Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].CC([Si](C)(C)[O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH2:37][CH2:38][NH:39][CH2:40]2)=[CH:35][C:34]=1[O:43][CH3:44])(C)C.C(N(CC)C(C)C)(C)C>C(#N)C>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][C:33]([OH:32])=[C:34]([O:43][CH3:44])[CH:35]=3)[CH2:40]2)[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(SC1CCCCC1)c1ccc(OC)c(OC)c1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 150.7 %

Procedure:
A mixture, under argon, of 2.17 g of product from Example 113, 1.8 g of product from Example 28, 13.0 ml of N,N-diisopropyl ethylamine and 80 ml of acetonitrile is heated under reflux temperature for 8 hours. The reaction is cooled and concentrated in vacuo and dried under high vacuum for 1 hour. The crude residue is dissolved in 70 ml of tetrahydrofuran and 10.0 ml of 1M tetrabutyl ammonium fluoride in tetrahydrofuran is added and the mixture is stirred at room temperature, under argon, for 2.5 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried, filtered, and concentrated in vacuo to give 4.0 g of a brown oil. The oil is purified by chromatography (silica gel: 1%, 1.5% and 2% methyl alcohol/methylene chloride)to give 2.1 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([C:8](=[O:27])[CH:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[O:25])=[CH:15][C:14]=2[F:26])C([O-])=O)[N:5]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:4]=1)#[N:2].CO.S(O)(O)(=O)=O.C(=O)([O-])O>C(OCC)(=O)C>[F:26][C:14]1[CH:15]=[C:16]([N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=[O:25])[CH:17]=[CH:18][C:13]=1[CH2:9][C:8]([C:6]1[N:5]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[N:4]=[C:3]([C:1]#[N:2])[CH:7]=1)=[O:27]
Reactant: COc1ccc(-n2nc(C#N)cc2C(=O)C(C(=O)[O-])c2ccc(-n3ccccc3=O)cc2F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C#N)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Temperature: 23 °C
Reaction time: 96 h
Yield: 83.4 %

Procedure:
Part H. To 3-[3-cyano-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-oxopropanoate (100 mg, 0.210 mmol) was added methyl alcohol (1.5 mL) and 4M aqueous dihydrogen sulfate (0.50 mL). The reaction was then warmed to reflux. After 4 days, the reaction was cooled to 23° C., and the resulting white suspension was poured into saturated aqueous hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated to afford 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile (75 mg, 85%) as a pale yellow oil. LC/MS (ESI+): 429.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:58])([F:57])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:49]([CH3:50])=[CH:48][C:43]([C:44]([O:46]C)=[O:45])=[CH:42][C:41]=5[CH3:51])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:56])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:41]([CH3:51])=[CH:42][C:43]([C:44]([OH:46])=[O:45])=[CH:48][C:49]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:27]=3)[C@H:20]2[CH3:56])[CH:10]=[C:9]([C:8]([F:7])([F:58])[F:57])[CH:14]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Solvent: C1CCOC1
Product: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Morpholine (206 μl, 2.358 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 44, 355 mg, 0.472 mmol), and THF (2.4 mL) were stirred at 100° C. for 10 minutes in the microwave reactor, at which time LCMS showed complete conversion to target. The reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude isolate was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 8.01 (d, 1H), 7.89 (s, 1H), 7.80 (d, 2H), 7.73 (s, 2H), 7.27 (d, 1H), 5.66 (d, 1H), 4.72 (d, 1H), 4.32 (m, 1H), 4.00 (m, s, 4H), 3.93 (s, 3H), 3.84 (m, 4H), 3.80 (m, 4H), 2.15 (s, 3H), 2.13 (s, 3H), 0.72 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10]O.S(Cl)([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][Cl:20]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(Oc2cccc(CO)c2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cccc(CCl)c2)c1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
The alcohol (5.31 g, 23 mmol) was dissolved in dichloromethane (40 ml) and treated with thionyl chloride (2.6 ml, 35 mmol) and dimethylformamide (catalytic 5 drops). The mixture was stirred overnight. The reaction mixture was evaporated in vacuo and azeotroped with toluene (2×10 ml) to give 3-(3-methoxyphenoxy)benzyl chloride as a light brown oil (5.57 g, 97%). The chloride (5.30 g, 21.3 mmol) was dissolved in dimethyl sulphoxide (20 ml), potassium cyanide (1.45 g, 22.4 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with water (100 ml) and extracted with ether. The combined extracts were dried (MgSO4) and evaporated to give 3-(3-methoxyphenoxy)phenyl acetonitrile as a brown oil (4.04 g, 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][C:37]1[C:38]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([F:36])[C:38]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCN2CCCCC2)c(F)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 42.2 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (92 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and diluted with 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography, followed by MeOH re-crystallization to give the title compound (54 mg, 0.076 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.42 (d, J=6.96 Hz, 1H), 8.50 (s, 1H), 8.30-8.34 (m, 1H), 8.11 (s, 1H), 7.80-7.86 (m, 1H), 7.77 (d, J=8.06 Hz, 1H), 7.71 (d, J=9.16 Hz, 1H), 7.43-7.48 (m, 1H), 7.32-7.40 (m, 1H), 7.26 (d, J=8.61 Hz, 1H), 7.16 (t, J=8.06 Hz, 2H), 7.00 (t, J=6.23 Hz, 2H), 6.67 (d, J=4.94 Hz, 1H), 3.97 (s, 3H), 3.82 (s, 3H), 3.26-3.27 (m, 2H), 2.70 (t, J=7.33 Hz, 2H), 2.34-2.42 (m, 4H), 1.43-1.50 (m, J=4.76 Hz, 4H), 1.32-1.39 (m, 2H). MS (ESI): 708 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:5]=1[OH:11]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)OC)c1O
Yield: 16 %

Procedure:
A mixture of 1.0 g (5.95 mmol) of 2,3-dihydroxybenzoic acid methyl ester, 1.98 g (5.95 mmol) of 1-bromooctadecane and 0.825 g (5.95 mmol) of potassium carbonate in 20 ml of acetone and 4 ml of DMF was stirred at reflux for 40 hours. The usual workup followed by purification by chromatography on 40 g of silica gel (230-400 mesh) using 50% toluene-hexane gave 0.40 g (16% yield, mp 57°-60°) of 2-hydroxy-3-(octadecyloxy)benzoic acid methyl ester. The structure was established by nmr and mass spectra.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([NH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nn1c(=O)c(=O)[nH]c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)Nn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 1-amino-1,4-dihydro-2,3-quinoxalinedione (53 mg, 0.30 mMol) and pyridine (1 mL, fresh distilled from KOH before use) and acetic anhydride (1 mL, Aldrich) was stirred under nitrogen at 60° C. for 4 hrs. The reaction mixture became a clear solution. All of solvent and reagent were then evaporated under reduced pressure and washed with benzene:cyclohexane=1:1(2×2 mL); ether (2×2 mL), dried at 60° C. with rotavapor for 2 h, affording 57 mg (86%) of pure 1-acetamido-1,4-dihydro-2,3-quinoxalinedione as a white powder; mp: 211°-213° C. IR (KBr, cm-1): 3430; 3127; 1741; 1717; 1668. NMR (1H, DMSO-d6) δ: 2.326 (s, 3H); 7.121-7.287 (m, 4H); 12.345 (s, 1H). Mass:calcd for C10H9N3O3 (M+) m/z: 219.0641; found: 219.0651.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>C(O)CCC>[N+:26]([C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=3)[CH2:3][CH2:4]2)[CH:25]=1)([O-:28])=[O:27]
Reactant: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CS(=O)(=O)Nc1ccc(N2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Reaction time: 24 h

Procedure:
A mixture of the product of (iii) above (1.46 g), 2-chloro-4-nitropyridine (0.79 g) and sodium bicarbonate (1.26 g) in n-butanol (30 ml) were heated under reflux with stirring for 24 hours and then cooled and filtered. The solid was washed with methanol and the combined filtrate and washings were evaporated to give a gum that was chromatographed on silica gel. Elution with dichloromethane, gradually increasing the polarity to dichloromethane/methanol (4:1) gave a mixture of the desired product, together with some N-{4-[4-(2-chloropyrid-4-yl)piperazin-1-yl]phenyl}methanesulphonamide biproduct, as a solid. The solid was crystallised four times from methanol to give pure N-{4-[4-(4-nitropyrid-2-yl)piperazin-1-yl]phenyl}methanesulphonamide (0.36 g), m.p. 182°-183° C. Found: C,50.90; H,5.07; N,18.51. C16H19N5O4S requires: C,50.91; H,5.07; N,18.56%.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:21]([O:23]CC)C>>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:19][C:18]=1[CH:21]=[O:23]
Reactant: CCOCC
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: CC[Mg]Br
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (18 ml of 3M solution in diethyl ether) was added dropwise to a stirred solution of 4-nonylphenol (11.2 g) in diethyl ether (100 ml) at 0°-10° C. under nitrogen. Stirring was continued at 10° C. for 30 minutes, the mixture was allowed to warm to ambient temperature, the bulk of the diethyl ether was removed by distillation, toluene (100 ml) and methanol (6.5 g) were added and removal of diethyl ether and free (uncoordinated to Mg) methanol was continued by fractional distillation with vigorous stirring until the temperature of the mixture rose to 100°-105° C. The mixture was cooled to 95° C. and a slurry of paraformaldehyde (6 g) in toluene (12 ml) was added dropwise over 20 minutes, the temperature of the reaction mixture being maintained at 95°-100° C. with removal of volatile by-products by distillation. Stirring was continued at 95°-100° C. for 2 hours, the mixture was added to a cold stirred solution of sulphuric acid (12 g of 98% strength material) in water (500 ml) at 10° C., the resulting mixture was stirred at 20°-30° C. for 2 hours, the mixture was filtered and the upper organic layer separated from the lower aqueous layer. The organic layer was washed with water (3×50 ml) and solvent was removed by evaporation under reduced pressure to give crude 2-hydroxy-5-nonylbenzaldehyde.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(I)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(I)cc2c1O

Procedure:
Analogously to Example D-43 d), 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester was allowed to react with 5 ml of POCl3 to afford 0.057 g of a pale white solid: Proton NMR (200 MHz, chloroform-d): δ 11.9 (s, 1H), 8.89 (m, 1H), 8.1 (m, 1H), 7.97 (m, 1H), 4.5 (t, J=7 Hz, 2H), 2.0-1.8 (m, 2H), 1.65-1.4 (m, 2H), 1.00 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:20][OH:21].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[N:20][OH:21])[CH2:10][CH2:9]1
Reactant: O=C1CCC(c2ccccc2F)c2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C1CCC(c2ccccc2F)c2ccccc21

Procedure:
32 g of 4-(2-fluorophenyl)-1-tetralone in 75 ml of ethanol are treated with a solution of 9.26 g of hydroxylamine hydrochloride in 10 ml of water and then with 17 g of powdered sodium hydroxide. The mixture is heated to boiling under reflux for 5 minutes, again cooled and then poured into a mixture of ice and dilute hydrochloric acid. The mixture is extracted with ether and the extract obtained is washed with water. After evaporation of the solvent, there is obtained 4-(2-fluorophenyl)-1-tetralone oxime of melting point 120°.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][C:17]1[C:21]2[C:22]([OH:30])=[C:23]([CH2:27][CH2:28][CH3:29])[CH:24]=[C:25]([F:26])[C:20]=2[O:19][CH:18]=1>C(Cl)CCl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:18]2[O:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([CH2:27][CH2:28][CH3:29])=[C:22]([O:30][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)[C:21]=3[C:17]=2[CH3:16])=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCc1cc(F)c2occ(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(F)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1OC(=O)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
A solution of p-anisoyl chloride (2.70 gm; 15.5 mmoles) in ethylene dichloride (10 mL) was added slowly to a cooled suspension of aluminium chloride (3.0 gm; 21.8 mmoles) in ethylene dichloride (100 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.79 gm; 3.8 mmoles) in dichloroethylene (5 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 1.18 gm (63%) of 2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)-5-propyl-7-fluorobenzofuran.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:19]=1[CH2:20][C:21](Cl)=[O:22]>>[CH3:17][C:13]1[CH:12]=[C:11]([CH:2]([NH:1][C:21]([CH2:20][C:19]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:18]=2)=[O:22])[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(C(N)CCN2CCCCC2)c1
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Product: Cc1cccc(C(CCN2CCCCC2)NC(=O)Cc2ccc3ccccc3n2)c1
Yield: 62.7 %

Procedure:
The procedure of Example 1 was repeated using 697 mg (3.0 mmol.) of 1-[3-amino-3-(3-methylphenyl)propyl]piperidine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 755 mg (yield: 65%) of the subject compound as a pale yellow solid product.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[CH3:11][C:12]([CH2:14][CH2:15]O)=[CH2:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH2:13][C:4]2([CH2:5][CH:6]([CH3:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3]2)[O:9][CH2:15][CH:14]=1
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: C=C(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=CCOC2(C1)CC(C)CC(C)(C)C2
Temperature: 115 °C
Yield: 69.6 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added 3,3,5-trimethyl cyclohexanone (1.4 kg, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provide to 4,8,8,10-tetramethyl-1-oxaspiro [5.5] undec-3-ene (1.45 kg) having a purity of 94% (sum of the isomers) for a total yield of 55%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]CC)=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].Cl>C(O)(=O)C.O>[C:14]([C:4]1[C:5]([CH3:13])=[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=1)[S:10][CH2:9][CH2:8][C:7]2=[O:12])([OH:16])=[O:15]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)cc(Cl)c2c1C(=O)CCS2
Temperature: 25 °C
Yield: 89 %

Procedure:
2.0 Grams (7.0 mmol) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one was dissolved in 10 ml of acetic acid, and 10 ml of a 4N hydrochloric acid aqueous solution was added. The mixture was refluxed under heat for 5 hours. After allowed to cool to room temperature, the reaction mixture was diluted with about 100 ml of water, and a precipitated solid was extracted with ethyl acetate. A carboxylic acid component was extracted from an organic layer with a saturated sodium hydrogencarbonate aqueous solution, and an aqueous layer was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution. A precipitated solid was extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 1.6 g (yield 90%) of 6-carboxy-8-chloro-5-methylthiochroman-4-one in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].I[CH2:12][CH3:13]>CN(C=O)C>[CH2:12]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:13]
Reactant: CCI
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen inlet and charged with 4-nitropyrazole (3.00 g, 26.5 mmol) and DMF (50 mL). The mixture was cooled to 0° C. using an ice bath. Sodium hydride (60% dispersion in mineral oil, 1.17 g, 29.2 mmol) was added portionwise. After the addition was complete, the mixture was stirred at 0° C. for 30 min. After that time, iodoethane (6.21 g, 39.8 mmol) was added over 15 min. After the addition was complete, the mixture was stirred at 0° C. for 30 min and then at room temperature for 3 h. After this time, the mixture was concentrated in vacuo. The residue was diluted with water (200 mL). The resulting precipitate was filtered, and the filter cake was dried in the oven to afford a 51% (1.90 g) of 111a as an off-white solid. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 50% hexanes/ethyl acetate) to afford another 49% yield (1.84 g, in total quantitative yield (3.74 g)) of 111a as an off-white solid: mp 54-55° C.; 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 8.07 (s, 1H), 4.22 (q, 2H, J=7.2 Hz), 3.41 (s, 3H), 1.56 (s, 3H, J=7.2 Hz); MS (ESI+) m/z 142.0 (M+H).