Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][CH2:11][C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:26])([C@@:5]([OH:25])([C:21](=[O:24])CO)[CH2:6][CH2:7]2)[CH2:3]1.I(O)(O)(O)(O)(O)=[O:28]>CO.O>[OH:1][C@@H:2]1[C@H:18]2[C@@H:9]([CH2:10][CH2:11][C:12]3[C@:17]2([CH3:19])[CH2:16][CH2:15][C:14](=[O:20])[CH:13]=3)[C@H:8]2[C@@:4]([CH3:26])([C@@:5]([OH:25])([C:21]([OH:28])=[O:24])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)O
Yield: 81 %

Procedure:
In a 1000 mL round-bottomed flask was suspended (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (10.4 g, 28.69 mmol) in MeOH (200 mL) and a solution of orthoperiodic acid (9.81 g, 43.04 mmol) in water (200 mL) was added to give a colorless solution. The mixture was stirred for 45 minutes after which an additional 3 g of orthoperiodic acid was added and stirring was continued for another hour. MeOH was removed in vacuo and the residual aqueous mixture was diluted with 200 ml of water. The resulting solid was isolated by filtration and was air-dried on the sinter to yield 8.1 g of the desired compound as a white solid. APCI-MS m/z: 349 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:37][CH2:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([O:12][CH2:37][CH2:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NCCO)c1ccccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCCNC(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoic acid (3.95 g, 8.27 mmol), N-(2-hydroxyethyl)[2-(phenylmethoxy)phenyl]carboxamide (1.8 g, 6.63 mmol), and 4-(dimethylamino)pyridine (84 mg) in 40 mL of anhydrous dichloromethane was added slowly 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (2.0 g, 10.34 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice followed by the addition of brine. The organic layer was separated, dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:2 then 1:1.5 ethyl acetate/hexane) of the residue afforded 3.7 g (73%) of 2-{[2-(Phenylmethoxy)phenyl]carbonylamino}ethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:13][C:12]=1[O:32][CH3:33].[NH:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=1>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=2)=[O:20])=[CH:13][C:12]=1[O:32][CH3:33]
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of pentafluorophenyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxy-phenylacetate (314.8 mg, 0.650 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (146.2 mg, 0.619 mmol), Et3 N (103 ul, 0.743 mmol) in DMF (1.5 mL) was stirred for 1 hr at room temp. The mixture was diluted with Et2O, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 2-[[1-[4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a crude pale yellow oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]1([NH:15]N)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[C:4]1(=[O:8])[C:3]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:15][C:2]=2[CH:7]=[CH:6][NH:5]1
Reactant: O=c1cc(O)cc[nH]1
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
4-Hydroxypyridin-2(1H)-one (3 g, 27 mmol) and phenylhydrazine (8.74 g, 81 mmol) in diphenyl ether (54 mL) were heated at 240° C. for 5 hours in a Dean Stark apparatus. The reaction mass was cooled to room temperature, diluted with benzene, stirred for 2 hours and filtered. The solid collected was dried under high vacuum and washed with ether to afford 3 g of the product (60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl: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].I[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N.N>O1CCOCC1.[Cu]I.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:17][N:16]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[C:15](=[O:18])[N:14]1[CH3:19])=[O:12]
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(Cl)cc1Cl
Reactant: Cn1nccc1I
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1C(=O)N(c2ccnn2C)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 15.8 %

Procedure:
To a stirred mixture of N-[(2,4-dichlorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (200 mg, 0.662 mmol) (prepared as described in Example 30), 5-iodo-1-methyl-1H-pyrazole (165 mg, 0.794 mmol) in 1,4-dioxane (20 ml) was added potassium phosphate (703 mg, 3.31 mmol), copper (I) iodide (126 mg, 0.662 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.104 ml, 0.662 mmol) and the reaction mixture was heated at reflux under argon for 18 hours. After cooling to room temperature, ethyl acetate (20 ml), water (10 ml) and 0.880 ammonia solution (5 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The organic extracts were combined, washed with citric acid solution (20 ml), water (10 ml) and brine (10 ml), dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane followed by mass-directed automated HPLC to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-1-(1-methyl-1H-pyrazol-5-yl)-2-oxo-4-imidazolidinecarboxamide (40 mg, 16%). LC/MS [M+H]+=382, retention time=2.12 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Br)c(Oc2ccnc(Cl)c2)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3Br)ccn2)cn1
Temperature: 90 °C
Yield: 52.3 %

Procedure:
A mixture of 5-bromo-4-((2-chloropyridin-4-yl)oxy)-2-fluoroaniline (994 mg, 3.13 mmol), K3PO4 (1.993 g, 9.39 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (716 mg, 3.44 mmol) in DMF (10 mL) and water (1.5 mL) was sparged with Ar, treated with Pd(PPh3)4 (362 mg, 0.313 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (594 mg, 52%). MS (ESI) m/z: (M+H+): 363.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH:11]([OH:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:19])([CH3:20])[CH2:9][C:10]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:11](=[O:13])[CH3:12])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)=O)C(F)(F)F
Reaction time: 20 h
Yield: 71.7 %

Procedure:
1.46 g (4.5 mmol) of 5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)hexane-2,3-diol and 3.14 ml (22.5 mmol) of triethylamine in 16.3 ml of DMSO and 50 ml of methylene chloride are mixed in portions with 4.3 g (27 mmol) of pyridine-sulfur trioxide complex at room temperature. After 20 hours at room temperature, it is hydrolyzed with saturated ammonium chloride solution while being cooled with ice and extracted with diethyl ether. The combined extracts are dried (sodium sulfate) and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 1.04 g of the product.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[O:49]CC1C=CC=CC=1)(=[O:42])=[O:41])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCO.[Pd]>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[OH:49])(=[O:41])=[O:42])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 104.9 %

Procedure:
Methyl 4-(2-{1-benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl ]-5-chloro-1H-indol-3-yl}-ethoxy)-benzoate (0.55 g, 0.70 mmol), (Step 1, Example 184) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml) was hydrogenated. The resulting mixture was filtered through Celite and concentrated. The residue was chromatographed with 35-40% EtOAC/hexane to give the desired product (0.50 g, 95%).
Reaction SMILES: [I:1]Cl.ClCCl.[Cl:6][C:7]1[N:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1>CN1CCCC1=O.N1C=CC=CC=1>[Cl:6][C:7]1[N:8]=[C:9]2[C:15]([I:1])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: Clc1cnc2[nH]ccc2n1
Reactant: ClI
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1cnc2[nH]cc(I)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A 1M solution of iodine chloride in dichloromethane (4 ml, 4 mmol) was added dropwise to an ice-cold solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (4) in N-methylpyrrolidone (residual from previous step) and pyridine (5 ml). The reaction mixture was stirred for 60 minutes at 0° C. and then was concentrated in vacuo. The residue was purified by flash chromatography, using as eluent pentane/EtOAc 0% to 50%, to give the title compound (820 mg, 75% over two steps). 1H NMR (DMSO-d6) 8.2 (lH,s), 8.4 (1H, s). MS(ES+): 280
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C>[CH:3]1([N:2]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CN(Cc1ccccc1)C1CCCCC1

Procedure:
The compound N-cyclohexyl-N-methylbenzylamine was synthesized by treatment of N-methylcyclohexylamine (1) [1.98 ml, 1.70 g, 0.015 moles] with benzyl bromide (2) [1.78 ml, 2.56 g, 0.015 moles] in the presence of potassium carbonate [2.28 g, 1.1 equivalents] in 4-methyl-2-pentanone (50 ml). The reaction mixture was heated under reflux overnight. After filtering the insoluble potassium salts, the filtrate was concentrated to dryness. The solid was dissolved in boiling 4-methyl-2-pentanone, treated with activated carbon, followed by hot filtration after which the purified compound precipitated upon cooling. It was collected by vacuum filtration. m.p. 173.5°-174.5° C. Proton NMR (CDCl3) reported downfield from TMS: 1.11-1.92 ppm multiplet 10 H cyclic alkyl ring, 2.65 ppm singlet 3 H N-methyl, 3.01-3.11 ppm multiplet 1 H tertiary proton, 4.19 ppm singlet 2 H benzylic --CH2 --, 7.44-7.80 ppm 5 H aromatic; C-13 nmr 131.12, 130.19, 129.08, 128.40, 63.11, 55.12, 35.23, 26.37, 25.06, 24.33. EI Mass Spec. M/e-(int) M+203 (28.4), M++1 204 (4.7), M++2 205 (0.2), 160 (70.7), 146 (10.6), 91 (100), 92 (7.1), 85 (5.6), 82 (5.2), 70 (17.6), 65 (24.7), 57 (5.7), 56 (5.3), 55 (15.0), 43 (3.6), 42 (32.3), 41 (20.1).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1.C(OC(C)C)(C)C>CN(C)C=O>[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:23])[NH:1][CH:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:3]2=[O:14])[CH:16]=1
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: Cc1cccc(N=C=O)c1
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)NC2C(=O)Nc3ccccc3NC2=O)c1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of 3-amino-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1.761 g, 9.21 mmol) and m-tolylisocyanate (1.31 g, 10.13 mmol) in dimethylformamide (17 ml) is stirred for 1 hr under ice-cooling. To the reaction mixture is added diisopropyl ether (50 ml) and the resultant crystalline precipitates are filtered off to obtain Compound 5 (2.98 g; yield, 99%). M.p. >300° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:6](=S)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:5].C(O)(=O)C>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:6]3=[N:1][CH2:2][CH2:3][N:4]3[N:5]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:10]=1
Reactant: NCCN(N)C(=S)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NN1CCN=C1N2

Procedure:
A mixture containing 10.0 grams of the intermediate 1-(2-aminoethyl)-N-(2-benzoyl-4-chlorophenyl)-hydrazinecarbothioamide (Example 14) and 200 ml of glacial acetic acid was refluxed for 30 minutes with stirring. The acetic acid was removed in vacuo to leave a yellow oil. The residue was dissolved in methylenechloride, washed with separate rinses of 10% sodium hydroxide and water, and dried with magnesium sulfate. The solvent was evaporated to leave the 8-chloro-2,3-dihydro-6-phenyl-11H-imidazo(2,1-b)(1,3,4)benzotriazepine. The product was recrystallized from isopropanol to yield yellow crystals having a melting point of 191.5° to 193.5° C. Infrared analysis was used to confirm the structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:42]([OH:44])=[O:43])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[CH3:55][C:54]([CH3:57])([CH3:56])[C:53](=[O:58])[CH2:52][O:43][C:42]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1)=[O:44]
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 57.5 °C
Reaction time: 0.67 h

Procedure:
50 mL N,N-dimethylformamide, 5 g of 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester, 1.8 g of anhydrous potassium carbonate and 2.3 mL of 1-bromo-3,3-dimethylbutan-2-one are added into a 3 neck round bottomed flask. The reaction mixture is heated to 55-60° C. and stirred for 20-60 min. After completion of reaction, the mixture is cooled to 25-30° C. and 100 mL of ice water are added. The slurry is stirred at 25-30° C. for about 30 min and filtered. The product is washed with 50 mL demineralized water, then by 20 mL isopropyl alcohol and suck dried for about 30 mins. Finally the product is dried at 35-40° C. under vacuum to yield 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester 3,3-dimethyl-2-oxobutyl ester.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:22]1[C:35]2[C:36]3=[C:37]4[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[C:28]4[CH:27]=[CH:26][C:25]3=[CH:24][CH:23]=1.C(Cl)Cl>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:29]1([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[C:28]2[C:37]3=[C:36]4[C:25](=[CH:26][CH:27]=2)[CH:24]=[CH:23][CH:22]=[C:35]4[CH:34]=[CH:33][C:32]3=[CH:31][CH:30]=1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1N2c1ccc2ccc3cccc4ccc1c2c34
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A mixture of 10.00 g of acridan (55.2 mmol), 247.7 mg of Pd(OAc)2 (1.10 mmol), 178.6 mg of tri-t-butylphosphine (0.88 mmol), 7.95 g of sodium t-butoxide (82.7 mmol), and 17.06 g of 1-bromopyrene (60.7 mmol) in 100 mL of dry toluene was allowed to stir under inert atmosphere. The exothermic reaction heated to reflux, causing a precipitate to form. An additional 200 mL of toluene was added to the mixture and stirring was continued at room temperature for 1 h. The reaction mixture was poured into a mixture of 600 mL of CH2Cl2 and 100 g of silica gel. The mixture was filtered, and the solid material was washed with 600 mL of CH2Cl2. The filtrate was concentrated in vacuo to afford a thick liquid containing a precipitate. The precipitate was collected by filtration, washed with 300 mL of toluene and 500 mL of hexanes, and dried to afford 12.69 g of N-pyrenylacridan by 1H-NMR analysis. The mother liquor was concentrated to a yellow solid which was triturated in 300 mL of hexanes for 30 min. The precipitate was collected by filtration, washed with 200 mL of hexanes and dried to afford 7.46 g of solid. 1H-NMR analysis showed the second crop of product was slightly less pure than the first. The two lots were combined to afford 20.15 g of the N-pyrenylacridan (95.7%).
Reaction SMILES: [CH3:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].O[N:9]=[C:10]([C:12]12[CH2:19][CH2:18][C:15]([C:20]3[N:24]([CH3:25])[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=3)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)[NH2:11]>CN(C=O)C>[F:7][C:2]([C:3]1[O:4][N:11]=[C:10]([C:12]23[CH2:19][CH2:18][C:15]([C:20]4[N:24]([CH3:25])[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)[N:9]=1)([CH3:6])[CH3:1]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(N)=NO)(CC1)CC2
Reactant: CC(C)(F)C(=O)O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3noc(C(C)(C)F)n3)(CC1)CC2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-methyl-2-fluoropropionic acid (108 mg, 1.02 mmol) and 1′1′-carbonyldiimidazole (144 mg, 0.888 mmol) in anhydrous DMF (2.5 ml) was stirred at room temperature under nitrogen atmosphere for 30 min. To this was added N′-Hydroxy-4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carboximidamide (1-G) (139.5 mg, 0.355 mmol) and the solution stirred overnight under N2. The reaction was heated for 1.5 hr at 100° C. in a heat block. DMF was removed in vacuo and the solid was redissolved in CH3CN (4 ml). The product was purified by C-18 reverse phase chromatography eluting with 10-90% CH3CN (0.1% TFA)/water (0.1% TFA). The solvent was removed and the residue taken up in DCM and free-based from saturated aqueous sodium bicarbonate solution. The organic layers were dried over MgSO4 and filtered. The solvent was replaced with CH3CN/water and lyophilized to afford 5-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (3-A) as a white solid. MS (ESI+)=464.13 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.89-7.85 (m, 1H), 7.75-7.69 (m, 2H), 7.55 (t, 1H), 3.52 (s, 3H), 2.30 (dd, 6H), 2.15 (dd, 6H), 1.90 (s, 3H), 1.86 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O-2].[Ca+2:7].[Ca]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Ca+2:7]
Reactant: NCC(=O)O
Agent: [Ca+2]
Agent: [Ca]
Agent: [O-2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
Into about 923 grams of water was dissolved 150.14 grams of glycine. Next, 57.25 grams of calcium oxide, which was about 70% calcium by weight, was added. The solution was continually stirred until all of the calcium oxide was dissolved. This took about 15 minutes. No heat was applied for this particular reaction, though heat could optionally be used in this or other examples. The resulting reaction formed a calcium bisglycinate chelate or complex and water, i.e., the hydrogen ions were removed from the glycine and the oxygen was removed from the calcium oxide.