Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12C=C[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 6 (0.25 g) and potassium carbonate (0.3 g) in methanol-water (15 ml, 9:1) was stirred at room temperature for 8 hr. Solution was concentrated diluted with cold water, cooled and the precipitated solid was filtered, and crystallized from methanol. White solid, mp. 138-40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].C(OC(=O)C)(=[O:14])C.CO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][OH:14])[C:3]=1[O:10][CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(Cl)ccnc1CO
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
30 g (173mmol) of 4-chloro-3-methoxy-2-methylpyridine N-oxide (cf. Example 1a) were dissolved in 100 ml of glacial acetic acid, after which 150 ml of acetic anhydride were added dropwise, at 80° C. and while stirring, and the mixture was then stirred at 110° C. for 2 h. The mixture was then cooled down to 80° C. and 200 ml of methanol were added dropwise; the mixture was then heated to boiling for 15 min. and, after having been cooled down, concentrated in vacuo; the residue was taken up in methanol and this mixture was allowed to flow into 300 ml of 1.5N methanolic sodium hydroxide solution, with this mixture then being stirred at 20° C. for 30 min. and concentrated in vacuo; the residue was taken up in water, and this mixture extracted three times with dichloromethane, with the organic phase being dried and concentrated; the residue was crystallized using petroleum ether. 23 g of product were obtained, m.p. 64°-66° C.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(=O)=O.[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>C(OCC)(=O)C>[CH3:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(OCCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A flask was charged with 3-morpholinopropyl methanesulfonate (1.5 g, 6.9 mmol), 3-methyl-4-nitrophenol (0.96 g, 6.3 mmol), cesium carbonate (4.0 g, 12 mmol) and DMA (100 mL), and the reaction mixture was heated to 90° C. for 15 hours. Ethyl acetate (200 ml) was added to the cooled reaction mixture, and the mixture was extracted with water (2×100 ml), 1N sodium hydroxide (2×50 ml) and aqueous 5% lithium chloride (2×50 ml). The organic solvent was removed on a rotary evaporator under reduced pressure. Purification of the crude product by silica column chromatography using 50:50 ethyl acetate:hexanes as eluant gave 0.75 g of 4-(3-(3-methyl-4-nitrophenoxy)propyl)morpholine. (39% yield). MS (EI): 281 (MH+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15](OC)(=O)[C:16]([O:18][CH3:19])=[O:17].C[O-].[Na+].C(O)(=O)C>CN(C)C=O>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:11](=[O:12])[CH:13]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[O:10][C:9]=2[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: COC(=O)C(=O)OC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a solution of 99.7 g (0.513 mole) of 2,4-dihydroxy-3-propylacetophenone and 72.7 g (0.77 mole) of dimethyl oxalate in 1 liter of dry dimethylformamide was added in portions 97 g (1.8 mmole) of sodium methoxide. After stirring for 4 hours, 1.8 l of acetic acid was added and stirring was continued for 4 days. The reaction mixture was heated in a steam bath for four hours and evaporated to dryness. Water was added to the residue and the mixture was heated to boiling. A solid was filtered off and recrystallized from ethanol to give 89.8 g of the title compound, mp. 222°-224°. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=C(S(O[CH2:31][C@H:32]2[O:34][CH2:33]2)(=O)=O)C=CC=1)([O-])=O>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:31][C@H:32]2[O:34][CH2:33]2)=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Yield: 83 %

Procedure:
To an 8 ml dimethylformamide suspension of 60 mg of sodium hydride was added, under ice cooling, 300 mg of 4-(tert-butoxycarbonylamino)phenol. The resultant mixture was stirred at room temperature for 1 hour. Under ice cooling, 372 mg of (S)-glycidyl 3-nitrobenzenesulfonate was gradually added, then the resultant mixture was stirred at room temperature for 2 hours. The reaction was quenched with a 5 ml of saturated aqueous ammonium chloride solution, then the product was extracted with ether. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column.chromatography (hexane:ethyl acetate=3:1) to give the above-referenced compound (9) in an amount of 315 mg (yield 83%).
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[ClH:21].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([Cl:1])=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Agent: Cl
Product: O=C(Cl)c1c2ccccc2nc2ccccc12
Temperature: 110 °C

Procedure:
A mixture of acridine-9-carboxylic acid hydrochloride (74 mg, 0.33 mmol) in thionyl chloride (3 ml, 41.1 mmol) was refluxed at 110° C. under nitrogen for 2 hours. After cooling, the solution was evaporated under reduced pressure to dryness. The solid was washed with anhydrous diethyl ether (5 ml) to give acridine-9-carbonyl chloride hydrochloride. This acid chloride was dissolved in anhydrous pyridine (4 ml), followed by addition of benzyl 3,5-diisopropyl-4-hydroxy-benzoate (102 mg, 0.33 mmol) and 4-N,N-dimethylamino-pyridine (16 mg, 0.13 mmol). After 16 hours of stirring at 25° C. under nitrogen, the solution was evaporated under reduced pressure to dryness. The residue was purified on a Chromatotron plate (1 mm silica gel) by elution with 20% diethyl ether/hexane to yield (4-benzyloxycarbonyl-2,6-diisopropyl)phenyl acridine-9-carboxylate (64 mg, 38%). Rf 0.6 (silica gel, 20% ethyl acetate/toluene). MS(EI): m/z 517(M).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.[F:29]C1C=CC=CC=1C(O)=O>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:26][CH2:27][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:29])=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4)CC3)c12
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4F)CC3)c12

Procedure:
Prepared according to a procedure analogous to that described for synthesis of [4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydro-2H-pyridin-1-yl]-phenylmethanone except using 2-fluorobenzoic acid. 1H NMR (400 MHz, CDCl3): δ=2.03 (ddd, J=11.75, 8.84, 3.16 Hz, 1H) 2.16 (ddd, J=14.46, 9.03, 5.56 Hz, 1H) 2.41-2.63 (m, 4H) 2.78 (br. s., 1H) 2.88 (br. s., 1H) 3.64 (t, J=5.05 Hz, 1H) 3.76 (quin, J=8.59 Hz, 1H) 4.11 (t, J=5.81 Hz, 2H) 4.51 (d, J=2.53 Hz, 1H) 5.82-6.12 (m, 1H) 6.64 (br. s., 2H) 6.87-6.98 (m, 1H) 7.04 (dd, J=5.31, 1.77 Hz, 1H) 7.15 (td, J=8.91, 3.66 Hz, 1H) 7.20-7.25 (m, 0H) 7.41-7.50 (m, 2H). MS (ES+): m/z 391.96 (100) [MH+]. HPLC: tR=2.16 min (OpenLynx polar—5 min).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].O=[CH:8][C:9]1[CH:18]=[CH:17][C:15]([OH:16])=[C:11]([O:12][CH2:13][CH3:14])[CH:10]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:13]([O:12][C:11]1[CH:10]=[C:9]([CH:8]=[CH2:1])[CH:18]=[CH:17][C:15]=1[OH:16])[CH3:14]
Reactant: CC(C)(C)[O-]
Reactant: CCOc1cc(C=O)ccc1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(O)c(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.15 mole) and potassium tert-butylate (1.33 moles) in 1 liter toluene was stirred for 1 hour at room temperature. 1.0 mole of ethylvanillin was added to the ylide thus formed. The reaction mixture was stirred for another hour and then washed with dilute hydrochloride acid. The solution was concentrated by evaporation and the residue distilled under reduced pressure. In this way 2-ethoxy-4-vinylphenol was obtained in a yield of 55%. Boiling point: 75° C./15 Pa.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1>C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:32]=2)=[O:18])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: O=C(NCc1ccccc1)Nc1nc(C(=O)O)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1
Reaction time: 20 h
Yield: 51 %

Procedure:
419 mg of 2-(3-benzyl-ureido)-thiazole-4-carboxylic acid, 265 mg of CDMT, 4.5 ml of THF and 0.18 ml of N-MM are 4.5 hrs. at RT. After the addition of 350 mg of ethyl 4-amino-phenyloxyacetate hydrochloride and 0.18 ml of N-MM the mixture is stirred for a further 20 hrs. at RT. For the working up, the mixture is diluted with ethyl acetate and washed in succession with dilute hydrochloric acid, water, dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and evaporated in a vacuum. Chromatography on silica gel with methylene chloride-alcohol 99:1 and crystallization from ether gives 350 mg of ethyl (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-phenoxy)-acetate, m.p. 173° C., MS: 455 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CO.[OH-].[Na+].C1(CO[C@H]2CC[C@H](C(O)=O)CC2)CC1>C1COCC1>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC(OCC2CC2)CC1
Agent: O=C(O)[C@H]1CC[C@H](OCC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCC(OCC2CC2)CC1

Procedure:
Ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D42, 20.8 g, 45.8 mmol) was taken up in THF (50 mL)/methanol (50 mL). Sodium hydroxide (20 mL, 250 mmol, concentrated) was added to the solution which was left to stir o/n. The THF/methanol was evaporated and the crude residue washed with Et2O. The aqueous layer was acidified with 5 M HCl and extracted with EtOAc (2×). The EtOAc organics were combined, dried (Na2SO4) and the solvent evaporated to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D43, 9.47 g, 94%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)/[N:9]=[CH:10]/N(C)C.C[Si]([CH:27]=[C:28]=[O:29])(C)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[C:28](=[O:29])[CH:27]=[CH:10][N:9]=1
Reactant: Cc1ccc(N=C(/N=C/N(C)C)c2ccccc2Br)cc1F
Reactant: C[Si](C)(C)C=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2c(-c3ccccc3Br)nccc2=O)cc1F
Temperature: 23 °C
Reaction time: 120 h

Procedure:
A solution of 2-bromo-N-[(1E)-(dimethylamino)methylidene]-N′-(3-fluoro-4-methylphenyl)benzenecarboximidamide (1-3, 500 mg, 1.38 mmol, 1.0 equiv) in ethyl acetate (5 mL) was treated with a solution of (trimethylsilyl)ketene (0.39 mL, 2.76 mmol, 2 equiv) in toluene (5 mL). The reaction mixture was stirred at 23° C. for 5 days. The resulting mixture was concentrated, and the residue was purified via reverse-phase HPLC (Acetonitrile:H2O gradient with 0.1% TFA present) to afford 2-(2-bromophenyl)-3-(3-fluoro-4-methylphenyl)pyrimidin-4(3H)-one (1-4) as a dark orange solid. 1H NMR (500 MHz, CD3OD) δ 8.12 (d, 1H, J=6.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.46 (d, 1H, J=7.6 Hz), 7.32 (t, 1H, J=7.6 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.20-7.08 (m, 3H), 6.67 (d, 1H, J=6.6 Hz), 2.19 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:14]=2[C:15]#[N:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(Nc2ccc(Cl)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 160 °C
Yield: 37.5 %

Procedure:
Combine 1,4-dichloro-2-nitro-benzene (0.513 g, 2.67 mmol), 2-amino-5-isopropyl-benzonitrile (0.514 g, 3.21 mmol), potassium carbonate (0.754 g, 5.45 mmol), and fine granular copper (0.031 g, 0.48 mmol) in dimethylformamide (5 ml). Heat the reaction mixture to 160° C. for 16 hours, and cool to ambient temperature. Dilute the reaction mixture with 50 ml of ethyl acetate and wash 3 times with 50 ml water and once with 50 ml of brine. Collect organic layer, dry over sodium sulfate and evaporate solvent. Purify the residue via flash chromatography eluting with a step gradient starting with 90% hexanes: 10% ethyl acetate and going to 85% hexanes: 15% ethyl acetate to obtain 0.316 g (1.00 mmol, 37% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 316 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:13])[C:9]([F:10])([F:11])[F:12])(=[O:24])=[O:23]
Reactant: O=C(N1CCC[C@H]1CO)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CCCN1C(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of the product of step A (1.002 g, 5.08 mmol) and triethylamine (0.78 ml, 5.60 mmol) in CH2Cl2 (50 ml) at -25° C. was added methane sulfonyl chloride (0.40 ml, 5.17 mmol) over a period of 5 min and stirring was continued for 1 hr. The solvent was evaporated in vacuo and the residue purified by chromatography(SiO2, 33% EtOAc in hexanes, elution). The title compound was obtained as a colorless oil.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].Br[CH2:7][CH2:8][O:9][CH2:10][CH2:11]Br.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[O:9]1[CH2:10][CH2:11][C:2]([C:1]#[N:5])([C:3]#[N:4])[CH2:7][CH2:8]1
Reactant: BrCCOCCBr
Reactant: N#CCC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: N#CC1(C#N)CCOCC1
Temperature: 85 °C
Yield: 80.8 %

Procedure:
A mixture of malononitrile (0.991 g, 15 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.83 g, 16.50 mmol) and DBU (4.97 ml, 33.0 mmol) in DMF (6 ml) was heated at about 85° C. for 3 hours, and then cooled to ambient temperature. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate, washed three times with water and dried overnight under high vacuum to yield the desired product as a light brown solid (1.65 g). GC-MS: 136 [M]; Retention time=5.76 min. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.14-2.32 (m, 4 H) 3.77-3.96 (m, 4 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH2:20]([N:26]=[C:27]=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN=C=O
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Product: CCCCCCNC(=O)Oc1ccc2c(c1)C(C)(C)CN2Cc1cccnc1

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.7 mg, 36%) having the following characteristics.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].S(=O)(=O)(O)O.[CH3:11][C:12]1([CH3:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14](=[O:22])[NH:13]1>>[CH3:11][C:12]1([CH3:23])[C:21]2[C:16](=[CH:17][C:18]([N+:1]([O-:4])=[O:2])=[CH:19][CH:20]=2)[CH2:15][C:14](=[O:22])[NH:13]1
Reactant: CC1(C)NC(=O)Cc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)NC(=O)Cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
With cooling with ice, 692 mg of potassium nitrate was added to 4 mL of sulfuric acid, and 1 g of 1,1-dimethyl-1,4-dihydroisoquinolin-3(2H)-one obtained in Production Example 33-1 was added thereto, and stirred overnight at room temperature. The reaction solution was processed with ice water, and the precipitated solid was taken out through filtration. This was washed with water, and dried at 50° C. under reduced pressure to obtain 937 mg of a mixture of the entitled compound with its position isomer, as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH3:2].[C:14](=O)=[O:15].CC(C)=O.C(N1CCCCC1)=O.Cl>O1CCCC1>[CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[C:8]([CH:14]=[O:15])[S:7][CH:6]=1)[CH3:2]
Reactant: CCCCC(CC)Cc1ccsc1
Reactant: O=C=O
Agent: Cl
Agent: O=CN1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCC(CC)Cc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
3-(2-Ethylhexyl)-thiophene (19.6 g, 100 mmol) and anhydrous tetrahydrofuran (250 mL) were charge into a 500 ml flask. The solution was cooled to −78° C. with dry ice/acetone. N-butyl lithium (40 mL, 2.5 M in hexane, 100 mmol) was dropped into the solution. After addition, the reaction solution was warmed to room temperature and stirred for 30 min. Then, the solution was cooled to −78° C. again and 1-formylpiperidine (13.6 g, 120 mmol) was added in one shot. The reaction solution was allowed to warm slowly to room temperature and stirred at room temperature for overnight. The solution was acidified with hydrochloric acid (2 N) and then extracted with ether (2×100 mL). The organic extracts were combined and washed with distilled water (2×100 mL), dried over anhydrous magnesium sulfate and rotary evaporated to remove the solvent. The residue was run through a silica-gel column using ethyl acetate/hexanes (1/10, v/v, Rf=0.3) as the eluent to give a colorless liquid product (18.4 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.86 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 2.59 (d, 2H, J=6.8 Hz), 1.58 (m, 1H). 1.18-1.34 (m, 8H), 0.84 (t, 6H, J=7.2 Hz); (Note: contain about 5% of 3-substituted isomer).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:19]([C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Yield: 40 %

Procedure:
2-chloro-1-(4-phenoxyphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-phenoxyphenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (40% yield). ESI/MS 398 (M+H); RT=2.95 min; NMR (CDCl3) 10.28 (1H, s); 8.28 (1H, d, J=9 Hz); 7.46-7.10 (1H, m); 7.00 (1H, d, J=9 Hz); 3.31 (4H, m); 2.81 (4H, m).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[C:1]([NH:3][C:4]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: COCCN
Product: COCCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (4.05 g) was dissolved in 2-methoxyethylamine (15 ml) and heated under reflux for 6 hours. Evaporation of the solvent and chromatographic purification of the residue on a column of silica gel with elution by chloroform and then with chloroform/methanol (20:1) yielded the title compound as a pale yellow oil (2.7 g). (Found: C, 47.8; H, 7.0; N, 28.0; S, 11.2%. C12H20N6OS requires: C, 48.6; H, 6.8; N, 28.4; S, 10.8%). n.m.r. analysis in DMSO-d6 at 100 mHz:
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([Cl:15])[CH:10]=2)[C:5]1=O.O.[NH2:20][CH2:21][C@H:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:15][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH3:17])[C:5]1[N:20]([CH2:21][C@H:22]([OH:24])[CH3:23])[CH:2]=[CH:3][C:4]=1[C:12]2([CH3:14])[CH3:13]
Reactant: C[C@@H](O)CN
Reactant: COc1cc2c(cc1Cl)C(C)(C)C(CC=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Cl)C(C)(C)c1ccn(C[C@@H](C)O)c1-2
Reaction time: 0.75 h
Yield: 91.5 %

Procedure:
A solution of 6.67 g of (RS)-2-(2-oxoethyl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone and 150 mg of p-toluenesulfonic acid in 200 ml of anhydrous toluene was heated on a water separator. A solution of 7.51 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 40 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). 7.0 g (92%) of (R)-1-(6-chloro-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.