Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:17](Br)(=[O:19])[CH3:18]>C(Cl)Cl>[C:4]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:17](=[O:19])[CH3:18]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CC(=O)Br
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
Lithium hydroxide monohydrate (600 mg, 25.0 mmol) was added to a solution of the amine 3 (1.44 g, 8.53 mmol) dissolved in CH2Cl2 (125 mL) at 0° C. A solution of acetyl bromide (1.97 mL, 25.6 mmol) in CH2Cl2 (10 mL), was added dropwise over 5 minutes at 0° C. to the reaction mixture which was then allowed to warm to ambient temperature and stirred for 2 hours. The reaction crude was filtered, concentrated under reduced pressure, and purified by flash chromatography over silica, eluting with a gradient of 100% CH2Cl2 to 10% MeOH/90% CH2Cl2, yielding product 4 as white solid (1.11 g, 61.5%).
Reaction SMILES: [CH2:1]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2
Reactant: C=C1c2ccccc2CC(=O)Cc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1c2ccccc2CC(=O)Cc2ccccc21

Procedure:
31.4 g. (0.134 mole) of 12-methylene-5,6,7,12-tetrahydrodibenzo[a,d]cycloocten-6-one and 270 mg. of 10% palladium on charcoal were combined in 225 ml. of 95% ethanol and shaken under 50 p.s.i.g. of hydrogen. When hydrogen uptake ceased at about 1 mole equivalent, the mixture was filtered and evaporated in vacuo to give 31.1 g. of white solid, m.p. 152°-155° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:52]=[CH:51][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:44])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+].O>O1CCOCC1.CO>[C:3]([C:5]1[CH:52]=[CH:51][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:44])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccc(C(=O)OC)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccc(C(=O)O)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 12 h
Yield: 22.4 %

Procedure:
To the solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-(methoxycarbonyl)phenethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (5 mg) in dioxane (2 ml) and MeOH (2 ml), 3 mg of lithium hydroxide was added followed by 0.5 ml of water. The resulting clear solution was stirred at 50° C. for 12 h. The solvent was removed in vacuo and yellow solid was obtained. The crude material was purified by prep. HPLC to afford the title compound as a white solid (1.1 mg, 22.0%). LCMS: m/e 692.5 (MH+), 2.28 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 6.50 (d, J=8.3 Hz, 2H), 6.38 (d, J=8.3 Hz, 2H), 5.91 (d, J=8.3 Hz, 2H), 5.68 (d, J=8.3 Hz, 2H), 3.75-3.81 (m, 1H), 3.22 (s, 1H), 3.11 (s, 1H), 1.79-1.91 (m, 2H), 1.66-1.75 (m, 1H), 1.51-1.66 (m, 2H), 1.33 (s, 1H), 0.84-1.02 (m, 1H), 0.44-0.68 (m, 2H), 0.10-0.33 (m, 8H), 0.12-0.10 (m, 6H), 0.34-0.12 (m, 6H), 0.42-0.34 (m, 6H), 0.46 (s, 3H), 0.49 (s, 3H), 0.57 (s, 3H), 0.59 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:52]=[CH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(#N)C>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[CH:52]=[CH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:16]
Reactant: C=Cc1ccccc1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC1(CCO)OCCc2c1[nH]c1c(C=Cc3ccccc3)cc(C(C)C)cc21
Temperature: 90 °C

Procedure:
The title compound is prepared according to the following procedure. To solution of 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.0 mmol) in dried acetonitril (10 mL) at under nitrogen is added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri(dibenzylideneacetone)dipalladiumn (0) (0.1 mmol). The reaction mixture is heated at 90° C. (oil bath) overnight. It is quenched with water and extracted with ethyl acetate. Extracts are dried over magnesium sulfate and concentrated under reduced pressure. The chromatography (silica gel) gives the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](OC)([O:10]C)[CH2:8][CH2:7][O:6][CH2:5]1)[CH3:2].Cl>C1COCC1.O.CCOC(C)=O>[CH2:1]([O:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][O:6][CH2:5]1)[CH3:2]
Reactant: CCOC1COCCC1(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC1COCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 3-ethoxy-4,4-dimethoxytetrahydro-2H-pyran (2.1 g, 11 mmol) in THF/water (50 mL/10 mL) was added concentrated HCl (6 mL). After being stirred at room temperature for 1 h, the mixture was diluted with EtOAc. The organic layer was separated and the aqueous layer was extracted with ether five times. The combined organic layers were dried over MgSO4, filtered and concentrated to give 1.55 g (97%) of the desired product 1H NMR (CDCl3) δ 4.30-3.50 (7H, m), 2.62-2.57 (2H, m), 1.30-1.20 (3H, t, J=5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C=O)C>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1ccc2cc(Br)ccc21
Reaction time: 0.5 h

Procedure:
5-Bromoindole (1.96 g, 10 mmol) was dissolved in 20 mL of DMF, 60%-NaH (0.44 g, 11 mmol) was added. It was stirred for 30 minutes, then 2-fluorobenzyl bromide (1.33 mL, 11 mmol) was added. Stirring continued at 50° C. for 5 hours. After dilution with EtOAc, the organic layer washed with brine (5×), dried over MgSO4. After evaporation to dryness, it was then dried under high vacuum to yield N-2-Fluorobenzyl-5-bromoindole in quantitative yield. The title compound was prepared by substituting N-2-Fluorobenzyl-5-bromoindole (3.04 g, 10 mmol) for 4-bromo-2-nitrophenylamine in EXAMPLE 2A. Crude material was purified by silica gel column chromatography, eluting with 2.5% EtOAc in hexane. 2.18 g of the title compound was obtained. MS: ESI(+) m/e 352.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH2:12][C:13]([OH:15])=O)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].Cl.Cl.[OH:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[CH2:23][NH:24][NH2:25]>C(O)C>[Br:9][C:6]1[CH:5]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:15])[N:24]([CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([OH:19])[CH:21]=3)[N:25]=2)[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: O=C(O)CCC(=O)c1cc(Br)c(O)c(Br)c1
Reactant: NNCc1cccc(O)c1
Agent: Cl
Solvent: CCO
Product: O=C1CCC(c2cc(Br)c(O)c(Br)c2)=NN1Cc1cccc(O)c1
Yield: 49.1 %

Procedure:
A stirred mixture of 4-(3,5-dibromo-4-hydroxyphenyl)-4-oxobutanoic acid (H) (150 mg, 0.426 mmol) and 3-hydroxybenzylhydrazine dihydrochloride (135 mg, 0.639 mmol) in ethanol was heated to reflux. After heating for 16 h, the reaction mixture was cooled down and the precipitate formed was collected and dried in vacuo. This gave the title compound as a red solid (95 mg, 49%)1H NMR δ (ppm) (DMSO-d6): 2.59 (2 H, t), 3.01 (2 H, t, J=8.2 Hz), 4.88 (2H, s), 6.67 (1 H, d, J=8.2 Hz), 6.69-6.76 (2 H, m), 7.14 (1 H, t, J=7.8 Hz), 7.92 (2 H, s), 9.39 (1 H, s), 10.44 (1 H, s). LCMS (10 cm_apci_formic) Rt 3.33 min; m/z 453/455/457 [M+H].
Reaction SMILES: [C:1]1([CH:7](O)[C:8]2[CH:9]=[C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[C:1]1([CH:7]([Cl:23])[C:8]2[CH:9]=[C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)c1cccc(C(O)c2ccccc2)c1
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc(C(Cl)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl 2-[3-(phenylhydroximethyl)phenyl]propionate (128 g) was dissolved in 100 mL of dry methylene chloride and the solution was cooled to 0° C. Then 41 mL of thionyl chloride in 50 mL methylene chloride were added along 1 hour, keeping the reaction temperature between 5 and 10° C. After staying for 1 hour at 5° C. and 1 hour at room temperature, solvents were removed and the residue (130.5 g, yellow oil) was vacuum distilled, yielding 103 g (75% yield) of the title compound as a yellow transparent liquid, b.p. 158-163° C./1 tor. In the 200 MHz 1H-NMR apparatus the signal of CH3 -- appears as two doublets of similar intensity, indicating the presence of the two possible diasteromers. By following analogous procedures, compounds IIc of Table 3 were obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[O:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][OH:30]>CCO>[N:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[O:23][C:24]([C:27](=[NH:28])[NH:29][OH:30])=[CH:25][CH:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(N3CCCCC3)cc2N2CCCCC2)o1
Reactant: NO
Solvent: CCO
Product: N=C(NO)c1ccc(C(=O)Nc2ccc(N3CCCCC3)cc2N2CCCCC2)o1
Temperature: 0 °C
Yield: 23 %

Procedure:
To a solution of 5-cyano-furan-2-carboxylic acid (2,4-di-piperidin-1-yl-phenyl)-amide (48 mg, 0.12 mmol, as prepared in the previous step) in 1 mL of EtOH at room temperature was added NH2OH (26 mg, 0.4 mmol, 50% wt/H2O) via syringe. The reaction was heated to reflux for 10 min, and then cooled to 0° C. The bright yellow precipitate was filtered, washed with cold 50% EtOH—H2O (2 mL) and dried to afford 11 mg (23%) of the title compound as a bright yellow solid. 1H-NMR (DMSO-d6; 400 MHz): δ 9.83 (s, 1H), 9.37 (s, 1H), 7.84 (d, 1H, J=9.0 Hz), 7.21 (d, 1H, J=3.5 Hz), 6.89 (d, 1H, J=3.6 Hz), 6.74 (s, 1H), 6.66 (d, 1H, J=8.8 Hz), 5.96 (br s, 2H), 3.08-3.10 (m, 4H), 2.78-2.77 (m, 4H), 1.71-1.52 (m, 12H); Mass spectrum (ESI, m/z): Calcd. for C22H29N5O3 412.2 (M+H), found 412.2;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1)([O-:10])=[O:9]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1N1CCSCC1
Temperature: 25 °C

Procedure:
A solution of 1-fluoro-2-nitro-benzene (2.0 mmol, 0.21 mL), triethylamine (3.0 mmol, 0.42 mL) and thiomorpholine (3.0 mmol, 0.30 mL) in dioxane (2 mL) was irradiated using microwave for 15 minutes at a temperature of 160° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide 4-(2-Nitro-phenyl)-thiomorpholine. To the solution of this nitro compound in MeOH (10 mL) was added Pd on carbon (5% Pd, 100 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide compound 39A. HPLC-MS RT=1.06 minutes, mass calculated formula C10H14N2S 194.09, observed LCMS m/z 195.10 (M+H).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]O)=[CH2:2].[Br:10]P(Br)Br>ClCCl>[BrH:10].[Br:10][CH2:8][C:7]1[S:6][CH:5]=[N:4][C:3]=1[CH:1]=[CH2:2]
Reactant: BrP(Br)Br
Reactant: C=Cc1ncsc1CO
Solvent: ClCCl
Product: Br
Product: C=Cc1ncsc1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-ethenyl-1,3-thiazol-5-yl)methanol (370 mg, 2.6 mmol) in anhydrous dichloromethane (20 mL) was added dropwise tribromophosphane (275 uL, 2.9 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated, and the residue was dried in vacuo to afford 5-(bromomethyl)-4-ethenyl-1,3-thiazole hydrobromide. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:17])=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:6]2.[CH3:18]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:17])=[C:5]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:6]2[CH3:18]
Reactant: Cc1c(-c2ccccc2)[nH]c2cccc(Br)c12
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(C)c2cccc(Br)c12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 4-bromo-3-methyl-2-phenyl-1H-indole (1.574 g, 5.5 mmol) was reacted with k-t-butoxide (0.648 g, 5.775 mmol) and methyl iodide (0.820 g, 5.775 mmol) in DMF (15 ml) to give the product (1.188 g, 3.957 mmol, 72%) as a colorless oil. 1H DMSO-d6) δ 2.39 (s, 3H), 3.55 (s, 3H), 7.05 (t, J=7.8 Hz, 1H), 7.23 (dd, J=0.8, 7.6 Hz, 1H), 7.42-7.45 (m, 2H), 7.47-7.51 (m, 2H), 7.55 (t, J=6.9 Hz, 2H); [ESI(+)], m/z 300/302 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14].C([O-])([O-])=O.[Na+].[Na+].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:7]1[C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3](=[O:14])[C@@H:2]1[CH3:1])(=[O:23])[CH3:22]
Reactant: C[C@@H]1N[C@H](c2ccccc2)COC1=O
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1[C@@H](C)C(=O)OC[C@H]1c1ccccc1
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a vigorously stirred mixture of (3S,5R)-3-methyl-5-phenyl-3,4,5,6-tetrahydro-2H-1,4-oxazin-2-one (300 mg, 1.56 mmol), Na2CO3 (500 mg, 4.68 mmol, 3.0 equiv.) in anhydrous dichloromethane (30 mL) was added acetyl chloride (0.17 mL, 2.34 mmol, 1.5 equiv.) dropwise over 1 min. The resulting solution was stirred for 15 minutes under an atmosphere of nitrogen. The reaction was quenched by the addition of saturated Na2CO3 (20 mL), the aqueous phase was extracted with diethyl diethyl ether (3×10 mL) and the combined extracts were dried over MgSO4. The solvents were removed in vacuo and the crude material was purified by flash column chromatography on silica, eluting with diethyl ether and dichloromethane (9:1) to furnish the title compound as fine colourless needles (270 mg, 74%); m.p. 82-85° C.; V(max) (KBr) 2943 (C—H), 1733 (C═O, lactone), 1647 (C═O, amide) cm″1; δH (250 Mhz, DMSO-d) 7.42-7.36 (5H, m, Ph), 5.49 (0.4H, PhCH×0.4) 5.33 (0.6H, PhCH×0.6), 5.08-5.05 (1H, m, CH3CH), 4.65 (2H, d, J 6.10 Hz CH2); 2.13 (1H, s, CH3CON×1), 1.86 (2H, s, CH3CON×2), 1.39 (3H, d, J 12.40 Hz CH3CH): δc (62.5 MHz, DMSO—O 170.5, 169.8, 137.8, 129.4, 128.4, 127.1, 68.6, 55.5, 50.7, 49.7, 22.7, 19.0; m1τ (CL, NH3), 234 (MH+, 8%), 233 (M, 13%), 220 (4%), and 219 (100%); HRMS for C13H16NO3 requires 234.1126. found 234.1130; [α]D20 −29.8 (c 1.16 CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[OH:14].[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH:29](OC2C=CC(Cl)=CC=2C=O)C1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCOC(C)=O>CN(C=O)C.O>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH:30]([O:14][C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[CH2:29]1)=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: Oc1cc(F)ccc1OCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2OCc2cccc(Cl)c2)C1
Temperature: 50 °C
Yield: 124.1 %

Procedure:
To the title compound of Step B (200 mg, 0.79 mmol) in DMF (5.0 mL) was added 60 wt % NaH (34.3 mg, 0.86 mmol). The mixture was heated to 50° C. for 1 h then cooled to rt and 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (Example 90 Step A, 229 mg, 0.91 mmol) in DMF was added. This mixture was heated to 80° C. for 18 h, cooled to rt and treated with EtOAc (50 mL) and H2O (100 mL). The organic layer was separated, washed with H2O (2×50 mL) and dried to give a solid (400 mg). This solid was purified on RP HPLC to yield the title compound (90 mg, 28%). 1H NMR (CDCl3) 7.44 (s, 1H), 7.36-7.23 (m, 3H), 6.86 (dd, J=8.9, 5.4 Hz, 1H), 6.60 (dd, J=8.0, 2.9 Hz, 1H), 6.33 (dd, J=9.6, 2.9 Hz, 1H), 5.03 (s, 2H), 4.90-4.80 (m, 1H), 4.33-4.22 (m, 2H), 4.07-4.02 (m, 2H), 1.54-1.28 (m, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=[N:3]1.[CH3:10][C:11](C)([O-])C.[K+].BrCCBr.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2([C:8]#[N:9])[CH2:11][CH2:10]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1CC#N
Reactant: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: Cn1nccc1C1(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.3 %

Procedure:
To a solution of 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile (65 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) were added potassium t-butoxide (1M in tetrahydrofuran, 1.2 mL, 1.2 mmol) and 1,2-dibromoethane (130 μL, 1.5 mmol). The reaction mixture was stirred for 16 h at room temperature then at 70° C. for 7 h. The mixture was cooled to room temperature, quenched with water (2 mL) and extracted with diethyl ether (3×10 mL). The combined organic layers were washed with brine (3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dried under high vacuum. A solution of the residue and 1,2-dibromoethane (65 μL, 0.75 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise to a suspension of sodium hydride (washed, 23 mg, 1.0 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After 16 h, additional portions of 1,2-dibromoethane (25 μL, 0.29 mmol) and sodium hydride (8 mg, 0.35 mmol) were added to the reaction mixture at room temperature. After 2 h, the mixture was quenched with water (3 mL) and extracted with diethyl ether (2×10 mL). The combined organic layers were washed with brine (3 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to yield the volatile 1-(1-methyl-1H-pyrazol-5-yl)cyclopropanecarbonitrile (20.1 mg, 25%) as a brown oil. 1H NMR (500 MHz, CDCl3) δ 1.34-1.41 (m, 2H), 1.70-1.76 (m, 2H), 4.03 (s, 3H), 6.10 (d, 1H), 7.39 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:28]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(F)(F)F)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6.8, 1H), 9.32 (s, 1H); Anal. Calcd for C20H16F4N2O+1.25 HCl: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45; N, 7.03.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([OH:14])(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][CH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:22](O)=[C:20](O)[CH:19]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][Cl:38])=[O:35]>O1CCCC1>[C:1]([O:7][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][NH:15][C:34]([O:36][CH2:37][Cl:38])=[O:35])[CH:25]=[CH:24][C:22]=1[O:13][C:8](=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)(C)C(=O)O
Reactant: NCCc1ccc(O)c(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)OCCl)cc1OC(=O)C(C)(C)C
Reaction time: 0.25 h

Procedure:
Dopamine dipivalate, oxalate salt (822 mg, 2 mmol) was suspended in 15 mL of dry tetrahydrofuran. Triethylamine (278 mL, 1 mmol) was added, the mixture was stirred for 15 minutes and a further 278 mL (1 mmol) of triethylamine were then added. Addition of ClCO2CH2Cl (390 mg, 6 mmol) resulted in immediate formation of a heavy white precipitate and the evolution of gas. The reaction mixture was stirred overnight at room temperature, then the precipitate was removed by filtration and the filtrate was washed with 10 mL of 0.1M hydrochloric acid. Drying over magnesium sulfate and evaporation to dryness afforded 1.1 g of a golden oil of the structural formula ##STR140## The identity of the product was confirmed by elemental analysis.
Reaction SMILES: C(O[CH:5]1[C:9]2[CH:10]=[C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=2[O:7][C:6]1=[O:22])(=O)C.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>O>[C:18]([C:11]1[CH:12]=[C:13]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:8]2[O:7][C:6](=[O:22])[CH:5]([C:29]3[CH:28]=[C:27]([CH3:30])[CH:26]=[CH:25][C:24]=3[CH3:23])[C:9]=2[CH:10]=1)([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1ccc(C)cc1
Reactant: CC(=O)OC1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Solvent: O
Product: Cc1ccc(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c1
Yield: 59.9 %

Procedure:
To a solution of 15.3 g (50.0 mmol) of 3-acetoxy-5,7-di-tert-butyl-3H-benzofuran-2-one (compound (206), Table 2, Example 2a) in 25 ml (0.20 mol) of p-xylene is added 1.0 g of Fulcat 22B and the mixture is refluxed for 17 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotaray evaporator. Crystallisation of the residue from 20 ml of methanol yields 10.5 g (60%)of 5,7-di-tert-butyl-3-(2,5-dimethylphenyl)-3H-benzofuran-2-one, m.p. 93°-97° C. (compound (101), Table 1).