Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:19]1([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[CH2:20]1.N1C=CN=C1.C(Cl)Cl>CN(C)C=O.CO>[CH3:15][C:14]([Si:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:25][CH2:24][C@H:23]1[O:26][C@@H:19]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:20][C@@H:21]1[OH:22])([CH3:17])[CH3:16]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 62.4 %

Procedure:
1.43 ml (5.5 mmol) of t-butyldiphenylsilyl chloride were added to a solution of 1.21 g (5 mmol) of thymidine and 0.749 g (11 mmol) of imidazole in 10 ml of dimethylformamide under an atmosphere of argon, and the resulting mixture was stirred at room temperature for 140 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 100 ml of methylene chloride. The solution was then washed 5 times, each time with 100 ml of water. The solution was then dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through 100 g of silica gel (70-230 mesh) using a gradient elution method, with methylene chloride containing from 0.5 to 3% by volume of methanol as the eluent, to give 1.5 g (yield 62%) of the title compound.
Reaction SMILES: CCN(CC)CC.[CH:8](=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:8]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC=C1CCCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC1CCCCC1=O
Temperature: 50 °C
Reaction time: 23 h
Yield: 95.1 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 845 mg (0.5 mmole) of Ru2Cl4 ((+)-BINAP)2 (NEt3), and 17.8 g (100 mmole) of 2-pentylidenecyclohexanone and 50 ml of methylene chloride were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 90 kg/cm2 for 23 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography- using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 16 g (percent yield: 90%) of 2-pentylcyclohexanone as a clear yellow liquid. 1H-NMR (CDCl3)δ(ppm): 1.20 (t, 3H, J=7 Hz), 1.40 (m, 8H), 1.50-2.50 (m, 9H)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][C:20](=[O:21])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a stirred solution of 2-fluoro-5-(trifluoromethyl)aniline (3.00 g, 16.7 mmol) in THF (80 mL) was added pyridine (2.71 mL, 33.5 mmol), followed by phenyl chloroformate (3.15 mL, 25.1 mmol) at rt. Some solid precipitated out. The mixture was stirred at rt overnight. Water was added to the reaction and it was extracted with EtOAc. The organic solution was washed with water (2×) and dried over MgSO4 and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (10:90 to 30:70 v/v EtOAc-hexanes) to afford the title compound (3.1 g, 62%). 1H-NMR (DMSO-d6) δ 10.36 (br s, 1H), 8.15 (d, J=7.1 Hz, 1H), 7.59 to 7.47 (m, 2H), 7.46 to 7.38 (m, 2H), 7.30 to 7.20 (m, 3H); TLC Rf=0.39 (9:1 v/v hexanes-EtOAc).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:4][C:3]=2[O:2]1.CC([O-:33])(C)C.[K+]>CN(C=O)C>[N:28]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:11]1[CH2:12][C:13]2[C:14](=[O:33])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: c1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncccn1)C2
Reaction time: 0.08 h

Procedure:
To a solution of 1-(3,4-methylenedioxyphenyl)-2-(pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline (0.153 g, 0.415 mmol) (prepared as in Example 16) in anhydrous DMF (4.1 mL) was added KOtBu (0.079 g, 0.70 mmol, 1.7 eq.). After 5 min, oxygen gas was bubbled through the solution for 1 h. Diethyl ether (45 mL) was added to the reaction mixture and the supernatant decanted. Brine (2 mL) was added to the residue and the pH was adjusted to pH˜7 by addition of a few drops of 1N HCl. The water was removed in vacuo as an azeotrope with toluene. The resulting deep red residue was dissolved in a minimum amount of THF, and purified by column chromatography (silca gel; EtOH: CH2Cl2=1:9) to yield the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][NH2:16])[CH:10]=1.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][N:16]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[CH3:17])[CH:10]=1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Reactant: COc1ccccc1-c1cc(NN)ncn1
Solvent: CCO
Product: COc1ccccc1-c1cc(NN=C(C)c2ccc(N(C)C)cc2)ncn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.8 %

Procedure:
[6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (500 mg, 2.3 mmol) and 4-dimethylaminoacetophenone (380 mg, 2.3 mmol) were dissolved in 4 mL of ethanol. The resultant reaction mixture was heated in the microwave (CEM Discover, 135 C, QuickTest Method) for 3 hours. The reaction mixture was cooled to room temperature and after standing for three days yellow crystals formed. The crystalline solid was isolated by filtration and dried in vacuo to yield 580 mg (70%) of the title compound. HPLC Purity: 93%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:25]=[O:26])=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[O-:27]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=[O:26])=[C:11]([CH:22]([CH3:23])[CH3:24])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccn3)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure D, ethyl3-formyl-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 36, 287 mg, 0.82 mmol) in t-BuOH (6 ml), 2-methyl-2-butene (2.29 ml) was added a solution of NaH2PO4 (1.97 g, 16.4mmol) and NaClO2 (80%, 1.48 g, 16.4 mmol) in H2O (6 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:35])([F:34])[C:13]1[CH:14]=[CH:15][C:16]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C@@H:28]4[CH2:30][C@H:29]4[CH2:31][OH:32])[CH2:23][CH2:22]3)=[CH:19][S:18][C:17]=2[CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[F:34][C:12]([F:11])([F:35])[C:13]1[CH:14]=[CH:15][C:16]2[C:20]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C@@H:28]4[CH2:30][C@H:29]4[CH:31]=[O:32])[CH2:23][CH2:22]3)=[CH:19][S:18][C:17]=2[CH:33]=1
Reactant: OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reaction time: 0.58 h

Procedure:
A solution of oxalyl chloride (62 μl, 0.72 mmol) in anhydrous methylene chloride (10 ml) under N2 was cooled to −78° C. while stirring. Dimethy sulfoxide (104 μl, 1.44 mmol) was then added followed by a solution of {(1R,2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropyl}-methanol (0.135 g, .36 mmol) in anhydrous methylene chloride (10 ml). Stirring was continued at −78° for 35 minutes and then triethyl amine (1.0 ml, .7.3 mmol) was added. This solution was stirred for 4 hours and then removed from the cold bath, filtered, concentrated and chromatagraphed on silica gel with methylene chloride/methanol (95:5). The resultant pure aldehyde, (1R,2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarbaldehyde was verified by NMR and LC/MS, yielding 0.102 g, 76%.
Reaction SMILES: [C:1]12([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:18][C:19]#[N:20]>>[C:1]12([N:11]3[CH2:16][CH2:15][N:14]([CH2:18][C:19]#[N:20])[CH2:13][CH2:12]3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Reactant: N#CCBr
Product: N#CCN1CCN(C23CC4CC(CC(C4)C2)C3)CC1

Procedure:
The title compound is synthesized by coupling of 1-Adamantyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=260.3: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.60-2.50 (m, 4H), 2.45-2.40 (m, 4H), 2.00 (bs, 3H), 1.60-1.50 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].B(F)(F)F.CO.[C:18](=O)(O)[O-].[Na+]>CO>[CH3:18][O:6][C:5](=[O:7])[C:4]1[C:3](=[C:2]([F:1])[CH:10]=[CH:9][CH:8]=1)[OH:11]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc(F)c1O
Agent: FB(F)F
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(F)c1O

Procedure:
A 15.6 g (0.10 mole) portion of 3-fluorosalicylic acid was dissolved in a 100 ml portion of absolute methanol. A 22 ml portion of borontrifluoride-methanol reagent (2 equivalents, 51% BF3) was added and the reaction allowed to reflux for about six hours. The reaction mixture was cooled and added carefully to a saturated solution of sodium bicarbonate. The resulting mixture was then extracted with ether, the ether layer dried over magnesium sulfate and evaporated in vacuo. The oil obtained was crystallized from methanol. The methyl-3-fluorosalicylate obtained had a melting point of 94°-5° C.
Reaction SMILES: BrC1C=C(C([N:16]2[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=O)OC=1C1C=CC=C(Cl)C=1.[Br:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1>>[Br:23][C:24]1[O:28][C:27]([C:29]([N:16]2[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=[O:31])=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Br)o1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(Br)o2)CCN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 27A starting with the compound from Example 22A. 48.0 mg (79% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH:11]=O.[NH2:13]/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:21][C:14]1[NH:13][C:14]([CH3:21])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: Cc1sc2ccccc2c1C=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1c(C)sc2ccccc12
Yield: 43.1 %

Procedure:
A mixture of 2.2 g of 2-methylbenzo[b]thiophene-3-carboxaldehyde, 4.9 g of ethyl 3-aminocrotonate, and 10 ml of ethanol were heated to reflux for approximately 18 hours. An additional 1.6 g of ethyl 3-aminocrotonate were added and the reaction was heated an additional 24 hours at reflux. The reaction mixture was cooled and concentrated and the resulting solid was recovered by filtration providing 2.15 g of the desired title product, m.p. 191°-193° C.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.Cl>CC(C)=O>[CH:3]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)=[O:2]
Reactant: COC(=O)c1ccc(C(OC)OC)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C=O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of methyl 4-dimethoxymethyl-2-nitrobenzoate (2 g, 7.8 mmol) in acetone (25 ml) was treated dropwise with hydrochloric acid (6M, 20 ml) and stirred for 2 hours. The solvent was removed under vacuo, the residue was then treated with water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 4-formyl-2-nitrobenzoate (1.5 g). 1H-NMR (400 MHz, CDCl3): 10.10 (1H, s), 8.39-8.41 (1H, m), 8.16 (1H, d), 7.88 (1H, d), 3.94 (3H, s) ppm.
Reaction SMILES: C(OC([CH:6]1[C:12](=[O:13])[CH:11](C(OCC)=O)[CH2:10][C:9]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:8]=2[CH2:7]1)=O)C.[OH-].[K+].O>C(O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:8]2[CH2:7][CH2:6][C:12](=[O:13])[CH2:11][CH2:10][C:9]=2[CH:19]=1
Reactant: CCOC(=O)C1Cc2ccc(OC)cc2CC(C(=O)OCC)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCC(=O)CC2
Yield: 58 %

Procedure:
2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6,8-dicarboxylic acid diethyl ester (18.2 g, 0.0544 mol) was dissolved in ethanol and the solution was treated with Potassium hydroxide (24.4 g, 0.435 mol) in Water (140 g, 7.6 mol). The reaction was then refluxed until HPLC showed consumption of starting material (˜5 hours). The reaction was then acidified with 1N HCl and the product was extracted with dichloromethane. Organic extracts were dried over sodium sulfate, filtered and reduced. The crude mixture was filtered through a plug of silica rinsing with dichloromethane before purification. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 6.0 grams (58%) of 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[O:10]1[CH2:11][CH2:12][CH2:13][CH:14]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][O:10]2)[C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: c1ccncc1
Product: O=c1c(F)cn(C2CCCO2)c(=O)n1C1CCCO1
Temperature: 160 °C

Procedure:
In 20.8 ml of pyridine were dissolved 5.2 g (40 m mol) of 5-fluorouracil and 9.8 g (140 m mol) of 2,3-dihydrofuran. The solution was heated at about 160° C. in a closed tubular reactor under agitation for 5 hours. The resultant reaction mixture was treated similarly to Example 7 to give the above mentioned-compound.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4]1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:33][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)N4CCC(CO)CC4)cc3)n(C)c(=O)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc2nc(SCc3ccc(C(=O)N4CCC(CBr)CC4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
In dichloromethane (25 ml) was dissolved 2-[4-(4-hydroxymethylpiperidylcarbonyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (1.081 g) followed by addition of carbon tetrabromide (1.050 g). Then, triphenylphosphine (982 mg) was added over 10 minutes and the mixture was stirred at room temperature for 2 hours. The salt was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate =1:1) and rinsed with ether to provide the title compound as colorless solid (496 mg).
Reaction SMILES: [F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([O:30][CH3:31])[C:22]=1[CH2:23]Br.O>CN(C)C=O>[F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][CH2:23][C:22]2[C:25]([O:30][CH3:31])=[CH:26][CH:27]=[C:28]([F:29])[C:21]=2[F:20])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: COc1ccc(F)c(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)c([N+](=O)[O-])cc1NCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a suspension of 4-fluoro-2-methoxy-5-nitroaniline (0.37 g) and potassium carbonate (0.36 g) in N,N-dimethylformamide (10 mL) was added 2,3-difluoro-6-methoxybenzyl-bromide (0.47 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 5-fluoro-2-(2,3-difluoro-6-methoxybenzylamino)-4-nitroanisole (0.32 g). This material was dissolved in N,N-dimethylformamide (9.3 mL). To the solution were added sodium hydride (55%, 45 mg) and methyl iodide (0.18 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (4 mL)-tetrahydrofuran (4 mL). To the solution were added nickel(II) bromide (11 mg) and sodium borohydride (0.11 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.17 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1>C(O)(C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[C:3]([N:11]1[C:12]2[C:19]3[C:9]([CH2:8][C@@H:7]4[C:17]([C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:18][C@@H:3]([CH2:2][OH:1])[CH2:4][N:5]4[CH3:6])=[CH:10]1)([CH3:18])([CH3:4])[CH3:2]
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)(C)O
Product: CN1C[C@H](CO)C=C2c3cccc4c3c(cn4C(C)(C)C)C[C@H]21
Reaction time: 90 h
Yield: 122.9 %

Procedure:
To a mixture of 8 g of lysergol in 150 ml of t-butanol, 200 ml of trifluoroacetic anhydride were added dropwise with vigorous stirring. After the solution had been left at room temperature for 90 hours, it was evaporated. The residue was dissolved in water, made alkaline with ammonium hydroxide and the aqueous layer was extracted with ethyl acetate. After removal of the ethyl acetate, the residue was purified by silica gel column chromatography using 1:1 cyclohexane:ethyl acetate for elution to give 6 g of the title compound melting at 181 to 183° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:7]1=[O:21])=[O:4].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CC(O)=O.[Pd]>[C:24]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:23])([F:22])[F:1])[C:7]2=[O:21])=[CH:13][CH:14]=1)(=[O:26])[CH3:25]
Reactant: O=C1[C@@H](NC(=O)C(F)(F)F)CCN1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CN2CC[C@H](NC(=O)C(F)(F)F)C2=O)cc1
Reaction time: 4.5 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-acetamide (0.75 g, 2.27 mmol) in AcOH (12 mL) is added acetic anhydride (1 mL) and a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is hydrogenated at room temperature on a Parr apparatus under 70 p.s.i. of H2. After 4.5 h, the reaction mixture is filtered through a pad of Celite, washed with CH2Cl2 and then MeOH. The crude product is concentrated in vacuo to yield 1.2 g of crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide as a residue (wet with HOAc). A solution of the crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide (1.2 g, wet with AcOH) in AcOH (12 mL) is cooled at 0° C. and acetic anhydride (1 mL) is added. The resulting mixture is treated with a catalytic amount of NaNO2, followed by the dropwise addition of fuming HNO3 (3.8 mL). The reaction mixture is stirred at 0° C. for 1.5 hours, then at room temperature for 1.5 hours. Upon re-cooling to 0° C., a mixture of ice/ice water is added slowly with stirring. The mixture is diluted further with water and extracted with EtOAc (3×50 mL). The combined organic layers are washed twice with water. The organic phase is dried over anhydrous MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to provide the title compound (0.65 g, 1.67 mmol) as a beige solid.