Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.O>CN(C=O)C>[OH:30][C:24]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:25][CH2:26][N:27]([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)=[O:4])[CH2:28][CH2:29]1
Reactant: COc1cccc(C2(O)CCNCC2)c1
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(C2(O)CCN(CC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a stirred solution of 6-(Chloroacetyl)-3,4-dihydroquinolin-2(1H)-one (7.30 g, 32.7 mmol) in DMF (32 ml) were added 4-(3-methoxyphenyl)-4-piperidinol (J. Labelled Compd. Radiopharm., 41, p464, 1998). (8.12 g, 39.2 mmol) and triethylamine (13.7 ml, 98.0 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 4 hours at room temperature and poured into water (80 ml). The precipitate was collected by filtration and washed with dichloromethane (20 ml). The solid was stirred in 0.5N NaOH (65 ml) for 1 hour at room temperature and the suspension was filtered to afford the title compound (5.98 g, 46%) as a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH3:55])(=[O:54])=[O:53])=[CH:48][CH:47]=2)[CH:44]=1)[C:39]([OH:41])=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[CH3:66][O:67][CH2:68][C:69]1[N:70]=[C:71]([NH2:74])[S:72][CH:73]=1>CN(C=O)C>[Si:25]([O:32][CH2:33][C@H:34]([CH3:56])[O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:45][C:46]2[CH:47]=[CH:48][C:49]([S:52]([CH3:55])(=[O:53])=[O:54])=[CH:50][CH:51]=2)[CH:44]=1)[C:39]([NH:74][C:71]1[S:72][CH:73]=[C:69]([CH2:68][O:67][CH3:66])[N:70]=1)=[O:41])([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Reactant: COCc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 4 h
Yield: 57 %

Procedure:
HATU (446 mg, 1.17 mmol) was added to 3-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]benzoic acid (450 mg, 0.94 mmol) followed by addition of DMF (4.5 mL), DIPEA (0.42 mL) and 4-(methoxymethyl)-1,3-thiazol-2-amine (160 mg, 1.11 mmol) and the reaction was stirred under argon for 4 h. The solvent was evaporated and the residue was dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:2 to 2:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (325 mg, 56%).
Reaction SMILES: [CH:1]1([CH2:18][C:19]([C:21]2[S:25][C:24]([CH:26]=[CH:27][C:28]([O:30]CC)=[O:29])=[CH:23][CH:22]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+].Cl>CCOCC>[CH:1]1([CH2:18][C:19]([C:21]2[S:25][C:24]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=Cc1ccc(C(=O)CC2CCCCCCCCCCCCCCCC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)C=Cc1ccc(C(=O)CC2CCCCCCCCCCCCCCCC2)s1
Temperature: 25 °C

Procedure:
A mixture of 23.0 g (0.05 mole) of the above ester and 250 ml of ethanol are heated to reflux, 100 ml of 1 N aqueous sodium hydroxide is added and the mixture refluxed for 3 hours, then cooled to room temperature. The mixture is acidified to pH 1 with 1 N hydrochloric acid, ether is added and the layers separated. The ether layer is washed with water and evaporated to dryness to give 3-[5-(cycloheptadecylacetyl)-2-thienyl]-2-propenoic acid. This acid is added to 6.9 g (0.06 mole) of α,α-dichloromethyl methyl ether in 100 ml of dichloromethane. The mixture is refluxed overnight then evaporated to dryness to give the corresponding acid chloride which is added to 200 ml of tetrahydrofuran. To the above mixture is added 100 ml of strong ammonium hydroxide solution. The mixture is stirred overnight, is diluted with 500 ml of water and filtered. The precipitate is washed with water and dried to give 3-[5 -(cycloheptadecylacetyl)-2-thienyl]-2-propenamide.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:10])([CH3:9])[O:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1CCCCC1>[C:18]([S:1][CH2:2][CH2:3][CH2:4][Si:5]([O:6][CH2:7][CH3:8])([CH3:10])[CH3:9])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCO[Si](C)(C)CCCS
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)SCCC[Si](C)(C)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
Added dropwise at 5° C., under argon, to 3-mercaptopropyldimethylethoxysilane (34.0 g, 0.191 mol) in solution in triethylamine (19.2 g, 0.191 mol) and cyclohexane (400 ml) is octanoyl chloride (31.0 g, 0.191 mol) over 15 minutes at 8° C. The reaction medium is stirred for 15 hours at ambient temperature. The precipitate of triethylamine hydrochloride Et3N.HCl is filtered. The mixture obtained is purified by flash chromatography (eluent: petroleum ether, 500-600 ml). After evaporating the solvents under reduced pressure at 24° C., the S-octanoylmercaptopropylethoxydimethylsilane E with CAS number [1024594-66-8] (45.0 g, 0.148 mol) is obtained in the form of a colourless liquid with a yield of 78%.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.C(O)CC>[NH:5]1[CH:6]=[C:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][OH:7])[N:3]=[CH:4]1
Reactant: Brc1c[nH]cn1
Reactant: OCc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: OCc1ccccc1-c1c[nH]cn1
Temperature: 85 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of 1-propanol (7.5 mL) and water (2.5 mL) was purged with nitrogen for 5 minutes. To the solution were added 4-bromo-1H-imidazole (146.97 mg, 1 mmol), 2-(hydroxyl-methyl)phenylboronic acid (190 mg, 1.25 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), PPh3 (39.3 mg, 0.15 mmol) and potassium carbonate (276 mg, 2.0 mmol). After stirring at 85° C. for 16 h, the mixture was allowed to cool to room temperature and was partitioned between EtOAc (30 mL) and water (15 mL). The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with water, brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography on silica gel to afford the pure product (62 mg, 37% yield). 1H NMR: 4.48 (s, 2H), 6.25 (br s, 1H), 7.18-7.28 (m, 2H), 7.39-7.47 (m, 2H), 7.62 (d, 1H, J=7.0 Hz), 7.80 (d, 1H), 12.30 (br s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2Cl)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.CCOC(C)=O.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]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(NC(=O)c2cccnc2Cl)c1
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1cccc(NC(=O)c2cccnc2-c2cccc(F)c2)c1
Temperature: 90 °C
Yield: 0.6 %

Procedure:
To a mixture of N-(3-tert-butylphenyl)-2-chloronicotinamide (570.2 mg, 2 mmol), 3-fluorophenylboronic acid (401.2 mg, 2.8 mmol), 3 mL of toluene, and 1 mL of 2 N potassium carbonate in water was added tetrakis(triphenylphosphine)palladium(0) (234.5 mg, 0.2 mmol). The mixture was then heated at 90° C. for 3 hour under nitrogen, before it was cooled down to room temperature. The reaction mixture was then diluted with 30 mL of water and 150 mL of EtOAc. The organic layer was separated, washed with brine, and dried (Na2SO4). The organic solvent was removed under reduced pressure and the residue was purified by silica gel column (40% EtOAc in hexane) to give N-(3-tert-butylphenyl)-2-(3-fluorophenyl)nicotinamide (691. 4 mg, 99%). MS: (ES) m/z 394.5 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:21])[NH2:20])[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[K+].Cl[CH2:39][C:40](=O)[CH3:41]>O1CCCC1.O.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([N:23]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][C:40]([CH3:41])=[CH:39][N:21]=4)[C:8]=3[CH:22]=2)[CH2:2][CH2:3]1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)N)c2cc1C1CC1)S(C)(=O)=O
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2c(-c3ccc(F)cc3)oc3cc(N(CCC(C)C)S(C)(=O)=O)c(C4CC4)cc23)[nH]1
Temperature: 75 °C
Yield: 54.1 %

Procedure:
In a 5-mL round bottom flask, a mixture of 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-isopentylmethylsulfonamido)benzofuran-3-carboximidamide (34 mg, 0.061 mmol) and potassium hydrogencarbonate (18.30 mg, 0.183 mmol) in tetrahydrofuran (500 μL) and H2O (125 μL) was heated at reflux in an oil bath at 75° C. under a glass stoppered condenser with Teflon joint sleeve. A solution of chloroacetone (6.53 mg, 0.067 mmol) in tetrahydrofuran (125 μL) was added dropwise to the refluxing reaction mixture over 15 minutes. After 7 hours at reflux, the reaction was cooled to room temperature, diluted with ethyl acetate (25 mL), washed with H2O (2×10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The residue was dissolved in 1 mL acetonitrile and 1 mL 0.1% trifluoroacetic acid in H2O, and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova-Pak HR C18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30 minute gradient of 95:5 0.1% trifluoroacetic acid in H2O/acetonitrile to 25:75 0.1% trifluoroacetic acid in H2O/acetonitrile, then 10 minutes to 100% CH3CN at 20 mL/minute. Pure fractions were concentrated by rotary evaporation and dried on a vacuum pump to afford the title compound as a white solid (20 mg, 0.033 mmol, 53%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.58-0.65 (m, 1H), 0.83 (t, J=6.56 Hz, 6H), 0.91-0.96 (m, 1H), 0.98-1.05 (m, 2H), 1.21-1.31 (m, 2H), 1.34-1.43 (m, 1H), 1.57-1.68 (m, 1H), 2.37 (d, J=0.92 Hz, 3H), 2.38-2.43 (m, 1H), 3.15 (s, 3H), 3.60-3.68 (m, 1H), 3.72-3.80 (m, 1H), 7.12 (s, 1H), 7.41 (t, J=8.85 Hz, 2H), 7.61 (s, 1H), 7.66 (dd, J=8.70, 5.34 Hz, 2H), 7.99 (s, 1H); MS (ESI+) m/z 496 (M+H)+, 991 (2M+H); MS (ESI−) m/z 494 (M−H)−, 530/532 (M+Cl)−, 608 (M+trifluoroacetic acid−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:32](=[O:33])[NH2:31])[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(N)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) in methylene chloride (30 ml) is added trimethylsilyl isocyanate (180 mg) under ice-cooling, and the mixture is stirred at room temperature for 15 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent; chloroform: methanol=40:1) to give 4-amino-5-chloro-N-[1-(1-carbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2-methoxybenzamide (440 mg) as white amorphous.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[C:13]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=3[S:11][C:10]=2[CH2:21][CH3:22])=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[C:13]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=3[S:11][C:10]=2[CH2:21][CH3:22])=[O:8])=[CH:5][CH:4]=1
Reactant: CCc1sc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1sc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 185 °C

Procedure:
A mixture of 7.7 g (0.0225 mole) of 3-(4-methoxy benzoyl) 2-ethyl 5-nitro benzothiophene and 35 g of pyridine hydrochloride are heated at 185° C. for 2.5 h. The mixture is cooled and taken up in 100 ml of water. The product is filtered off and washed on the filter with water and dried in a vacuum at a temperature of 50° C. After purification by chromatography on a column of silica (eluant: heptane/ethyl acetate 6/4), 5.6 g of 3-(4-hydroxy benzoyl) 2-ethyl 5-nitro benzothiophene are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22](O)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)O
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a mixture of 8.2 mg of 7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid, 3.8 mg of 1-(2-aminoethyl)piperidine, 13.1 μL of DIPEA, and 0.4 mL of DMF was added a mixture of 9.8 mg of HATU and 0.1 mL of DMF, followed by stirring at room temperature overnight. The reaction mixture was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 3.6 mg of 7-methyl-4-oxo-N-[2-(piperidin-1-yl)ethyl]-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=O)[C:11](=O)[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][CH:2]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH3:18]
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: CCO
Product: CCOC1c2ccccc2-c2nccnc21
Yield: 25 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was refluxed in 25 ml dry ethanol for 7 hours. The mixture was evaporated to few ml and the precipitate was filtered off, washed with ethanol and dried to give 0.229 g of the crude compound, which was recrystallized from acetic acid-water to yield 0.131 g (25%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 1.1 (t, 3H), 3.25 (dq, 1H), 3.43 (dq, 1H), 5.22 (s, 1H), 7.17 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.51 (d, 1H), 12.1 (s, 1H), 12.31 (s, 1 H).
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].[CH3:9][C@H:10]1[C@@:19]2([CH3:20])[C:14]([CH2:15][CH2:16][C@@H:17]([C:21](Cl)([CH3:23])[CH3:22])[CH2:18]2)=[CH:13][C:12](=[O:25])[CH2:11]1.O>C(O)(=O)C>[CH3:9][C@H:10]1[C@:19]2([CH3:20])[CH2:18][C@H:17]([C:21]([CH3:23])=[CH2:22])[CH2:16][CH2:15][C:14]2=[CH:13][C:12](=[O:25])[CH2:11]1
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H](C(C)(C)Cl)C[C@]21C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=C(C)[C@@H]1CCC2=CC(=O)C[C@@H](C)[C@]2(C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Sodium acetate trihydrate (0.22 g, 1.6 mmol) was added to a single-neck round bottom flask that had been fitted with a reflux condenser. A solution of the chloroenone Compound 8 (0.14 g, 0.54 mmol) in glacial acetic acid (4 mL) was injected into the flask, and the mixture was heated to 100° C. and held at that temperature for 2 hours. The reaction mixture was then cooled to room temperature, poured into cold water, and extracted with chloroform. The organic layer was then washed with successive portions of 2% aqueous KOH, 2 N HCl, NaHCO3, and brine, and then dried over MgSO4. The excess solvent was removed via rotary evaporator to provide nootkatone as a yellow oil (93%). The overall yield from β-pinene to nootkatone was 23% using path b, and 25% using path a, both of which are relatively high overall yields. Because the Oxy-Cope reaction and the methylation both provided the desired enantiomeric product, the enantiomeric purity of the final nootkatone product was little changed from that of the β-pinene starting product. Qualitatively, the fragrance of the synthesized nootkatone was identical to the fragrance of nootkatone derived from other sources. NMR data matched that previously reported for nootkatone: 1H NMR: (250 MHz, CDCl3), δ 5.77 (s, 1H), 4.75–4.72 (m, 2H), 2.62–2.43 (m, 1H), 2.41–2.22 (m, 4H), 2.09–1.87 (M, 3H), 1.46–1.38 (m, 1H), 1.12–1.10 (m, 4H), 0.98 (d, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:28])[NH:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[Cl:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[NH:19][C:18]([C@@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1Cl)[C@H]1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (78 mg, 193 μmol, Eq: 1.00) in CH2Cl2 (6 mL) was added TFA (2 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to afford (S)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH3:23][CH:24]([CH2:28][S:29][CH3:30])[C:25](Cl)=[O:26]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N:8]([CH2:9][CH3:10])[C:25](=[O:26])[CH:24]([CH3:23])[CH2:28][S:29][CH3:30]
Reactant: CSCC(C)C(=O)Cl
Reactant: CCNc1sc(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(C(=O)C(C)CSC)c1sc(-c2cccnc2)nc1Cl
Temperature: 35 °C
Yield: 90 %

Procedure:
Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, reflux condensor, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-amine hydrochloride (20.0 g, 72.4 mmol green solid) and dichloromethane (150 mL). To this suspension was added pyridine (14.32 g, 181 mmol, 2.5 eq) (portionwise over 1 min to form a dark green-black solution. To this solution was added DMAP (4.4 g, 36 mmol) followed by 2-methyl-3-methylthiopropanoyl chloride (16.5 g, 108.6 mmol), which was added portionwise over 1 minute. The reaction exotherm went from 20° C. to 31° C. during the addition of the acid chloride. The reaction was heated to 35° C. for 10 hours then cooled to 25° C. for 14 h. To the dark brown reaction mixture was added dichloromethane (200 mL) and the solution was transferred to a 500 mL separatory funnel. The solution was washed with water (100 mL) and the layers were separated. The brown aqueous layers was extracted with dichloromethane (50 mL) and the dark brown dichloromethane extracts combined, washed with brine (100 mL), dried (MgSO4), filtered and rotary evaporated. This gave 30.49 g (74% pure by HPLC at 254 nm) of a crude black oil. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (23.2 g, 89%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1).
Reaction SMILES: [Si](O[C@H]1CC(C)(C)CC2N=C(C(C)C)C(C=O)=C(I)C1=2)(C(C)(C)C)(C)C.C(C1C=CC([Mg]Br)=CC=1)(C)(C)C.[Si:39]([O:46][C@H:47]1[CH2:56][C:55]([CH3:58])([CH3:57])[CH2:54][C:53]2[N:52]=[C:51]([CH:59]([CH3:61])[CH3:60])[C:50]([C@@H:62]([C:64]3[CH:69]=[CH:68][C:67]([C:70]([CH3:73])([CH3:72])[CH3:71])=[CH:66][CH:65]=3)[OH:63])=[C:49]([I:74])[C:48]1=2)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>>[Si:39]([O:46][C@H:47]1[CH2:56][C:55]([CH3:58])([CH3:57])[CH2:54][C:53]2[N:52]=[C:51]([CH:59]([CH3:61])[CH3:60])[C:50]([C@H:62]([C:64]3[CH:65]=[CH:66][C:67]([C:70]([CH3:71])([CH3:73])[CH3:72])=[CH:68][CH:69]=3)[OH:63])=[C:49]([I:74])[C:48]1=2)([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40]
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: CC(C)(C)c1ccc([Mg]Br)cc1
Agent: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-tert.-butylphenylmagnesium bromide. (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-tert-butylphenyl)methanol:
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:8]1[C:9](=[O:11])[C:10]2[N:1]=[CH:2][CH:3]=[N:4][C:5]=2[C:6](=[O:12])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)c2nccnc21
Solvent: CCO
Product: O=C1C=C(Nc2ccccc2)C(=O)c2nccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Approximately 2 g. of 5,8-quinoxalinedione were dissolved in 200 ml. of 2B ethanol. Aniline (1.2 g.) was added and the reaction was stirred overnight at room temperature. The reaction was evaporated, water was added, and the mixture was extracted several times with methylene chloride. The combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over a silica gel column, eluting with ethyl acetate. The desired fractions were combined and evaporated. The material was crystallized from ethyl acetate to give 50 mg. of the title product as a red powder, m.p. about 203°-205° C.