Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([OH:17])[CH:8]=1)=[O:6].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:5](=[O:6])[NH:4][CH2:3][CH2:2][OH:1])=[CH:8][C:9]1=[O:17])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: O=C(NCCO)c1cc(O)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCn1c(=O)cc(C(=O)NCCO)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(2-hydroxy-1-ethylcarbamoyl)-2-hydroxyquinoline (1.2 g), N-(tert-butoxycarbonyl)-6-bromo-hexylamine (2.2 g), cesium carbonate (4 g) and N,N-dimethylformamide (50 ml) was stirred for 6 hours at 60° C. followed by stirring overnight at room temperature. Ice and water were added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (45:5:1.5) as eluent gave the desired compound as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: COc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-[(4-methoxyphenyl)methyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([Cl:11])=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[C:18]([CH2:19]Cl)=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=[CH:15][CH:14]=1.[C:24](=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)=O>[Cl:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:19][C:18]3[C:13]([CH3:12])=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-:23])=[O:22])[C:3]2=[N:10][C:9]=1[CH3:24]
Reactant: Cc1cccc([N+](=O)[O-])c1CCl
Reactant: O=C([O-])[O-]
Reactant: Nc1cccn2c(Cl)cnc12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc([N+](=O)[O-])c1CNc1cccn2c(Cl)c(C)nc12

Procedure:
Starting from 8-amino-3-chloroimidazo[1,2-a]pyridine (9.26 g), 6-methyl-2-nitrobenzyl chloride (10.5 g), sodium carbonate (13.7 g) and sodium iodide (8.55 g) in acetone (380 ml) according to the procedure indicated in Example B1 gives, after chromatography on silica gel (eluent: toluene/dioxane=20:1) and crystallization from ethyl acetate/cyclohexane, 10.6 g (63%) of the title compound of m.p. 142-144° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3].[CH:28]1(Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:23]([CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: BrC1CCCCCC1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1)C1CCCCCC1

Procedure:
10 g (0.0275 mol) of methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]acetate are reacted, in analogy to the procedure of Example 1, with 10.04 g (0.055 mol) of cycloheptyl bromide and 6.17 g (0.055 mol) of potassium tertiary butylate to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:19]#[N:20])[CH:15]=[C:16]([CH2:18][Br:21])[CH:17]=2)[O:9][N:8]=1
Reactant: Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(CBr)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol), N-bromosuccinimide (0.339 g, 1.91 mmol), and benzoyl peroxide (0.0010 g, 0.04 mmol) in carbon tetrachloride (25 mL) was heated at 80° C. for 18 hours. After this time the reaction mixture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine to afford 0.595 g (91%) of 3-(2-pyridyl)-5-(3-bromomethyl-5-cyanophenyl)-1,2,4-oxadiazole.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].[C:8]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[C:8]1([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]3[NH:4][CH2:5][CH2:6][S:7]3)[CH2:18][CH2:19]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCS
Reactant: O=Cc1ccccc1OCCN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2.21 g of sodium hydroxide are added to a solution of 5.75 g of cysteamine hydrochloride in 200 ml of ethanol, and a solution of 14.28 g of 2-[2-(4-phenylpiperazin-1-yl)ethyloxy]benzaldehyde in 100 ml of ethanol is added thereto. After the mixture is stirred at room temperature for 2 hours, the mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is recrystallized from ether. 15.54 g of 2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine are obtained.
Reaction SMILES: [ClH:1].C(N(CC(O)CNC([C:13]1[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)CC)C.C(N(CC)CC)C.[Cl-].[CH3:38][O:39][C:40](=[O:46])[CH2:41][CH2:42][C:43](O)=[O:44]>C(Cl)Cl>[ClH:1].[CH3:38][O:39][C:40]([CH2:41][CH2:42][C:43]([O:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:13]=1)=[O:44])=[O:46]
Reactant: CCN(CC)CC(O)CNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Oc1cn(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride (0.005 mole) are mixed in 25 ml of methylene chloride with 0.7 ml triethylamine (0.005 mole) and 0.6 ml of succinic acid methylester chloride and the reaction mixture agitated for 1 h at room temperature. The solution is then washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated. The residue is purified by low pressure chromatography using methylene chloride as the elution agent, as described in Example 3. 2-[3-N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-methoxycarbonylethylcarbonyloxy-1-phenylindole hydrochloride is obtained as an oily product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.Br[CH:16](Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[CH2:17][CH2:16][S:11]1
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 110 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)thiourea (6.1 g), dibromoethane (5.7 g) and anhydrous potassium carbonate (11.5 g) in acetone (60 ml) was refluxed for 1 day. The solvent was removed by distillation therefrom, and the residue was extracted with ethyl ether, washed with water, dried over anhydrous magnesium sulfate and subjected to column chromatography to give 7.5 g of 2-imino-3-(3-trifluoromethylphenyl)thiazolidine. The thus obtained 2-imino-3-(3-trifluoromethylphenyl)thiazolidine (1.0 g), n-butyl chlorocarbonate (0.61 g) and triethylamine (1.2 g) were dissolved in tetrahydrofuran, and the resultant solution was stirred at room temperature for 5 hours. The solvent was removed, and the residue was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.57 g of 2-butoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:25][C:26](OC(C)(C)C)=[O:27])[C:10](=[O:24])[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.CCN(C(C)C)C(C)C.[N:43]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][C@H:44]1C(O)=O.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:25][C:26]([C@@H:44]2[CH2:45][C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:52][N:43]2[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[O:27])[C:10](=[O:24])[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
tert-Butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)-piperazinyl]ethyl}carbamoyl)-(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)piperazinyl]ethyl}(tert-butoxy) carboxamide (Step 1) (270 mg, 0.58 mmol) according to the procedure used for Example 93, Step 2 using 25 mL HCl satd EtOAc, for the first step, then DIEA (100 μl, 0.574 mmol), Boc-L-Tic-OH (82 mg, 0.296 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (101 mg, 0.340 mmol), and HOAT (50 mg, 0.367 mmol) for the second step (139 mg). MS (ESI, pos. ion) m/z: 618 (M+H), (ESI, neg. ion) m/z: 616 (M−H). Calc'd for C34H40ClN5O4: 618.17.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:17]12CC(C=C1)C=[CH:18]2>O1CCOCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][N:1]3[CH:18]=[CH:17][N:3]=[N:2]3)[O:9][N:8]=2)=[CH:11][CH:12]=1
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)cc2)=NO1
Solvent: C1COCCO1
Product: Brc1ccc(C2=NOC(Cn3ccnn3)C2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
5-Azidomethyl-3-(4-bromo-phenyl)-4,5-dihydro-isoxazol (12.3 g, 43.6 mmol) and bicyclo[2.2.1]hepta-2,5-diene (23.6 ml, 218.1 mmol) were added to dioxane (200 ml), heated to 100° C. and stirred for six hours. The reaction mixture was concentrated in vacuo followed by addition of ethyl ether (200 ml). The precipitate was collected and washed with ethyl ether (3×20 ml) and dried under nitrogen to give the desired product (8.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=1)[C:15](O)=[O:16])([O-:3])=[O:2].[NH:43]([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:54]([O:53][C:51](=[O:52])[CH2:50][N:43]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:15](=[O:16])[C:14]1[CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:40]=[CH:41][CH:42]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:13]=1)[CH3:55]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2cccc([N+](=O)[O-])c2)cc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2cccc([N+](=O)[O-])c2)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.6 %

Procedure:
A solution of 4.0 g (6.83 mmol) of 3-[3-(3-nitrophenoxy)propoxy]-5-(octadecyloxy)benzoic acid in 65 ml of thionyl chloride was stirred at reflux for 2.5 hours. The excess thionyl chloride was removed at reduced pressure and the residual solid acid chloride was dissolved in 75 ml of methylene chloride and added dropwise to a stirred, ice bath cooled solution of 1.5 ml of diethyl iminodiacetate (8.5 mmol) and 1.9 ml (13.7 mmol) of triethylamine in 25 ml of methylene chloride. The reaction mixture was stirred in the cooling bath for 30 minutes, at room temperature for 20 hours and then was washed with NaHCO3 solution. The dried organic layer was concentrated at reduced pressure to an oil which was purified by HPLC using 25% ethyl acetate-hexane to give 4.32 g (84% yield) of N-(2-ethoxy-2-oxoethyl)-N-[3-[3-(3-nitrophenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine ethyl ester as an oil. The structure was confirmed by the nmr and mass spectra.
Reaction SMILES: [C:1]1([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH2:32]([NH:38][C:39]([NH:41][C:42]1[CH:47]=[CH:46][N:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]O)[C:44](=[O:55])[N:43]=1)=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH2:32]([NH:38][C:39](=[O:40])[NH:41][C:42]1[CH:47]=[CH:46][N:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:1]2[C:14]3[C:15]4=[C:16]5[C:11](=[CH:12][CH:13]=3)[CH:10]=[CH:9][CH:8]=[C:7]5[CH:6]=[CH:5][C:4]4=[CH:3][CH:2]=2)[C:44](=[O:55])[N:43]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)CCCc1ccc2ccc3cccc4ccc1c2c34
Reactant: CCCCCCNC(=O)Nc1ccn(CCCCCCO)c(=O)n1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCNC(=O)Nc1ccn(CCCCCCOC(=O)CCCc2ccc3ccc4cccc5ccc2c3c45)c(=O)n1
Reaction time: 1 h

Procedure:
To a solution of pyrene butyric acid (commercially available) (0.05 g, 0.17 mmol) in CH2Cl2 (5 ml) was added at 0° C., dicyclohexylcarboimide (0.044 g, 0.210 mmol) and dimethylaminopyridine (4 mg). The mixture was stirred for 1 h. 1-Hexyl-3-[1-(6-hydroxy-hexyl)-2-oxo-1,2-dihydro-pyrimidinyl]-urea) (J) was then added to the mixture and the solution was stirred at room temperature for 16 h. The solid was filtered off and the filtrate washed with water (2×10 ml) then saturated sodium chloride solution (5 ml). The organic phase was then dried (MgSO4) and the solvent evaporated in vacuo. The crude solid was purified using flash silica gel chromatography using a gradient: 1) (CHCl3) 2) (CHCl3/EtOAc, 5:1) and 3) (CHCl3/EtOAc/Et3N, 5:1:0.2). 4-Pyren-1-yl-butyric acid 6-[4-(3-hexyl-ureido)-2-oxo-2H-pyrimidin-1-yl]-hexyl ester (K) was obtained as a yellow solid (0.025 mg, 23%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:38]#[N:39])[NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[NH:25][C:26]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]([CH:15]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]([C:28]1[N:29]([CH3:37])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:18])[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:39]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CC2CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CC2CCNCC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 4-[2-cyano-2-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 2.24 mmol) in 20 mL of CH2Cl2, was added TFA (4.0 mL, 52 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, concentrated, poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried with sodium sulfate, and concentrated to give 541 mg (55%) of 1-methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(cyano-piperidin-4-ylmethyl-methyl)-carbamoyl]-cyclohexyl}-amide as a pale-yellow amorphous material. MS: 436 (M+H+).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:16]=[C:15]([C:25](OCC)=[O:26])[C:14]=2[CH3:30])=[CH:9][CH:8]=1.Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1>[CH3:35][O:34][N:33]([CH3:32])[C:25]([C:15]1[C:14]([CH3:30])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:16]=1)=[O:26]
Reactant: CNOC
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
Isopropylmagnesium chloride (15 ml, 30 mmol) was added dropwise over a 10 to 15 minute period to a stirred solution of ethyl 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (8.15 g, 21.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) in THF at −25° C. After stirring for an additional 15 minutes at −25° C., the reaction mixture was quenched with saturated aqueous NH4Cl and then extracted with methyl-tert-butyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound I-1a as a golden oil (8.76 g).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:17])[NH:7]1.C[O:20][C:21](=[O:36])[CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1.Cl>[OH-].[Na+]>[O:29]=[C:26]1[NH:25][CH:24]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][C:21]([OH:36])=[O:20])[CH2:28][CH2:27]1.[O:17]=[C:8]1[NH:7][CH:6]([CH2:5][CH2:4][C:3]([OH:18])=[O:2])[CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9]1
Reactant: COC(=O)CC(c1ccccc1)C1CCC(=O)N1
Reactant: COC(=O)CCC1NC(=O)CC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(c1ccccc1)C1CCC(=O)N1
Product: O=C(O)CCC1NC(=O)CC1c1ccccc1

Procedure:
A solution of 93.4 g of 5-oxo-3-phenyl-2-pyrrolidinepropanoic acid methyl ester and 5-oxo-β-phenyl-2-pyrrolidinepropanoic acid methyl ester in 370 ml of 1N aqueous sodium hydroxide solution is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (1 N, 370 ml) is added and the solution is concentrated under reduced pressure to yield 5-oxo-β-phenyl-2-pyrrolidinepropanoic acid and 5-oxo-3-phenyl-2-pyrrolidinepropanoic acid. The acids are dissolved in 300 ml of acetic anyhydride and the solution heated to 90° C. The solution is filtered hot and the filtrate concentrated in vacuo. The oil is chromatographed on silica gel (200-400 mesh) to give cis- and trans-dihydro-1-phenyl-1H-pyrrolizine-3,5(2H,6H)-diones as a white solid with mp 151°-3° C.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.CN(P(N(C)C)(N(C)C)=O)C.[S:24]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25]1.CON(C)[C:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[O:36]>C1COCC1>[C:35]([C:25]1[S:24][CH:28]=[CH:27][C:26]=1[C:29]([OH:31])=[O:30])(=[O:36])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: O=C(O)c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccsc1C(=O)c1ccncc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
n-BuLi (23.2 mL, 56.2 mmol, 2.5M in THF) was added dropwise to a solution of diisopropylamine (5.2 g, 51.5 mmol) in anhydrous THF (40 mL) at −30° C. The mixture was stirred at the same temperature for 0.5 h and then cooled to −78° C. and HMPA (0.8 g, 4.7 mmol) was added slowly. Then a solution of thiophene-3-carboxylic acid (3.0 g, 23.4 mmol) in anhydrous THF (50 mL) was added slowly. The mixture was stirred at the same temperature for 1 h. Then N-methoxy-N-methyl-4-pyridinecarboxamide (5.0 g, 46.9 mmol) was added dropwise to the stirring mixture at −78° C. The reaction mixture was stirred for another 1 h at room temperature and was then quenched with H2O (10 mL). The aqueous layer was acidified with 5% aq. HCl to pH 1-2 and the resulting precipitate collected by filtration. The filter cake was washed with DCM and the filtrate was extracted with DCM (3×200 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with DCM to give the title product (2.2 g, 40% yield) as a white solid. LC-MS (Method A): m/z 234 (M+H)+, Rt: 0.57 min.
Reaction SMILES: [Cl-].[Cl:2][C:3]([Cl:21])([Cl:20])[CH:4]1[O:9][CH:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[C:7]2[CH:14]=[C:15]([N+]#N)[CH:16]=[CH:17][C:6]=2[O:5]1.S(=O)(=O)(O)[OH:23]>O>[OH:23][C:15]1[CH:16]=[CH:17][C:6]2[O:5][CH:4]([C:3]([Cl:21])([Cl:20])[Cl:2])[O:9][CH:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[C:7]=2[CH:14]=1
Reactant: O=S(=O)(O)O
Reactant: N#[N+]c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: [Cl-]
Solvent: O
Product: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 160 °C

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-diazonium chloride (5 g.) concentrated sulphuric acid (125 ml.) and water (125 ml.) was stirred and heated at 160° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and the product was filtered off, washed with water, and crystallised from cyclohexane, to give 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 167°-169° C.