Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:18]([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH2:18])=[CH:10][CH:9]=2)[CH:16]=1
Reactant: O=C([O-])O
Reactant: O=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 0.17 h

Procedure:
To a solution of Ph3PCH3I (0.97 g) in toluene (5 mL), KN(TMS)2 (0.5M in toluene, 4.8 mL) was added dropwise at room temperature. After 10 min, the solution of 4-(5-bromo-2-chlorobenzyl)benzaldehyde (intermediate AL) (0.62 g) in toluene (2 mL) was added dropwise. After 2 h, aqueous NaHCO3 was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AM (0.5 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[OH:5][CH2:6][CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C:26](=[O:43])[CH2:27][CH2:28][C:29]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)=[O:30])[CH:14]=[C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[OH:17])(=[O:10])=[O:9].C(=O)([O-])[O-]>CN(C=O)C>[OH:5][CH2:6][CH2:7][S:8]([C:11]1[CH:12]=[C:13]([C:26](=[O:43])[CH2:27][CH2:28][C:29]([C:31]2[CH:32]=[C:33]([O:41][CH3:42])[C:34]([O:39][CH3:40])=[C:35]([O:37][CH3:38])[CH:36]=2)=[O:30])[CH:14]=[C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[O:17][CH2:1][CH2:2][CH3:3])(=[O:10])=[O:9]
Reactant: CCCBr
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OCc3ccccc3)c(O)c(S(=O)(=O)CCO)c2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Temperature: 75 °C
Reaction time: 2 h

Procedure:
n-Propyl bromide (1.63 mL, 17.8 mmol) was added to a solution of 1-[3-(2-hydroxyethylsulfonyl)-4-hydroxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (5.53 g, 9.91 mmol) in DMF (10 mL) containing postassium carbonate (2.74 g, 19.9 mmol). The mixture was stirred at 75° C. for 2 h, and partitioned between ethyl ether and water. The aqueous layer was re-extracted with ether (2 ×) and ethyl acetate. The organic extracts were combined, dried, and evaporated to dryness. The residue was triturated with Et2O to give crystals, which was washed with Et2O containing a small volume of acetone. This material, Rf 0.53 (hexane-ethyl acetate; 1:2, v/v), was used directly in the next experiment without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][C:8](Cl)=[O:9]>ClCCl>[Cl:6][CH2:7][C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: C1CCNC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: O=C(CCl)N1CCCC1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
3.82 moles of pyrrolidine were added to a solution of 1.92 moles of chloroacetyl chloride in 600 ml of dichloromethane. The temperature was maintained at 0° C. The organic phase was washed with solutions of sodium hydrogen sulphate and sodium carbonate and dried. After evaporation of the solvent, 242 g of N-(2-chloroacetyl)pyrrolidine were obtained. 1.64 moles of this compound were dissolved in 500 ml of toluene and 231 ml of triethylamine were added. This was heated under reflux for 3 hrs and after cooling 311.5 g of product were isolated in the form of a precipitate. 119.07 g of the product obtained were dissolved in
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]2[C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:4][CH:5]=[N:1]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncnn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (7.06 g), 4-nitrobenzyl bromide (10 g), potassium carbonate (16.6 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 4 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give methyl 1-(4-nitrobenzyl)-1H-1,2,4-triazole-5-carboxylate (1.50 g, 12%) as crystals from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-130° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:14][CH3:15])=[N:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([NH:10][OH:11])=[NH:9])[CH3:2].[CH2:16](OC(OCC)OCC)C.B(F)(F)F.CCOCC>>[CH2:1]([C:3]1[C:4]([O:14][CH3:15])=[N:5][C:6]([CH3:13])=[C:7]([C:8]2[N:9]=[CH:16][O:11][N:10]=2)[CH:12]=1)[CH3:2]
Reactant: CCc1cc(C(=N)NO)c(C)nc1OC
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: CCc1cc(-c2ncon2)c(C)nc1OC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a crude mixture of 5-ethyl-N-hydroxy-6-methoxy-2-methylnicotinamidine (formed on 1.705 mmol scale following the procedures of Step 3, Example 22), under a nitrogen atmosphere, is added triethylorthoformate (2 mL), followed by boron trifluoride etherate (42.6 μL, 0.336 mmol). The resulting solution mixture is heated at 100° C. for 3.25 hr. The mixture is allowed to cool, concentrated under vacuum, then treated with aqueous hydrochloric acid (1M, 2 mL). The resulting mixture is allowed to stand for 30 min before making basic with excess solid sodium bicarbonate. The mixture is extracted with five portions of ethyl acetate, dried over magnesium sulfate, filtered and evaporated to leave an oily, brown residue that is purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:dichloromethane (1:1, increasing to 4:1). Fractions containing the product are combined, the solvent evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:dichloromethane (9:1, increasing to 17:3 then 1:1). Fractions containing the product are combined, the solvent evaporated and further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:dichloromethane (87:13, then 1:1). Clean fractions containing the product are combined, evaporated and triturated with heptane to give 3-ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-3-yl)-pyridine (57 mg, 15% yield, 2 steps). MS: m/e=220 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.72 (1H, s), 7.99 (1H, s), 4.00 (3H, s), 2.76 (3H, s), 2.61 (2H, q), 1.11 (3H, t)
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([OH:12])[CH:10]([N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:20])[CH:8]=2)[CH2:3]1.[CH:22](O)=[O:23]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[CH:11]([OH:12])[CH:10]([N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:20][CH:22]=[O:23])[CH:8]=2)[CH2:3]1
Reactant: CC1(C)Cc2ccc(N)cc2C(n2ccccc2=O)C1O
Reactant: O=CO
Solvent: c1ccncc1
Product: CC1(C)Cc2ccc(NC=O)cc2C(n2ccccc2=O)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-amino-1,2,3,4-tetrahydro-3-naphthol in 15 ml of formic acid and 1 ml of pyridine is boiled for 16 hours and evaporated. Working up in the customary manner gives 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-formamido-1,2,3,4-tetrahydro-3-naphthol.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[F:23])=O>O1CCCC1>[F:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:13]([CH3:1])=[CH2:12]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OC)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium bis(trimethylsilyl)-amide, 1.0M in tetrahydrofuran (714 ml, 0.714 m) was added to a suspension of methyltriphenylphosphonum bromide (255 g, 0.714 m) in THF (2.50 L) cooled with an ice bath. The resultant yellow colored suspension was stirred for 30 minutes at ice bath temperature and then cooled to −78° C. A total of 2-fluoro-4-methoxyacetophenone (10 g, 0.595 m) in THF (200 ml) was added dropwise and stirred at −78° C. for 1.5 hours. Reaction mixture was allowed to warm to room temperature for one hour, quenched with acetic acid (˜80 ml) where color change was observed from yellow to off white and stirred for 30 minutes (pH˜7)(slight exotherm noted). The mixture was concentrated to a slush, diluted with 7:2 hexane:ethyl acetate, and was allowed to sit overnight. Solids were removed by filtration and the filtrate was concentrated to yellow oil. The title compound was obtained after flash column using 9:1 hexane:ethyl as the eluant.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][C:35]1([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]1[CH3:46])[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][C:35]3([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]3[CH3:46])[CH2:34]4)=[O:20])[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1C(=O)NC(=O)C12Cc1ccc(NC(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(Cc4ccncc4)C3=O)cc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-[4-chloro-8-oxo-9-(pyridine-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]acetic acid dihydrochloride (105 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (65 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]12[CH2:22][CH:13]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=31)[CH2:12][NH:11][CH2:10][CH2:9]2.[C:23]1([CH2:29][C:30](Cl)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH2:30]([N:11]1[CH2:10][CH2:9][CH:8]2[CH2:22][CH:13]([CH:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=32)[CH2:12]1)[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1c2ccccc2C2CCNCC1C2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OC1c2ccccc2C2CCN(CCc3ccccc3)CC1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of anhydrous toluene was added to 1 g of 2,3,4,5-tetrahydro-1,6-methano-1H-4-benzazonin-7(6H)-one and 2 g of triethylamine, and 1 g of phenylacetyl chloride was added dropwise to the mixture over a period of 30 minutes under ice cooling and agitation. After completion of the dropwise addition, the mixture was agitated for 1 hour at room temperature. The reaction mixture liquid was washed twice with 50 ml of water and the toluene layer was dried with anhydrous sodium sulfate and filtered. Toluene was removed from the filtrate by distillation under reduced pressure, and the residue was dissolved in 20 ml of anhydrous dioxane and the solution was heated and refluxed for 6 hours together with 0.3 g of lithium aluminum hydride. Then, excess lithium aluminum hydride was decomposed with drops of ethyl acetate, and 50 ml of saturated aqueous solution of Rochelle salt was added and the mixture was shaken. The resulting solution was extracted with ether, and the ether extract was subjected to distillation to remove ether therefrom. The residue was subjected to vacuum distillation to obtain 0.9 g of a fraction of 4-phenethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol boiling at 148° to 152° C. (bath temperature) under 1 mmHg. The product was a light-yellow oil.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[BrH:11].[CH2:12]([N:15]([CH2:28][CH2:29][CH3:30])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([NH2:27])=[C:21]([OH:26])[CH:22]=2)[CH2:17]1)[CH2:13][CH3:14]>C(OCC)C>[BrH:11].[CH2:28]([N:15]([CH2:12][CH2:13][CH3:14])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([NH:27][CH:8]=[O:10])=[C:21]([OH:26])[CH:22]=2)[CH2:17]1)[CH2:29][CH3:30]
Reactant: O=CO
Reactant: CCCN(CCC)C1CCc2cc(O)c(N)cc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCN(CCC)C1CCc2cc(O)c(NC=O)cc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.7 ml of acetic anhydride is added to 3 ml of 98% formic acid, kept at 0° C., and the whole is left for 15 minutes at 0° C. 2.2 g of 2-dipropylamino-7-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide are then added thereto and the mixture is then stirred for one hour at 0° C. After 50 ml of diethyl ether have been added and the solid has been filtered off, the latter is recrystallised from a 50/50 methanol/ethyl acetate mixture. This gives 1 g of the final product melting at 213° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=[O:19]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)[OH:19]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Fc1cccnc1
Product: OC(c1ccc2ccccc2c1)c1ccncc1F

Procedure:
Using 5.2 mL of 3-fluoropyridine and 10.2 g of 2-naphthaldehyde as starting materials, 17.0 g of the title compound was obtained as a colorless powder in the same manner as described in Production example 18.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC(C)C(=O)Cl
Reactant: Cn1ccc2ccc(N)cc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1ccc2ccn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a solution of 1-methyl-1H-indol-6-amine (45 mg, 0.31 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (35 μL, 0.34 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 24.3 mg (36%) of the title compound (LCMS RT=5.73 min, MH+ 217.2)
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:60][CH3:61].C(OCC)(=O)C>CN(C)C=O>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH2:60][CH3:61])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:12][N:13]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(O)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2cc(C(C)C)ccc2OC)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-hydroxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (70 mg) is dissolved in N,N-dimethylformamide (3 ml) and thereto are added potassium carbonate (26.4 mg) and iodoethane (29.8 mg) and the mixture is stirred at 50° C. for 8 hours. Thereto are added ethyl acetate and a water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-ethoxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (60.5 mg). MS (m/z): 762 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH2:18])[CH2:7][N:6]1[CH2:19][CH2:20][CH3:21].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].N>N1C=CC=CC=1>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH2:7][N:6]1[CH2:19][CH2:20][CH3:21]
Reactant: COCC(=O)Cl
Reactant: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Agent: N
Solvent: c1ccncc1
Product: CCCN1C[C@@H](NC(=O)COC)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Reaction time: 0.25 h

Procedure:
849 mg of 2-methyl6n-propyl-8alpha-ergolinylamine (3 mmol) is dissolved in 20 ml of pyridine and stirred with 2.28 ml of methoxy acetyl chloride (30 mmol) for 30 minutes at room temperature. Then it is poured onto ice, stirred for 15 minutes, make alkaline with ammonia and extracted with dichloromethane. The organic phases are dried and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/methanol and crystallized from ethyl acetate. Yield 420 mg (40% of theory), [α]D =+24° (0.5% in chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1C=CC=CC=1.CO>[CH3:15][O:9][C:8](=[O:10])[C:7]1[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[NH2:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 4-nitro-anthranilic acid (2.200 g, 10.9 mmol, 1 eq) in benzene/methanol (4/1) (100 mL) was added TMSCHN2 (2M in hexanes) (12 mL, 24 mmol, 2.2 eq). The reaction was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 4-nitro-anthranilic acid methyl ester (1.841 g, 86%) as a bright yellow solid. 1H NMR (300 MHz, CDCl3); δ 8.00 (d, 1H), 7.50 (d, 1H), 7.40 (dd, 1H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH2:20])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10].Cl[C:24]([O:26][CH3:27])=[O:25].O>N1C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([NH:20][C:24]([O:26][CH3:27])=[O:25])[S:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10]
Reactant: Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 2-amino-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate in 25 cm3 of pyridine is added 0.308 cm3 of methyl chloroformate. The solution is stirred at a temperature in the region of 20° C. overnight. After addition of 0.62 cm3 of methyl chloroformate, the mixture is stirred for 72 hours at a temperature in the region of 20° C. 50 cm3 of water are added, and the precipitate formed is filtered off by suction and then washed with three times 10 cm3 of water and dried under reduced pressure. 785 mg of 2-[(methoxycarbonyl)amino]-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)O>CC(C)=O>[F:9][C:8]([F:11])([F:10])[CH2:7][O:19][C:18]1[CH:20]=[CH:21][C:14]([O:6][CH2:7][C:8]([F:9])([F:10])[F:11])=[CH:16][CH:17]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a mixture of 2.42 moles (334.4 g.) of potassium carbonates, 2.2 moles (510.6 g.) of 2,2,2-trifluoroethyl trifluoromethanesulfonate in 1.02 liter of acetone is added a solution of 1.0 mole (110 g.) of hydroquinone in 1.1 liter of acetone, slowly over a 2 hour period. The reaction is then heated at reflux for 24 hours, the reaction mixture is evaporated, and 2 liters of chloroform and 2 liters of water are added to the residue. The chloroform layer is separated, the aqueous layer is washed twice with 1 liter of chloroform, and the combined chloroform solution is washed with 1 liter of water. The chloroform solution is dried over magnesium sulfate, then concentrated under vacuum. Hexane is added to the residue and the solid product is collected by filtration and washed with hexane. Additional material is collected from the concentrated residues. A yield of 88 percent, 241 g. of 1,4-bis(2,2,2-trifluoroethoxy)benzene, m.p. 75°-77° C. is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-])=O.[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:8]
Reactant: CCCCCCCCCCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: CCCCCCCCCCNC(=O)c1cccc(N)c1

Procedure:
Using this procedure 3-nitrobenzoyl chloride was treated with decylamine togive 3-nitro-N-decylbenzamide, mp 86°-88°, which was hydrogenated to give 3-amino-N-decylbenzamide, mp 56°-58°, which gave nmr and mass spectra consistent with the structure.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO>[O:13]=[C:9]([CH3:8])[CH2:10][C:11]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[O:12]
Reactant: C=C1CC(=O)O1
Reactant: CCCNCCC
Solvent: CO
Product: CCCN(CCC)C(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A solution of 27.80 g (0.28 mol) N,N-di-n-propylamine was added dropwise to a solution of 20.00 g (0.24) diketene in 100 ml MeOH at 0° C. After stirring for 3 hours at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was purified by means of column chromatography. 38.05 g of product was obtained as a slightly yellow oil.