Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[Cl-].[CH:47]1([C:53]2([CH2:59][N:60]3[C:64]([CH3:66])([CH3:65])[CH2:63][O:62][C:61]3=[O:67])[CH2:58][CH2:57][NH2+:56][CH2:55][CH2:54]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]2[C:14]([N:56]2[CH2:57][CH2:58][C:53]([CH2:59][N:60]3[C:64]([CH3:65])([CH3:66])[CH2:63][O:62][C:61]3=[O:67])([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[CH2:54][CH2:55]2)=[O:16])=[CH:6][CH:7]=1
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CC[NH2+]CC1
Reactant: O=C(O)[C@@H]1C[C@H](O)C[C@H]1c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@@H]2C[C@H](O)C[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar was charged with 0.285 g (1.18 mmol) of the product of Step E dissolved in 4 mL of methylene chloride. To the reaction mixture was added 0.340 g (1.77 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.240 g (1.78 mmol) of 1-hydroxybenzotriazole, 0.390 μL (3.55 mmol) of N-methylmorpholine, followed by 0.431 g (1.30 mmol) of 4-cyclohexyl-4-[(4,4-dimethyl-2-oxo -1,3-oxazolidin-3-yl)methyl]piperidinium chloride. The resulting solution was stirred at room temperature for 48 h, then was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4), filtered and evaporated in vacuo. The residual amorphous solid was used directly in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23][O:24]C)[C:10]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br>>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23][OH:24])[C:10]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCN(CCCn1ccnc1)C1=Nc2cccc3cccc1c23
Agent: Br
Product: OCCN(CCCn1ccnc1)C1=Nc2cccc3cccc1c23

Procedure:
Treatment of the compound of Example 127 with refluxing 48% HBr solution results in the demethylation of the compound. Removal of the HBr solution in vacuo and neutralization with alkali hydroxide solution yields the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:16][C:17]1[C:18](Cl)=[N:19][C:20]([Cl:23])=[N:21][CH:22]=1>C1COCC1>[Br:16][C:17]1[C:18]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:19][C:20]([Cl:23])=[N:21][CH:22]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(Cl)ncc2Br)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 79.2 %

Procedure:
To a solution of N-Boc-3-hydroxypyrrolidine (2.06 g, 11 mmol) in anhydrous THF (50 mL), was added NaH (60% oil dispersion, 0.44 g, 11 mmol). The mixture was stirred at room temperature for 19 h. The reaction mixture was cooled to −0° C. and was added slowly to a solution of 5-bromo-2,4-dichloropyrimidine (2.28 g, 10 mmol) in anhydrous THF (20 mL) at −5° C. The resulting mixture was stirred at −0° C. for 5 h and quenched with water. The aqueous solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on ISCO (hexane/ethyl acetate gradient, 0-20%) to give the title compound (3.0 g, 79.2%) as colorless oil. MS (ESI) m/z: Found: 378.0 (M++1); Calc. 377.0 (M+)
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:7])[C:3]([F:6])([F:5])[F:4]>C(O)(C)C.Cl.[Rh]>[OH:1][C:2]([CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([CH3:7])[C:3]([F:4])([F:5])[F:6]
Reactant: CC(O)(c1ccc(O)cc1)C(F)(F)F
Agent: [Rh]
Agent: Cl
Solvent: CC(C)O
Product: CC(O)(C1CCC(O)CC1)C(F)(F)F

Procedure:
18.9 g (0.092 mol) of 4-(2-hydroxy-1,1,1-trifluoro-2-propyl)phenol were hydrogenated in a mixture of 200 ml of isopropanol and 6 ml of concentrated hydrochloric acid in the presence of 2.3 g of rhodium (5% on charcoal) at 150 bar and 50° C. After filtration to remove the catalyst and concentration, 18.8 g (96.6% of theory) remained of a colorless product.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1)(=[O:29])[CH3:28]
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)ON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 0.5 g (1.87 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide in 25 mL of dichloromethane and 0.72 g (9.16 mmol) of pyridine was treated with 0.57 g (5.61 mmol) of acetic anhydride. The resulting mixture was stirred at room temperature overnight and then diluted with 10 mL of dichloromethane. The organic phase was extracted with 20 mL of 1M aqueous HCl, a saturated solution of NaHCO3 and brine, then dried by sodium sulphate. The solvent was then removed by evaporation under reduced pressure and the crude product was crystallised from a mixture of dichloromethane and ethyl acetate to give the desired product as white crystals of m.p. 175.8°-176.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[C:38]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40][CH2:39]1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:38](=[O:45])[CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C1CCCC(=O)O1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.6 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.084 ml), glutaric anhydride (51 mg), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and isopropyl ether was added to the obtained residue and the mixture was crystallized. The obtained crystals were collected by filtration and dried under reduced pressure at 50° C. to give the title compound (131 mg, 76%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.C=O.[C:10](=O)([O-])[O-:11].[Na+].[Na+]>O>[OH:11][CH2:10][N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C1C=CC(=O)N1
Agent: C=O
Agent: [Na+]
Solvent: O
Product: O=C1C=CC(=O)N1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 18971.5 %

Procedure:
A mixture of 9.8 g (0.1 mole) maleimide, 9 ml 37% aqueous formaldehyde and 40 mg sodium carbonate was stirred at room temperature for 1 hour. The mixture was diluted with 30 ml water and the crystals formed (9.1 g N-hydroxymethylmaleimide) were collected by filtration.
Reaction SMILES: [S:1]([C:19]1C=C(C2N(C(F)(F)F)N=NC=2)C(F)=CC=1Cl)[C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:13]([F:16])([F:15])[F:14])[N:10]=[N:11][CH:12]=2)[C:5]([F:17])=[CH:4][C:3]=1[Cl:18].C(S([O-])=O)O.[Na+].C(=O)([O-])[O-].[K+].[K+].[F:48][C:49]([F:53])([F:52])CI>>[F:48][C:49]([F:53])([F:52])[CH2:19][S:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:13]([F:15])([F:16])[F:14])[N:10]=[N:11][CH:12]=2)[C:5]([F:17])=[CH:4][C:3]=1[Cl:18]
Reactant: Fc1cc(Cl)c(Sc2cc(-c3cnnn3C(F)(F)F)c(F)cc2Cl)cc1-c1cnnn1C(F)(F)F
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Product: Fc1cc(Cl)c(SCC(F)(F)F)cc1-c1cnnn1C(F)(F)F
Yield: 96.6 %

Procedure:
1.8 g (3.0 mmol) of 1,1′-thiodi-[2-chloro-4-fluoro-5-(3-trifluoromethyltriazolyl)benzene], 2.0 g (13.0 mmol) of Rongalite, 2.0 g (14.5 mmol) of potassium carbonate and 3.2 g (17.6 mmol) of 2,2,2-trifluoroethyl iodide were reacted in the same way as in Example 2 (3) and afforded 1.1 g of [2-chloro-4-fluoro-5-(3-trifluoromethyltriazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (yield 47.8%) as white crystals (m.p. 56-58° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18]C)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:31])[N:13]2[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:21]=1.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(O)C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:31])[N:13]2[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:21]=1
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccccc4Cl)cc(OC)cc32)c1
Agent: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccccc4Cl)cc(O)cc32)c1

Procedure:
5-(2-Chlorophenyl)-3,4-dihydro-7-hydroxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from 5-(2-chlorophenyl)-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone (INTERMEDIATE 17) by a procedure analogous to that described in INTERMEDIATE 3. Mass spectrum (ESI) 422.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.93 (d, J=7.5 Hz, 1H); 7.85 (d, J=17.5 Hz, 1H); 7.49 (m, 3H); 7.7.26 (m, 1H); 6.34 (s, 1H); 5.78 (s, 1H); 3.85 (s, 3H); 2.62 (m, 4H); 2.14 (d, J=10.5 Hz, 3H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([N:10]1[C:14]([CH:15]=[N:16][N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:22][O:23][CH3:24])=[CH:13][N:12]=[C:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH3:9]>C1COCC1>[CH2:6]([N:10]1[C:14]([C@@H:15]([NH:16][N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:22][O:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:13][N:12]=[C:11]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCn1c(C=NN2CCC[C@@H]2COC)cnc1-c1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[C@H](NN1CCC[C@@H]1COC)c1cnc(-c2ccccc2)n1CCCC
Temperature: 25 °C

Procedure:
To a solution of BuLi (2.5 M in hexane, 12.5 ml, 31 mmol) under argon in anhydrous THF (15 mL) at −78° C. is slowly added a solution of crude 192 (14 mmol) in THF (15 mL). The mixture is allowed to warm to room temperature over a period of 15 h and quenched with saturated sodium bicarbonate. The aqueous phase is extracted with ethyl acetate and the combined organic phases were washed with water and dried over sodium sulfate. Removal of solvents under reduced pressure and purification of the residue by column chromatograpy affords the desired product as a colorless syrup. Yield: 5.1 g; [α]D−72 (c=1.2, CHCl3); LC-MS (MH+): 399.
Reaction SMILES: [Cl-].[NH4+:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([O:23]CC)=O)=[CH:8][CH:7]=1)([O-:5])=[O:4]>N>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([NH2:2])=[O:23])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: [NH4+]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccc([N+](=O)[O-])cc1
Agent: N
Agent: [Cl-]
Product: NC(=O)c1[nH]c2ccccc2c1-c1ccc([N+](=O)[O-])cc1
Temperature: 125 °C

Procedure:
A solution of 0.5 g of ammonium chloride in 30 ml of concentrated aqueous ammonia is added to a solution of 3.3 g of ethyl 3-(4-nitrophenyl)-1H-indole-2-carboxylate in 50 ml of 7N methanolic ammonia. The solution is then heated in a sealed tube at 125° C. for 15 hours. After cooling, the solid formed is filtered off, washed with water, and then filter-dried. After drying under vacuum, 1.5 g of 3-(4-nitrophenyl)-1H-indole-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [N:1]1[C:2]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Na+]>O.NN.C(O)C>[N:1]1[C:2]([CH2:10][NH2:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1c2ccccc2C(=O)N1Cc1cn2ccccc2n1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCc1cn2ccccc2n1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A solution of 1.37 g (4.94 mmol) of 2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-isoindole-1,3(2H)-dione in 14 ml of hydrazine hydrate 98% and 1 ml of ethanol. Was stirred at room temperature for an hour. The mixture was then poured into 25 ml of sodium hydroxide 35% and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 0.426 g of the title compound crystallized from diethylether.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C.O>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16]1)[C:13]([CH:12]=[O:11])=[CH:14]2
Reactant: OCC1=CN2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CC1=CN2CCC1CC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
Freshly distilled oxalyl chloride (4.2 ml, 47.3 mmol) was dissolved in 80 ml of methylene chloride and cooled to -78° C. A solution of DMSO (6.7 ml, 94.6 mmol) in 20 ml of methylene chloride was added dropwise to the cooled solution. After stirring 10 minutes, a solution of 3-hydroxymethyl-1-azabicyclo[2.2.2]oct-2-ene (6 g, 43 mmol) in 20 ml of methylene was added dropwise and the reaction stirred for 1 hour. Triethylamine (30 ml, 215 mmol) was added to the reaction and the reaction was slowly warmed to room temperature, then poured into 200 ml of water and the organic phase separated. The aqueous phase was extracted with methylene chloride (3×250 ml) and the combined organic phases were washed with 10% sodium carbonate (2×150 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow liquid. The crude liquid was stirred in diethyl ether, filtered, and concentrated to afford a clear, yellow liquid (4 g) which was distilled (42° C., 0.25 mm Hg) to give the product as a clear, colorless liquid (2.4 g, 40%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](I)[CH:6]=[CH:7][CH:8]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=2)([OH:25])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1cccc(I)c1
Product: OC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Yield: 47.3 %

Procedure:
Beginning with 3-trifluoromethyl-iodobenzene (3 g) and 1-benzyl-4-piperidone (2.1 g), 1.75 g of the title compound was recovered by the procedure described in preparation 1. MS m/z (rel. intensity, 70 eV) 335 (M+, 29), 244 (22), 146 (19), 91 (bp), 56 (19).
Reaction SMILES: [CH2:1]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[C@H:3]([C:16]([OH:18])=O)[CH2:2]1.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:44]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH2:49])[CH3:45]>C(Cl)Cl.C(N(CC)CC)C>[CH2:44]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:49][C:16](=[O:18])[C@@H:3]1[CH2:2][CH2:1][CH2:5][N:4]1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:45]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of Z-L-proline (12.7 g, 0.051M) in CH2Cl2 (200 ml) cooled to 0° was added 1-hydroxy benzotriazole (7.0 g) followed by a solution of DCC (10.6 g) in CH2Cl2 (50 ml). After 30 min. at 0° L-leucine ethyl ester (10.0 g, 0.051 molM) was added followed by triethylamine (15 ml) and the reaction mixture was then left to stir and warm up to room temperature overnight. The reaction mixture was then filtered and washed in turn with saturated aq. NaHCO3 (250 ml×3), H2O (250 ml), dilute aq. HCl (1 M, 250 ml×3) and water (250 ml×2). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to an oil which subsequently crystallised. Recrystallisation from ethyl acetate/hexane gave N-(benzyloxycarbonyl)-L-prolyl-L-leucine ethyl ester as a white crystalline solid, 15.5 g, (78%); m.p. 67°-68°; (Found: C, 64.55; H, 7.79; N, 7.22. C21H30N2O5 requires C, 64.61; H, 7.74; N, 7.17%); νmax (CHCl3) 1740 and 1680 cm-1 ; δ(CDCl3) 0.7-0.95 (6H, m, CH(CH3)2); 1.18 (3H, m, OCH2CH3); 1.3-1.95 and 2.05-2.25 (7H, m, CH2CH2, CH2CH(CH3)2); 3.4 (2H, m, CH2N); 4.05 (2H, m, OCH2CH3); 4.25 (2H, m, α-CH); 4.98 and 5.05 (together 2H, respectively q, J=7 Hz, and m, CH2C6H5); 7.35 (5H, broad s, C6H5) and 8.26 (1H, m, CONH); m/e 391 (100%, [m+1]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:9]([CH2:12][CH:13](N)CO)=[CH:10][NH:11][C:3]=12.[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])[CH2:18][CH2:19][CH3:20].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:17]1([CH2:18][CH2:19][CH3:20])[C:10]2[NH:11][C:3]3[C:4]([C:9]=2[CH2:12][CH2:13][O:21]1)=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH3:27]
Reactant: Cc1ccc(Br)c2c(CC(N)CO)c[nH]c12
Reactant: CCCC(=O)CC(=O)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(Br)c21
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 4-bromo-7-methyl tryptophol (1.12 g, 4.41 mmol) and ethyl butyrylacetate (0.71 mL, 4.41 mmol) in CH2Cl2 (20 mL) was added BF3.OEt2 (0.56 mL, 4.41 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and filtered through a pad of silica gel. The filter cake was washed with additional CH2Cl2 and the combined organic layer was evaporated to provide 1.62 g (93%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 9.33 (bs, 1H), 7.11 (d, J=7.65 Hz, 1H), 6.76 (d, J=7.65 Hz, 1H), 4.19 (m, 2H), 4.03 (m, 1H), 3.90 (m, 1H), 3.15 (m, 2H), 3.03 (d, J=16.6 Hz, 1H), 2.89 (d, J=16.6 Hz, 1H), 2.43 (s, 3H), 2.08 (m, 1H), 1.96 (m, 1H), 1.38 (m, 1H), 1.27 (t, J=7.14 Hz, 3H), 1.18 (m, 1H), 0.87 (t, J=7.29 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1C=C[CH:11]=[CH:10][C:9]=1O.C(OCC)C>N1C=CC=CC=1>[O:4]1[C:5]2[CH:6]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7][C:2]1=[O:3]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1O
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=c1[nH]c2ccccc2o1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
38.4 cc (0.4 mol) of ethyl chloroformate are added, at a temperature between 0° and 10° C., to a solution of 38.4 g (0.35 mol) of o-aminophenol in 150 cc of pyridine. When the addition has ended, the reaction mixture is stirred for a further 2 hours and then poured into 1.5 liters of diethyl ether. The precipitate is filtered off. The ether in the filtrate is evaporated off on a rotary evaporator. The residue is heated to 180° C. in order to distill off the pyridine. After cooling, the residue is recrystallized from ethyl acetate. The melting point of the obtained compound is 136° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[NH:13][CH:12]=[N:11][C:10](=O)[C:9]=1[F:15])[CH3:7].C(N(CC)CC)C.[ClH:23]>C(Cl)Cl>[Cl:23][C:10]1[C:9]([F:15])=[C:8]([CH2:6][CH3:7])[N:13]=[CH:12][N:11]=1
Reactant: CCc1[nH]cnc(=O)c1F
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1ncnc(Cl)c1F
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (0.787 mL, 8.44 mmol) was added slowly over 10 min to a mixture of 6-ethyl-5-fluoropyrimidin-4(1H)-one (1 g, 7.04 mmol) (Apollo Scientific) and triethylamine (0.981 mL, 7.04 mmol) in DCM (15 mL), keeping the reaction temperature below 40° C. The mixture was then heated to reflux for 5 hrs then cooled to room temperature. The reaction mixture was then slowly poured into aqueous HCl (4M, 20 mL), keeping the temp below 20° C. The organic layer was collected and the aqueous layer was further extracted with DCM (20 mL). The organic layers were combined then washed with water (20 mL), dried (MgSO4) filtered and the solvent was removed to give the title compound as a colourless oil (1 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)=[O:16]>C1COCC1.C(NC(C)C)(C)C>[C:17]12([C:15](=[O:16])/[CH:14]=[CH:7]/[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=Cc1ccncc1
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccncc1)C12CC3CC(CC(C3)C1)C2
Yield: 65.9 %

Procedure:
The method essentially followed that described in Example 17a but using 4-pyridinecarboxaldehyde (0.48 ml, 5.0 mmol) in THF (6 ml), diisopropylamine in THF (20 ml), butyllithium (3.13 g, 5.0 mmol) and 1-adamantyl methyl ketone (0.48 ml, 5.0 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:100:1, gave the title compound (881 mg, 66%), which crystallised from hexane, m.p. 128°-129° C., IR νmax 1690 cm-1 ; 1H-NMR (CDCl3) δ1.72-1.89 (12H, adamantyl CH2) 2.12 (3H, s, adamantyl CH), 7.36 (1H, d, J 15.6 Hz, COCHCH), 7.56 (1H, d, J 15.6 Hz, COCHCH), 7.71 (2H, d, J 5.5 Hz, Py 3-H and 5-H), 8.71 (2H, d, J 5.5 Hz, Py 2-H and 6-H); MS m/z 267 (M+). Anal. Calcd: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.96; H, 8.13; N, 5.04 %.