Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][C@:11]([CH2:17][O:18][CH2:19][CH3:20])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[CH2:19]([O:18][CH2:17][C@:11]1([C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:26]=[C:25]([C:24]([F:38])([F:23])[F:37])[CH:30]=[CH:29][N:28]=3)[CH2:32][CH2:33]2)=[O:16])[CH2:12][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)[CH3:20]
Reactant: CCOC[C@]1(C(=O)O)CCC(NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
(1S)-3-[(tert-Butoxycarbonyl)amino]-1-(ethoxymethyl)cyclopentanecarboxylic acid (429.4 mg, 1.494 mmol), 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (500.0 mg, 1.644 mmol), triethylamine (0.833 mL, 5.98 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (850.3 mg, 2.242 mol) (HBTU) were mixed in dry DMF (10.2 mL). The resulting brown solution was stirred at room temperature under N2 overnight. The reaction mixture was diluted with CH2Cl2 and washed with saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 four times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography to provide the desired product (304.4 mg, 40%). MS calculated for C24H36F3N4O4: (M+H) 501.3; found 501.3.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23]C[CH:25]1[CH2:30][CH2:29][CH2:28][O:27][CH2:26]1.[CH3:31]C#N>>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:31][CH:26]3[CH2:25][CH2:30][CH2:29][CH2:28][O:27]3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: CC#N
Reactant: BrCC1CCCOC1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CC3CCCCO3)(CC1)CC2
Product: [Br-]
Yield: 50.8 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0677 g, 0.231 mmol) and 3-(bromomethyl)tetrahydro-2H-pyran (0.050 mL, 0.390 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0508 g, 50.8%). EI-MS m/z 392 (M+) Rt (1.84 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].O[CH2:11][CH:12]([CH2:14]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([CH:11]=[CH:12][CH:14]=[N:6]2)=[CH:8][CH:9]=1
Reactant: OCC(O)CO
Reactant: COc1cccc(N)c1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: COc1ccc2cccnc2c1
Yield: 13.2 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-methoxyaniline (1.0 g, 8.12 mmol), glycerol (2.32 g, 25.2 mmol), 3-nitrobenzenesulfonic acid sodium salt (2.4 g, 10.6 mmol) and H2SO4/H2O (6 ml, 7:5) gave the title compound (170 mg, 14%) after purification by column chromatography with n-hexane/EtOAc (17:3) as the eluent.
Reaction SMILES: CO[CH:3]([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][CH:17]=[CH:16][O:15]1.[C:20](=O)([O-])[O-:21].[K+].[K+]>[Cl-].[Cl-].[Zn+2].O>[CH3:12][O:13][CH:14]1[CH:19]([CH:3]([O:10][CH3:11])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH:16]([O:21][CH3:20])[O:15]1
Reactant: O=C([O-])[O-]
Reactant: COC(OC)c1ccccc1
Reactant: COC1CCC=CO1
Agent: [Cl-]
Agent: [K+]
Agent: [Zn+2]
Solvent: O
Product: COC1CCC(C(OC)c2ccccc2)C(OC)O1
Temperature: 25 °C

Procedure:
152 g. (1.0 mole) benzaldehyde dimethyl acetal was combined with 3 g. ZnCl2. While stirring and cooling to 25° C., 114 g. (1 mole) 2-methoxy-2,3-dihydro-4H-pyran was added. After stirring for an hour, the catalyst was neutralized by the addition of 15 g. potassium carbonate in 30 ml. water. The mixture was then extracted with ether and the combined ether extracts were washed with water and dried over sodium sulfate. After the removal of the solvent, the residue was distilled in vacuo to give the title compound; b.p. 120°-128° C. (0.6 mm). Yield: 243 g. (91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:28])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[N+](=[CH2:31])=[N-]>CO.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:28])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:27]=[CH:26][CH:25]=[C:19]([O:20][CH2:21][C:22]([O:24][CH3:31])=[O:23])[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (2R)-(3-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy)acetic acid (trans-H) obtained in Example 46 (1.0 g) in methanol (10 ml) there was added an excess of diazomethane in ether solution, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure, separation and purification by silica gel column chromatography (ethyl acetate:hexane=5:l) gave 0.91 g of (1R)-1-(3-chlorophenyl)-2-[3-(3-methoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol (88% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Br:7].C1([P:19](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br-:7].[CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][PH3+:19]
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cccc(C[PH3+])c1
Product: [Br-]
Yield: 163.7 %

Procedure:
A solution of 730 mg (3.00 mmol) of m-trimethylsilylbenzyl bromide and 1.18 g (4.50 mmol) of triphenylphosphine in 10 ml of dry toluene was refluxed for 4.5 hours in an atmosphere of argon (125°-135° C. by oil bath). The precipitate was collected by filtration, and washed with toluene to give 1.361 g of white crystals, which were dried in vacuo (yield 90%).
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.Br[CH:33]([CH3:44])[C:34]([O:36][CH2:37][CH2:38][NH:39][C:40](=[O:43])[O:41][CH3:42])=[O:35].C(=O)([O-])[O-:46].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:46][CH:33]([CH3:44])[C:34]([O:36][CH2:37][CH2:38][NH:39][C:40](=[O:43])[O:41][CH3:42])=[O:35])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: COC(=O)NCCOC(=O)C(C)Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)NCCOC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture consisting of 2.8 g of hydroquinone monobenzyl ether, 3.56 g of methyl 2-(2-bromopropionyloxy)ethylcarbamate, 3.87 g of potassium carbonate and 30 ml of acetone is heated at reflux for 2 hours while stirring. The cooled mixture is filtered and the filtrate is evaporated. After flash chromatography, the residue gives pure methyl 2-[[2-(4-benzyloxyphenoxy)propionyl]oxy]ethylcarbamate of melting point 79°-81° C. 1.0 g thereof is dissolved in 100 ml of ethyl acetate and hydrogenated in the presence of 0.1 g of 5% palladium-on-carbon. After shaking for 45 minutes, the hydrogen uptake has finished. The catalyst is filtered off and the solvent is removed on a rotary evaporator. There is obtained methyl 2-[[2-(4-hydroxyphenoxy)propionyl]oxy]ethylcarbamate; nD20 1.5003.
Reaction SMILES: [CH2:1]([CH:9]1[C:13](=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:12](=[O:24])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1([Se][Cl:32])C=CC=CC=1.[H][H].Cl>ClCCl.O.N1C=CC=CC=1>[Cl:32][C:11]1[C:12](=[O:24])[C:13](=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=1
Reactant: CCCCCCCCC1C=CC(=O)C1=CCCCCCC(=O)OC
Reactant: Cl[Se]c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC1C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Yield: 0.1 %

Procedure:
17 mg (51 mmol) of 4-octyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone was dissolved in 1 ml of dichloromethane and 23 μl (280 μmol) of pyridine was added thereto. With stirring, 49 mg (254 mmol) of phenyl selenium chloride was added to the mixture and the reaction mixture was refluxed. 10 hours later, 23 μl (280 mmol) of pyridine and 49 mg (254 mmol) of phenyl selenium chloride were further added and the mixture was refluxed for 25 hours. 0.5 ml of pyridine was added to the reaction mixture and then, with vigorous stirring, 35% aqueous hydrogen, peroxide was further added and the mixture was stirred for another 1 hour. Hydrochloric acid and water were added thereto for extraction and the aqueous layer was then extracted twice with dichloromethane. The organic layer was washed first with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution and dried over sodium sulfate anhydride. Thereafter, it was filtrated, concentrated, and chromatographed on a column of silica gel (silica gel 5 g; eluent, hexane:ethyl acetate=30:1→10:1) to obtain 10 mg (yield 53%) of 2-chloro-4-octyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.C(N(CC)CC)C.[C:34]1([CH:40]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:41][N:42]([CH3:60])[C:43](=[O:59])[CH:44]([NH:51][CH2:52][CH2:53][C:54]2[N:55]=[CH:56][NH:57][CH:58]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:51]([CH:44]([C:43](=[O:59])[N:42]([CH2:41][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[CH3:60])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:52][CH2:53][C:54]1[N:55]=[CH:56][NH:57][CH:58]=1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(c1ccccc1)N(CCc1c[nH]cn1)C(=O)c1ccccc1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-Benzoylbenzoic acid (0.341 g, 1.51 mmol) was taken up in a 2M solution of oxalyl chloride in methylene chloride (1.5 mL, 3.0 mmol). One drop of N,N-dimethylfornamide was added and the frothy mixture was stirred overnight and concentrated. A solution of the crude 2-benzoylbenzoyl chloride in methylene chloride (4 mL) followed by triethylamine (0.25 mL, 1.8 mmol) was added to the product of step 2 (0.220 g, 0.502 mmol). The mixture was heated at reflux for 2 hours and concentrated. The residue was taken up in 5:1 methanol/1 N aqueous lithium hydroxide (12 mL) and stirred for 1 hour. The reaction was again concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a foamy amber solid. Flash chromatography over silica (methylene chloride/methanol) provided 0.229 g (71%) of product as a foamy pale amber solid: 1H NMR (CDCl3) δ 7.91-6.92 (m, 26H), 6.54-6.39 (m, 1H), 6.34-6.06 (m, 1H), 4.83-4.31 (m, 2H), 3.97-2.82 (m, 3H), 2.70-2.39 (m, 3H), 2.35-2.09 (m, 2H) ppm. MS (ESI) m/z 648 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.Br[CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:19]([S:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCC(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
K2CO3 (1.23 g, 8.92 mmol) was added to a mixture of methyl 4-sulfanylbenzoate (1.00 g, 5.95 mmol), 1-bromo-2-methyl-propane (970 μL, 8.92 mmol), and DMF (10 mL) at rt. The mixture was allowed to stir for 4 h at rt before the solids were filtered off. The solids were washed with ethyl acetate, and then were discarded. The combined filtrates were partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give methyl 4-(isobutylthio)benzoate (82%) as a clear oil. ESI-MS m/z calc. 224.1, found 225.2 (M+1)+. Retention time: 1.59 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:7]1=[O:23].C=O.[B-][C:32]#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([CH:17]2[CH2:18][CH2:19][N:20]([CH3:32])[CH2:21][CH2:22]2)[C:7]1=[O:23]
Reactant: COc1ccc(Cn2c(=O)n(C3CCNCC3)c3ccc(C#N)cc32)cc1Cl
Reactant: [B-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)n(C3CCN(C)CC3)c3ccc(C#N)cc32)cc1Cl
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a suspension of 3-(3-chloro-4-methoxybenzyl)-1-(piperidin-4-yl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one (91 mg) in methanol (5 mL) were added 37% formaldehyde aqueous solution (220 mg), sodium cyanotrihydroborate (43.2 mg) and acetic acid (5 drops) under nitrogen at ambient temperature. After stirring for 2 hours at same temperature, the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-benzimidazole-2-one (75 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[CH3:14][S:15]([O:18]C)(=[O:17])=[O:16]>C(OCC)(=O)C>[CH3:14][S:15]([O-:18])(=[O:17])=[O:16].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: COS(C)(=O)=O
Reactant: CO[Si](CCCN(C)C)(OC)OC
Solvent: CCOC(C)=O
Product: CO[Si](CCC[N+](C)(C)C)(OC)OC
Product: CS(=O)(=O)[O-]

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 4.0 g of methyl methanesulfonate was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethylamine and methyl methanesulfonate as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropyltrimethylammonium methanesulfonate.
Reaction SMILES: CC1(C)CC(CC(N)[C:10]([NH:12]N)=[O:11])CC(C)(C)N1.[CH3:18][O:19][CH2:20][N:21]=[C:22]=[O:23].[C:24]1(C)C=CC=CC=1>>[CH3:18][O:19][CH2:20][NH:21][C:22]([NH:12][CH2:10][O:11][CH3:24])=[O:23]
Reactant: COCN=C=O
Reactant: CC1(C)CC(CC(N)C(=O)NN)CC(C)(C)N1
Reactant: Cc1ccccc1
Product: COCNC(=O)NCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
36.3 parts of β-(2,2,6,6-tetramethylpiperidin-4-yl)-aminopropionic acid hydrazide were dissolved in 100 parts of toluene, followed by the dropwise addition of 28.2 parts of 93% methoxymethyl isocyanate. After stirring for 1 hour at 25° C., the deposit was filtered off under suction. The filter residue was stirred with 300 parts of petroleum ether and refiltered under suction. 48 parts of colourless crystals melting at 62° to 65° C. were left after drying. C18H36N6O5 (416.5).
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[C:18]([C:21]1[CH:34]=[CH:33][C:24](OCC2C=CC=CC=2)=[CH:23][CH:22]=1)(O)=[O:19]>CCOCC.O>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([O:19][CH2:18][C:21]2[CH:34]=[CH:33][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Ethyl 4-aminobenzoate (8.25g) in a mixture of conc. hydrochloric acid (12.5ml) and water 12.5ml.) at 0°C was diazotised by the addition of sodium nitrite (3.45g). The solution of the diazo compound was added to benzyl alcohol (20g) at 35°C with stirring then stirred at this temperature for 3hr. The reaction mixture was cooled and 4-ethoxycarbonylphenoxy phenyl methane isolated by extraction with ether, m.p. 45°C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[C:30]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[CH:31]=1)=[O:15]
Reactant: O=C(O)Cc1cccc2c(Br)cccc12
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reaction time: 8 h

Procedure:
5-Bromo-1-naphthylacetic acid (Bull. Soc. Chim. Fr 1968, 71, 2957, 4.7 g, 17.8 mmol) in dichloromethane (150 ml) was treated with oxalyl chloride (4.7 ml, 53.4 mmol) and a drop of dimethylformamide under an atmosphere of argon with stirring for 1.5 hours. The reation was then concentrated in vacuo to a gum which was azeotroped with toluene to remove excess oxalyl chloride. The acid chloride was dissolved in dichloromethane (100 ml) and treated with 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP 0533268A 1, 3.9 g, 17.8 mmol,) and triethylamine (2 ml) and the reaction stirred at room temp. overnight. The reaction was washed with saturated aqueous potassium carbonate solution, dried (Na2SO4) and concentrated in vacuo to give the title compound as needles from ethanol (3.7 g, 50%).
Reaction SMILES: CN(C)CCN.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][NH2:16])=[CH:11][CH:10]=1.C(O)(=O)C.[C:21]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[Cl:35][C:33]1[CH:32]=[CH:31][C:30]([NH:36][S:37]([C:40]([F:43])([F:41])[F:42])(=[O:39])=[O:38])=[C:29]([C:21](=[N:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:34]=1
Reactant: NOc1ccc(Cl)cc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOc1ccc(Cl)cc1)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
N,N-Dimethylethylenediamine (82 μL, 0.75 mmol) was added to a suspension of O-(4-chlorophenyl)hydroxylamine hydrochloride (141 mg, 0.51 mmol) in EtOH (15 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (3 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (170 mg, 0.47 mmol) in EtOH (5 mL), and the reaction stirred for 63 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in CH2Cl2 (50 mL), washed with water (twice), brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 3:7) and purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 119 to 1:4) to afford N-{4-chloro-2-[(4-chlorophenoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 164 (140 mg, 61%), as a orange-brown solid. M.p. 86-87° C. 1H n.m.r. (200 MHz, CDCl3) δ 10.99, br s, 1H; 7.73, d, J=8.8 Hz, 1H; 7.54, m, 3H, 7.43-7.27, m, 5H, 7.07, m, 1H, 7.01, m, 2H. O-(4-Chlorophenyl)hydroxylamine hydrochloride was prepared by the procedure described in Example 2C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[CH3:36][CH2:37][O-:38].[Na+].CCO.O>C(O)C>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][O:38][CH2:37][CH3:36])=[CH:4][CH:5]=4)([OH:35])[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOCc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (0.0002 mol), obtained in Example B14, and EtONa/EtOH (0.0005 mol) in ethanol (1 ml) was stirred at room temperature for 18 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.1 g) was purified by column chromatography over kromasil 10 μm (eluent: CH2Cl2/CH3OH; 90/10). The pure fractions were collected and the solvent was evaporated, yielding 0.034 g (33%) of 4-(3-chlorophenyl)-6-[[4-(ethoxymethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:514, 516 (MH+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[O:20]=[C:21]1[C:26](C(Cl)=O)=[CH:25][CH:24]=[C:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:22]1.[CH2:35]([N:37]1[C:49]2[CH:48]=[CH:47][C:46]([NH2:50])=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:26]2[C:21](=[O:20])[O:22][C:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=2)=[O:7])[C@H:9]([C:17]([NH:50][C:46]2[CH:47]=[CH:48][C:49]3[N:37]([CH2:35][CH3:36])[C:38]4[C:43]([C:44]=3[CH:45]=2)=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:19])[CH2:10]1)[CH3:16]
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCCCCc1ccc(C(=O)N2CC(=NOCC)C[C@H]2C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=557.4.