Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][CH3:15])[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Product: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
To a solution of 3-ethylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.33 g, 1.5 mmol) in DMF (5.0 mL) was added drop wise a solution of 4-chlorophenyl isocyanate (0.23 g, 1.51 mmol) in DMF (2.5 mL) at room temperature and the resulting mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified on silica using hexane/ethyl acetate (50%) followed by ethyl acetate (100%) to give the desired product as white foamy solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[N:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[O:20][C:21]([CH2:24][N:25]([CH3:32])[C:26](=[O:31])[C:27]([Cl:30])([Cl:29])[Cl:28])=[CH:22][CH:23]=1)OC1C=CC=CC=1)(=[O:4])=[O:3].[CH:33]1[C:38]([C@@H:39]([OH:42])[CH2:40][NH2:41])=[CH:37][CH:36]=[C:35]([OH:43])[CH:34]=1.C([O-])(=O)C.[K+].Cl>O.C(OCC)(=O)C.C(N(CC)CC)C.C(#N)C>[OH:42][CH:39]([C:38]1[CH:37]=[CH:36][C:35]([OH:43])=[CH:34][CH:33]=1)[CH2:40][NH:41][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[O:20][C:21]([CH2:24][N:25]([CH3:32])[C:26](=[O:31])[C:27]([Cl:28])([Cl:29])[Cl:30])=[CH:22][CH:23]=1
Reactant: NC[C@H](O)c1ccc(O)cc1
Reactant: CN(Cc1ccc(CSCCN=C(NS(C)(=O)=O)Oc2ccccc2)o1)C(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(CSCCN=C(NCC(O)c2ccc(O)cc2)NS(C)(=O)=O)o1)C(=O)C(Cl)(Cl)Cl
Yield: 82.7 %

Procedure:
To 160 ml of acetonitrile were added 32.6 g of N-methanesulfonyl-N'-[2-[[5-[N-methyl-N-(trichloroacetyl)aminomethyl]-2-furyl]methylthio]ethyl]-O-phenylisourea, 13.8 g of DL-octopamine, 21 ml of triethylamine and 2.94 g of potassium acetate. The mixture was refluxed for 1 hour in a nitrogen atmosphere. After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 250 ml of ethyl acetate and 150 ml of water. The mixture was adjusted to pH 2.0 with 2N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: benzene:ethyl acetate=1:2) to obtain 29.9 g (yield: 83%) of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-methanesulfonyl-N"-[2-[[5-[N-methyl-N-(trichloroacetyl)aminomethyl]-2-furyl]methylthio]ethyl]guanidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:21][C:22]1(C)OC(=O)CC(=O)[O:23]1.Cl.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:22](=[O:23])[CH2:21][C:14](=[O:16])[CH2:13][C:9]21[CH2:10][CH2:11][CH2:12]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC(=O)CC12CCC2

Procedure:
(1-tert-Butoxycarbonylamino-cyclobutyl)-acetic acid (6 g; 26 mmol) (Eur.J.Med.Chem. 34 (1999) 363), EDC (7.5 g; 39 mmol) DMAP (4.8 g; 39 mmol) and Meldrum's acid (3.77 g; 26 mmol) in CH2Cl2 (120 ml) are stirred at room temperature over night and poured on 2N HCl/water (40 ml/400 ml). The aqueous phase is extracted with CH2Cl2 twice, the organic phases are combined and dried over Na2SO4 and evaporated to dryness. The orange-colored residue is taken up in ethyl acetate (200 ml) and refluxed for 2.5 hours, diluted with hexanes (600 ml) and purified via chromatography (SiO2; Hexanes/acetone 92:8) yielding the title compound as yellowish crystals in a modest purity, which is sufficient to perform the next steps.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[O:6])[CH2:3][CH2:2]1.Cl>[OH-].[Na+].O>[CH:1]1([N:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[N:8][NH:7][C:5]2=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NNC(=O)c1ccc(F)cc1F)NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]nc(-c2ccc(F)cc2F)n1C1CC1

Procedure:
1.00 g (3.92 mmol) of N-cyclopropyl-2-(2,4-difluorobenzoyl)-hydrazinecarboxamide from Example 5A are heated under reflux in 4 ml 4 N aqueous sodium hydroxide for 28 hrs. After cooling, it is acidified to about pH 2 with 2 N hydrochloric acid, diluted with water and extracted four times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered, concentrated and the residue dried in vacuo. 0.415 g (31% of theory) of the target compound are thus obtained, which is further reacted as such.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][NH:6][C:7]([C:9]1[C:10]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:11]=2[S:12][C:13]=1[CH3:14])=[O:8]>C(Cl)Cl>[CH3:5][NH:6][C:7]([C:9]1[C:10]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:11]=2[S:12][C:13]=1[CH3:14])=[O:8]
Reactant: CNC(=O)c1c(C)sc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)c1c(C)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
A 1.0 M solution of BBr3 in CH2Cl2 (6 ml, 6 mmole) was added to a solution of 6-methoxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide 1c (683 mg, 2.9 mmole) in CH2Cl2 (60 ml) at 0°. The reaction was left stirring for 14 hours, gradually warming to ambient temperature, then poured onto crushed ice (˜70 g). The layers were separated and the aqueous phase was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 623 mg (97%) of a beige solid which was employed without further purification. 1H NMR (DMSO-d6) δ9.56 (1H, s), 8.11 (1H, q, J=4.4 Hz), 7.53 (1H, d, J=8.7 Hz), 7.18 (1H, d, J=2.3 Hz), 6.83 (1H, dd, J=2.3, 8.7 Hz), 2.79 (3H, d, J=4.4 Hz), 2.50 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=[O:25])[C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=[O:25])[C:18]([CH3:23])([O:24][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])[C:19]([F:22])([F:21])[F:20])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(O)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC(C)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-amino-6-bromo-W-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-5-(trifluoromethyl)picolinohydrazide (step 1) (4 g, 9.11 mmol) in DCM (60 ml), triethylamine (1.270 ml, 9.11 mmol) was added to give a yellow solution. The solution was cooled to 0° C. (ice bath) and treated with triisopropylsilyl trifluoromethanesulfonate (4.94 ml, 18.22 mmol). The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to RT and stirred for 3 days. The reaction mixture was partitioned between DCM (100 ml) and water (100 ml), phases shaken and separated. The organic portion was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo. The resulting oil was purified by chromatography on silica eluting with 0-30% DCM in iso-hexane to afford the title compound; LC-MS Rt=1.58 min [M+H]+ 595/597 Method 2minLC_v003.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([B:10]2[O:14][C:13](C)(C)C(C)(C)[O:11]2)=[C:6]([CH:9]=1)C=O.[BH4-].[Na+].O.Cl>CO>[B:10]1([OH:11])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:9][C:6]=2[CH2:13][O:14]1
Reactant: CC1(C)OB(c2ccc(O)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OB1OCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (5.5 g, 22 mmol, 1.0 equiv) in methanol (25 mL). This was followed by the addition of NaBH4 (1.24 g, 32.6 mmol, 1.5 equiv) in several batches at 0° C. The resulting solution was stirred for 10 min at 0° C., then it was concentrated under vacuum to get rid of half methanol at low temperature. To the residual solution was added water (6 mL) and HCl (6M, 14.5 mL) dropwise at 0° C. The resulting solution was stirred overnight at room temperature. Then it was concentrated under vacuum at low temperature to remove MeOH. The solid was collected by filtration. This resulted in 2.0 g of benzo[c][1,2]oxaborole-1,5(3H)-diol as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:15][C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Into a 500-ml four-necked flask were poured 61.8 g (0.163 mole) of ethyl (3R)-5-benzyloxycarbonylamino-3-(2-tetrahydropyranyloxy)pentanoate (2-b) obtained by the above process A and 124 ml of methanol. Then, the contents of the flask were cooled with ice. Furthermore, 72 ml of a 10 wt% aqueous sodium hydroxide solution were added to the contents, and the contents were allowed to completely hydrolyze for 2 hours at the same temperature. Into the solution was added 90 ml of water, and the aqueous mixture was extracted with two 75 ml portions of butyl acetate. 125 ml of toluene and 100 ml of a 5 wt % aqueous hydrochloric acid solution were added to the aqueous layer to thereby adjust the pH to 4.5. The toluene layer was washed with a saturated sodium chloride solution and then dried with magnesium sulfate. After removing the solvent by distillation, 46.9 g (82% yield) of the intended oily product was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([OH:28])=[CH:14][C:13]=1Cl.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.CN1CCCC1=O>[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([OH:28])=[CH:14][C:13]=1[O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH2:6][CH2:7][CH3:8]
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: CCCC(O)C(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCCC(O)C(C)(C)COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O

Procedure:
90 parts of 2,2-dimethyl-1,3-hexanediol, 27.3 parts of 1-amino-4-hydroxy-2-chloroanthraquinone, 45 parts of N-methylpyrrolidone, 9.4 parts of phenol and 12 parts of potassium carbonate are heated for 5 hours at 130°C and 8 hours at 140°C under nitrogen. When cold, the mixture is diluted with 140 parts of methanol and filtered. The filtrate is diluted with water. 21 parts of 1-amino-2-(2',2'-dimethyl-3'-hydroxyhexoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[C:31]([CH3:33])[CH:32]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:29]3[CH:30]=[C:31]([CH3:33])[CH:32]=[C:27]([CH3:26])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1cc(C)cc([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3,5-dimethylphenylmagnesium bromide. Yield: 66 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.7 min.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:14]=[CH:13][C:12]=1[O:21][CH3:22])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>O>[C:24]([NH:18][S:17]([C:15]1[CH:14]=[CH:13][C:12]([O:21][CH3:22])=[C:11]([CH:16]=1)[C:10]([NH:9][CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH2:1][CH3:2])=[O:23])(=[O:19])=[O:20])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Solvent: O
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC(C)=O)ccc1OC

Procedure:
A solution of N-(1-Ethyl-pyrrolidin-2-ylmethyl)-2-methoxy-5-sulfamoyl-benzamide, acetic anhydride and triethylamine are reacted at room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer is dried, filtered and concentrated under vacuum, and the residue recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([OH:24])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[C:5]1=[O:25])(=[O:3])[CH3:2].[CH2:26](N(C(C)C)C(C)C)C.F[B-](F)(F)F.C[O+](C)C>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([O:24][CH3:26])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[C:5]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc3c(c2)OCO3)c2ccc(Cl)cc21
Reactant: CCN(C(C)C)C(C)C
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
A solution of 20.9 g of 1-acetyl-6-chloro-3-[1-hydroxy-1-(3,4-methylenedioxyphenyl)-methylene]-2-indolinone and 40 ml of ethyldiisopropylamine in 200 ml dichloromethane is combined batchwise with 17.3 g of trimethyloxonium tetrafluoroborate, the mixture is stirred overnight and then extracted twice with water. The organic phase is dried with magnesium sulphate and evaporated to dryness. The residue is stirred with methanol, suction filtered, washed with methanol and dried at 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:17][NH:16][C:15](=[O:18])[N:14]1[CH3:19])=[O:12].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(=O)([O-])O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:17][N:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:15](=[O:18])[N:14]1[CH3:19])=[O:12]
Reactant: Brc1cccnc1
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1C(=O)N(c2cccnc2)CC1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A solution of N-[(2-chloro-4-fluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (28.6 mg, 0.1 mmol) (prepared as described in Example 29) and 3-bromopyridine (15.8 mg, 0.1 mmol) in 1,4-dioxane (3 ml) was treated with cesium carbonate (81 mg, 0.25 mmol), Xantphos™ (4.3 mg, 0.075 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 0.025 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The resulting residue was triturated with ether, the solid collected and dried to give N-[(2-chloro-4-fluorophenyl)methyl]-3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxamide (18 mg, 50%). LC/MS [M+H]+=363, retention time 1.68 minutes.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:31]2[CH:36]=[CH:35][C:34]([O:37]C(=O)C)=[CH:33][CH:32]=2)[C:12]2[CH:30]=[CH:29][CH:28]=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[O:15])=[CH:7][CH:6]=1)(=O)C>C(=O)([O-])O.[Na+].CO>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[C:12]2[CH:30]=[CH:29][CH:28]=[CH:27][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[O:15])=[CH:32][CH:33]=1
Reactant: COc1ccc(NC(=O)c2ccccc2C(c2ccc(OC(C)=O)cc2)c2ccc(OC(C)=O)cc2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(NC(=O)c2ccccc2C(c2ccc(O)cc2)c2ccc(O)cc2)c(OC)c1
Yield: 56 %

Procedure:
In a mixture of 50 ml of saturated aqueous sodium hydrogencarbonate solution and 50 ml of methanol was suspended 2.6 g of Compound 2 prepared in Example 1, and the suspension was heated under reflux for 30 minutes. The resulting mixture was concentrated under reduced pressure, and water was added to the residue. The resulting mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized to afford 1.23 g of the desired product.
Reaction SMILES: [F:1][C:2]([N+:11]([O-:13])=[O:12])([N+:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5](Cl)=[O:6].[F:14][C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([NH:18][NH2:19])=[O:17].N1C=CC=CC=1.Cl>C(OCC)C>[F:1][C:2]([N+:11]([O-:13])=[O:12])([N+:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5]([NH:19][NH:18][C:16](=[O:17])[C:15]([F:14])([F:24])[C:20]([F:22])([F:23])[F:21])=[O:6]
Reactant: NNC(=O)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)CCC(F)([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCC(F)([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a solution of 0.95 g (0.0045 mole) of 4-fluoro-4,4-dinitrobutyryl chloride in 20 mL of anhydrous diethyl ether stirred at 20° C. was added 0.8 g (0.0045 mole) of N-(perfluoropropionyl)hydrazine followed by the dropwise addition of 0.4 mL of pyridine. After 5 minutes, dilute hydrochloric acid (10 mL) was added, the ether layer was separated, dried (Na2SO4) and the volatiles were removed to give the product N-(4-fluoro-4,4-dinitrobutyryl)-N'-(perfluoropropionyl)hydrazine, 1.05 g, mp 128°-132° C. Crystallization from 1,2-dichloroethane gave 0.93 g (58%), mp 135°-136° C. 1H NMR (acetone d6 +D2O): 2.80 (t, 2H), 3.36, 3.58 (d of t, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:15][N:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:33][CH3:34]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:33][CH3:34])[C:12]1([CH2:15][N:16]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)CN(CC1(NC(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC1(N(CC)C(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C
Reaction time: 0.67 h

Procedure:
To a solution of ethyl N-[(1-{[(benzyloxy)carbonyl]amino}cyclopropyl)methyl]-N-(tert-butoxycarbonyl)glycinate (1.6 g, 3.94 mmol) in DMF (23 mL) at 0° C. under an atmosphere of nitrogen was added NaH (60% dispersion in oil, 19 mg, 7.87 mmol). The mixture was stirred for 40 min until gas evolution ceased. To the reaction was added iodoethane (346 μL, 4.33 mmol), followed stirring at room temperature for 3 h. The reaction was quenched with water, and DMF was removed in vacuo. The resulting aqueous mixture was extracted twice each with EtOAc and CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford a pale yellow, sticky solid. The crude product was subjected to column chromatography eluting with a gradient of 0-50% EtOAc/hexanes. Collection and concentration of the appropriate fractions afforded the product as a colorless oil.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>COCCO>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(CCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 18.6 parts of 2,2-diphenyl-4-bromobutyronitrile, 10.0 parts of 4-phenylpiperidine, 8.0 parts of N,N-diisopropylethylamine and 200 parts by volume of 2-methoxyethanol is heated at reflux for 16 hours. The solution is then cooled and stripped in vacuum. The resulting residue is partitioned between dilute sodium hydroxide and ether. Extraction of the ether phase with dilute hydrochloric acid results in the precipitation of an oil. This oil and the aqueous phase of the partitioning are combined, treated with aqueous sodium hydroxide and extracted with 1:1 ether-benzene mixture. The ether-benzene extract is dried over sodium sulfate and stripped in vacuum to give a solid. Crystallization of the solid from a mixture of skelly B and ether provided 2,2-diphenyl-4-(4-phenylpiperidino)butyronitrile, melting at 88° - 89.5° C. and having the following formula ##STR7##
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:11][C:12]1[S:16][C:15]([CH:17]2[S:23][CH2:22][CH2:21][NH:20][C:19](=O)[CH2:18]2)=[CH:14][CH:13]=1>C(OCC)C.C1COCC1>[Br:11][C:12]1[S:16][C:15]([CH:17]2[S:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=1
Reactant: O=C1CC(c2ccc(Br)s2)SCCN1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1ccc(C2CCNCCS2)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
Aluminum chloride (22.9 g) was added to a suspension of lithium aluminum hydride (19.5 g) in diethyl ether (400 ml) under ice-cooling and a nitrogen atmosphere, and the mixture was stirred for 20 minutes. After a suspension of 7-(5-bromo-2-thienyl)perhydro-1,4-thiazepin-5-one (75 g) in THF (500 ml) was added therein under the same condition, the reaction mixture was stirred at room temperature for 2 hours, poured into ice water and extracted with ethyl acetate (1500 ml). The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 7-(5-bromo-2-thienyl)perhydro-1,4-thiazepine (60.5 g) as a solid.