0.5) of the crude product (1.5 g) gave rel-(4S,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (930 mg, 57%) and a rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone/rel-(4S,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (60:40, 408 mg, 25%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].CO>C[O-].[Na+]>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 89.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (185 mg, 0.55 mmol), beta-alanine (489 mg, 5.5 mmol) in 0.5 M NaOMe in MeOH solution (8.8 mL, 4.4 mmol) was refluxed overnight. After cooled, the reaction mixture was concentrated and residue was dissolved in water (80 mL). It was acidified by 1 N HCl solution to pH ca. 3-4. Resulting gummy solid was collected by filtration, rinsed with water and then dissolved in EtOAc. The organic solution was dried over MgSO4, filtered and concentrated to provide the title compound (173 mg, 0.49 mmol) as an off-white solid in 89% yield. LC-MS ESI−: 351.14 (M−1)−.