Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN(C=O)C>[F:27][C:26]([F:28])([F:29])[O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) in DMF (15 mL, 3 mL/mmol) was added sodium hydride (143 mg, 5.95 mmol). After being stirred for 0.5 h at 0° C. 1-(bromomethyl)-4-(trifluoromethoxy)benzene (1.9 g, 7.97 mmol) was added and the reaction was stirred for 24 h at RT. The reaction was quenched with water and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure and purified by silica gel column chromatography to give tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate (1.8 g) which was taken to the next reaction without further purification. Observed mass (M+1): 376.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>CN(C=O)C.O>[F:27][C:26]([F:28])([F:29])[O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a dried flask charged with tert-butyl 4-hydroxypiperidine-1-carboxylate (3.60 g, 17887 μmol) was added dry DMF (40 mL) and the resulting solution cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (748 mg, 18781 μmol) in two portions 5 min apart. The reaction mixture was stirred for 1 hr and allowed to warm to RT over that time. The resulting suspension was cooled in an ice water bath prior to the addition of a solution of 1-(bromomethyl)-4-(trifluoromethoxy)benzene (5018 mg, 19676 μmol) in DMF (5 mL) via syringe. The resulting reaction mixture was allowed to slowly warm to RT while stirring for 15 h. The resulting pale yellow suspension was carefully diluted with water (about 150 mL) and extracted 2× with EtOAc. The combined organics were dried with Na2SO4, filtered and concentrated under reduced pressure. The material was purified through silica gel column chromatography ramping ethyl acetate in hexanes from 0% to 10% over 5 mins, then remaining at 10% for 10 min, then ramping to 50% over 5 min providing tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)-piperidine-1-carboxylate (5 g) as a white crystalline solid upon drying.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.CCOCC>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A suspension of 5-hydroxy-indol (5 g, 38 mmol), tert-butyldimethylsilyl chloride (6.1 g, 39.4 mmol) and imidazole (5.4 g, 68 mmol) in DMF (50 ml) was stirred for 20 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 9.4 g (38 mmol, quant.) 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH2:15])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2c1OCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1cc(F)cc2c1OCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
A solution of 2-(6-fluorochroman-8-yloxy)ethylazide (4.12 g, 0.017 mol) and triphenylphosphine (6.83 g, 0.026 mol) in tetrahydrofuran (80 ml) and water (1.5 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide and (40% methanol-methylene chloride plus ammonium hydroxide) afforded 3.45 g (94%) of product as a white solid: mp 68-70° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C[O:14][B:15](OC)[O:16]C.O>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([B:15]([OH:16])[OH:14])[CH:8]=1
Reactant: Brc1cccnc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OB(O)c1cccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To -78° C. cooled n-BuLi (61 ml; 2.5 M hexane solution) was added 3-bromopyridine (20.0 g), dissolved in Et2O (-78° C.) (100 ml) by cannula during 5 minutes. After 10 minutes, a precooled (-78° C.) solution of trimethyl-borate (17.1 g) in Et2O (80 ml) was added. The reaction mixture was stirred at -78° C. for 1 hour, warmed to room temperature during 1 hour, and stirred at room temperature for 1/2 hour. To the reaction mixture was added 20 ml water and stirring continued. The resulting solid percipitate was collected and the supernatent concentrated to a residue. To the residue was added ethyl alcohol (100 ml) and acetic acid (8 ml) followed by heating at reflux for 35 minutes, cooling to room temperature and concentrating to dryness to give a pale yellow foamy material. The crude product was used directly in the next step.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7]Br)(=[O:3])[CH3:2].[N-:9]=[N+:10]=[N-:11].[Na+]>O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:9]=[N+:10]=[N-:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OCCCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromopropyl acetate (1.0 g, 6.0 mmol) in water (10 mL) was added to sodium azide (780 mg, 12.1 mmol). The solution was stirred at 90° C. overnight. The solution was extracted three times with 15 mL CH2Cl2 and dried with MgSO4. Solvent was removed under reduced pressure to afford 3-azidopropyl acetate as a pale yellow oil. A solution of tripropargylamine (12.3 mg, 0.941 mmol) in tetrahydrofuran (6.5 mL) was added to 3-azidopropyl acetate (0.672 g, 4.71 mmol) and Cu(I) acetate (5.8 mg, 5 mol %). The solution was refluxed overnight under inert atmosphere. Solvent was removed under reduced pressure. Silica chromatography purification (Rf=0.5, 5-10% MeOH in CH2Cl2) afforded acetyl-protected THPTA as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=C[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.NN.Cl>C(O)C.O>[NH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[SH:10]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 6-nitrobenzo[d]thiazole (1.64 g, 9.10 mmol) in ethanol (16 mL) was added hydrazine hydrate (2.66 mL, 54.6 mmol). The resulting dark solution was stirred overnight at room temperature. The mixture was then diluted with water and slowly acidified with 3 M HCl, giving a yellow suspension. The mixture was then extracted with dichloromethane. The combined organics were dried, filtered, and concentrated, giving a yellow solid, used directly in the subsequent reaction. 1H NMR (DMSO-d6) δ 8.09 (brs, 1H), 7.87 (d, J=8.7 Hz, 1H), 6.74 (d, J=9.0 Hz, 1H), 6.27 (brs, 2H); MS-EI: (m/z, %) 170 (M+, 100), 140 (28), 124 (35).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15]CC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10% Palladium on carbon (1 g) is placed under an argon atmosphere into a round-bottom flask and covered with 50 ml of ethanol. A solution of (4-benzyloxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1) (35 g, 88.5 mmol) in 250 ml ethanol is added, followed by ammonium formiate (6.3 g, 97.4 mmol). The mixture is stirred for 30 min at rt (TLC control). After completion of the reaction, the mixture is filtrated and evaporation gives a white solid, which is further purified by recrystallization from diethyl ether/hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 605 %

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (100 mg) in dry THF (10 ml) containing potassium carbonate (380 mg) was treated slowly with morpholine (0.32 ml, 317 mg). The resulting mixture was stirred at room temperature under nitrogen for 18 h, before filtering and concentrating in vacuo to give the title compound as a white solid (620 mg). m.p. 82°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Brc1ccc(CN2CCOCC2)cc1

Procedure:
4-Bromobenzyl bromide (2.0 g) and morpholine (1.39 ml) were stirred in dimethylformamide (25 ml) for 18 h. The mixture was partitioned between diethyl ether (50 ml) and water (80 ml). The aqueous phase was extracted further with ether (50 ml) and the combined organics were washed with water (80 ml), dried (magnesium sulphate) and evaporated. The residue was purified by column chromatography, eluting with a gradient of ethyl acetate/iso-hexane; 0/100 to 50/50, to give the product as a white crystalline solid (1.44 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
A solution of 4-bromophenyl sulphonyl chloride (53.76 g) in dichloromethane (700 ml) was added to a stirred solution of ethyl piperidine-4-carboxylate (32.97 g) in dichloromethane (500 ml) containing triethylamine (36 ml) at 0° C. and under argon over 0.75 hours. The reaction was stirred for 18 hours. The reaction mixture was washed with water (2×500 ml), saturated brine (1×500 ml), dried and evaporated. The residual solid was triturated in isohexane (500 ml) for 1 hour, collected by filtration and dried to give, as a colourless solid, ethyl 1-(4-bromophenylsulphonyl)piperidine-4-carboxylate (79 g); mp 132-3° C.; NMR (CDCl3): 1.21(t, 3H), 1.70-1.90(m, 2H), 1.90-2.05(m, 2H), 2.18-2.33(m, 1H), 2.45-2.60(m, 2H), 3.53-3.67(m, 2H), 4.10(q, 2H), 7.55-7.70(m, 4H); EI-MS m/z 376 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([I:17])=[CH:10][N:9]=1)([CH3:6])[CH3:5]>C(O)C>[I:17][C:11]1[CH:10]=[N:9][C:8]2[NH:7][C:4]([CH3:6])([CH3:5])[C:3](=[O:2])[NH:14][C:13]=2[CH:12]=1
Reactant: COC(=O)C(C)(C)Nc1ncc(I)cc1[N+](=O)[O-]
Solvent: CCO
Product: CC1(C)Nc2ncc(I)cc2NC1=O
Yield: 46 %

Procedure:
2-(5-Iodo-3-nitro-pyridin-2-ylamino)-2-methyl-propionic acid methyl ester (618 mg) was dissolved in ethanol. SnCl22H2O (5 eq) was added and the reaction mixture was heated to 80° C. for three (3) hours. The resulting precipitate was filtered and washed with ethanol to give the title compound as an off-white solid (46% yield). M.p.>300° C., LCMS: m/z=304.30 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.29 (s, 6H), 7.11 (bs, 1H), 7.16 (d, J=1.8 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 10.38 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 6 h) between 4-(trifluoromethoxy)benzaldehyde (10.000 g; 52.598 mmol) and malonic acid (10.399 g; 99.937 mmol) gave the product 3-(4-trifluoromethoxy-phenyl)-acrylic acid as a colorless solid (12.080 g; 99%). LC-MS: tR=0.96 min.; [M+H]+: no ionisation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][Br:16])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(Br)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(Br)cn1
Yield: 47.9 %

Procedure:
A mixture of 5-bromo-2-methylpyrimidine (100 mg, 0.58 mmol), NBS (103 mg, 0.58 mmol), dibenzoyl peroxide (10 mg, 0.04 mmol) in tetrachloromethane (10 mL) was refluxed for 36 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 1% v/v) to give 5-Bromo-2-(bromomethyl)pyrimidine (70 mg, 48%) as a white solid. 1HNMR (400 MHz, CDCl3) δ 4.49 (s, 2H), 8.72 (s, 2H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].C(OCC)C.C(O[CH:25](OCC)[N:26]([CH3:28])[CH3:27])C>>[CH3:25][N:26]([CH3:28])[CH:27]=[N:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH:11]=1
Reactant: CCOC(OCC)N(C)C
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Solvent: CCOCC
Product: CN(C)C=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Yield: 77.7 %

Procedure:
A solution of 2.5 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole in 7.5 gm of N,N-dimethylformamide diethylacetal was stirred at room temperature for 2 days. Addition of diethyl ether precipitated a solid which was filtered off and dried, yielding 2.4 gm of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])[CH3:3].[CH3:11][N:12]=[C:13]=[O:14]>CN(C)C1C=CN=CC=1.C1C=CC=CC=1>[CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:13]([NH:12][CH3:11])=[O:14])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(N)no1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CNC(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A 50 milliliter flask with a magnetic stirring bar, addition funnel, thermometer and condenser/drying tube was charged with 3.0 grams (0.021 mole) of 5-(1,1-dimethylethyl)-3-isoxazolamine, a few crystals of 4-dimethylaminopyridine and 20 milliliters of benzene. The funnel was charged with 2.3 grams (0.040 mole) of methyl isocyanate in 5 milliliters of benzene, which was added dropwise over five (5) minutes. After standing overnight, the mass of crystals which formed was isolated by filtration, washed with hexane, and air dried to give 3.0 grams of white powder of 1-[5-(1,1-dimethylethyl)-3-isoxazolyl]-3-methylurea, M.P. 188°-189° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCl>[Br:14][CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CBr)c1

Procedure:
A mixture of [3-methylphenyl]acetic acid ethyl ester (5g), N-bromosuccinimide (5 g) and benzoyl peroxide (0.1 g) in dichloromethane (200 ml) was irradiated under a 500 W halogen lamp for 6 hours. The solvent was evaporated and the residue partitioned between diethyl ether and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 5.14 g.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:14])=O>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([Cl:14])=[O:11]
Reactant: COc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 30 g of 2-anisic acid in 500 mL of round-bottom flask was added dropwise 50 mL of thionyl chloride. After all of the thionyl chloride was added the reaction mixture was stirred at room temperature for 18 hours. Excess thionyl chloride was then distilled off by water aspirator and the remaining liquid was vacuum distilled (82°/0.7 mm Hg). Desired 2-methoxybenzoyl chloride was obtained as a colorless liquid, 32 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25]>CCOC(C)=O>[F:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
To a solution of piperidin-4-ol (11.11 g, 0.11 mol) and Et3N (12.14 g, 0.12 mol) in EtOAc (500 mL) was added 1,2-difluoro-4-nitrobenzene (15.91 g, 0.10 mol). The mixture was stirred at rt for 24 h, and washed with water (200 mL×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as orange oil (19.35 g, 80%).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[CH2:9][CH2:10][CH2:11][CH2:12]Br.O>CN(C)C=O>[C:5]([C:4]1([C:3]#[N:7])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[N:6]
Reactant: BrCCCCBr
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(C#N)CCCC1
Reaction time: 8 h

Procedure:
Sodium hydride (37.8 g; 0.94 moles) was suspended in dimethylformamide (250 mL) under an atmosphere of N2. A solution of malononitrile (30 g; 0.45 moles) and 1,4-dibromobutane 99.7 g; 0.45 moles) in dimethylformamide (150 mL) was added dropwise at such a rate so as not to exceed 30° C. The mixture was stirred for overnight, poured into H2O (500 mL), and then washed with two portions of ethyl ether. The organics were combined, washed with brine, and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated in vacuo, leaving a bilayered liquid. The lower portion was separated (28.8 g) and identified as the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:3]1[C:2](=[O:1])[CH:7]=[C:6]([CH3:8])[O:5][C:4]1=[O:9])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(O)cc(=O)o1
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-6-methyl-2-pyrone (11.50 g, 91.2 mmol) in toluene (30 mL) is added N,N-dimethylformamide dimethyl acetal (13.00 mL, 97.9 mmol). After stirring for 2 h at room temperature, the reaction mixture is evaporated under reduced pressure and co-evaporated with toluene several times. Yield: 18.5 g; ESI mass spectrum: [M+H]+=182; r.t. HPLC: 0.72 min (Z002_007).
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].O.[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:1][O:2][CH2:13][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:9][CH2:8]1
Reactant: CO
Reactant: Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
Slices of metal Na (17.4 g, 0.755 mol) were added in small portions to methyl alcohol (250 ml) agitated at room temperature to prepare sodium methoxide. After metal Na pieces disappeared, a solution obtained by dissolving the compound (IV) (200.0 g, 0.581 mol) obtained above, in dry toluene (600 ml), was gradually added through a dropping funnel so that the inner temperature could keep within a range of 50° to 60° C. After completion of the addition, the mixture was refluxed for 4 hours, followed by cooling, adding water (20 ml), transferring into a separating funnel, washing the resulting toluene layer with water until the aqueous layer became neutral, distilling off toluene under reduced pressure, distilling under reduced pressure and collecting fractions of boiling points of 105°~108° C./1.5 mmHg to obtain trans-4-methyloxymethyl-1-phenylcyclohexane (V) (100.0 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:5][CH:6]([CH2:10][CH3:11])[C:7]([C:15]1[CH:16]=[CH:17][C:12]([S:18][CH3:19])=[CH:13][CH:14]=1)=[O:8]
Reactant: CCC(C)C(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 mL RBF equipped with a mechanical stirrer was charged with AlCl3 (35.4 g) and CHCl3 (300 mL) and cooled in an ice bath. Then 2-methylbutanoyl chloride (31.4 g) was added over 0.5 h to the ice-cold suspension. Keeping the internal temperature <10° C., thioanisole (31.2 mL) was added dropwise over 1 h. After completion of addition, the resulting mixture was stirred at r.t. for 2 h. The resulting suspension was poured onto an ice-water mixture and stirred until decoloraton. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated to dryness. The resulting white solid was swished in hexane and collected by filtration to give the title compound as a white solid. 1H NMR(CD3COCD3): δ0.88 (3H, t), 1.12 (3H, d), 1.47 (1H, m), 1.78 (1H, m), 2.57 (3H, s), 3.49 (1H, m), 7.37 (2H, d), 7.93 (2H, d).