Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:32])[C:3]=1[OH:33].O[C@@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:36]([O:38]C)=[O:37].BrBr>>[Br:32][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:33][C@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:36]([OH:38])=[O:37]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Sc3ccccc3)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Sc3ccccc3)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-phenylsulfanyl-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenol (Example 64) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: NMR (DMSO-d6); δ8.50 (d, J=8 Hz, 1 H), 7.98 (d, J=8 Hz, 1 H), 7.83 (d, J=2 Hz, 1 H), 7.81 (d, J=2 Hz, 1 H),7.71 (ddd, J=6, 5, 2 Hz, 2 H), 7.58 (m, 2 H), 7.47 (ddd, J=8, 8, 1 Hz, 1 H), 7.42 (d, J=8 Hz, 2 H), 7.34 (t, J=7 Hz, 2 H), 7.29-7.20 (m, 4 H), 7.17-7.08 (m, 3 H), 6.67 (d, J=8 Hz, 1 H), 5.35 (t, J=7 Hz, 1 H, CH), 3.41 (d, J=7 Hz, 2 H); MS (+FAB): [M+], 2 bromine isotope pattern, 738 (35%), 740 (90%) 742 (60%); Anal. Calc. for C37H24Br203S2: C, 60.01, H, 3.27, N, 0.00. Found: C, 58.57, H, 3.04, N, 0.22.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32]>>[CH2:29]([NH:33][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:8][CH2:9][CH2:10][CH2:11][CH3:16])[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:7][CH2:6][CH2:5][CH2:4][CH3:3])[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Product: CCCCNc1nccc(-c2nn3c(NCCCC)cccc3c2-c2ccnc(NCCCC)n2)n1

Procedure:
N-Butyl-2,3-bis[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with n-butylamine as described in Example 7. 1H NMR, (400 MHz, CDCl3): δ 8.35 (d, 1H), 8.09 (d, 1H), 7.62 (d, 1H), 7.30 (t, 1H), 6.93 (m, 1H), 6.57 (d, 1H), 6.40 (d, 1H), 6.20 (d, 1H), 5.17 (m, 1H), 5.08 (m, 1H), 3.34–3.46 (m, 6H), 1.75 (m, 2H), 1.35–1.66 (m, 10H), 0.90–1.00 (m, 9H); MS m/z 488 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1.O.[C:20]1(C)C=CC(S(O)(=O)=O)=C[CH:21]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:16]([O:18][CH2:20][CH3:21])=[O:17])[CH2:13][CH2:14][CH2:15]3)[CH:8]=2)[NH:3]1
Reactant: O=C1Nc2ccc(C3(C(=O)O)CCC3)cc2C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3)CCC1
Temperature: 80 °C
Yield: 334.1 %

Procedure:
7.2 g of 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylic acid are dissolved in 100 ml of ethanol, and 500 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h and subsequently evaporated in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate, and the aqueous phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase), giving 2.4 g (30%) of ethyl 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylate;
Reaction SMILES: C([Cl:4])(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:16]([CH3:17])[C:15]([CH3:18])=[N:14][C:13]=1[C:19]#[N:20]>C(O)C>[ClH:4].[CH3:17][N:16]1[C:12]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[C:19]([NH2:20])[C:13]=2[N:14]=[C:15]1[CH3:18]
Reactant: Cc1nc(C#N)c(-c2ccccc2N)n1C
Reactant: CC(=O)Cl
Solvent: CCO
Product: Cc1nc2c(N)nc3ccccc3c2n1C
Product: Cl
Temperature: 25 °C
Yield: 76 %

Procedure:
Under a nitrogen atmosphere, a solution of acetyl chloride (55 mg, 0.70 mmol) in ethanol (10 mL) was stirred for 10 minutes. 5-(2-Aminophenyl)-1,2-dimethyl-1H-imidazole-4-carbonitrile (0.100 g, 0.471 mmol) was added, and the reaction was heated at reflux under nitrogen for one hour and then allowed to cool to room temperature. A solid was present and was isolated by filtration, washed with diethyl ether, air-dried, and further dried under vacuum (6.65 Pa) at room temperature for 30 minutes to provide 89 mg (76%) of 1,2-dimethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride, which was found to have a 1H NMR spectrum consistent with the product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][C:9]([N:18]([CH3:20])[CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].[Cl-].[CH3:22][O:23]C1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH:48]([CH2:52][CH2:53][CH3:54])C(O)=O)=[CH:40]1>CO>[CH3:19][N:18]([CH3:20])[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:11][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:22](=[O:23])[CH2:54][CH2:53][CH2:52][CH2:48][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:39][CH:40]=2)=[O:4])[CH2:7][CH2:8]1
Reactant: CCCC(C(=O)O)c1c[nH]c2ccccc12
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)CN)CC1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)CNC(=O)CCCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The more nonpolar diastereomer of 2-amino-N-(4-dimethylamino-4-phenylcyclohexyl)-acetamide (276 mg, 1.0 mmole) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (415 mg, 1.5 mmole) were added to a solution of indol-3-yl-pentanoic acid (217 mg, 1.0 mmole) in MeOH and stirred for 24 h at room temperature. Working up was performed by removing MeOH by distillation. The batch was re-dissolved with water, adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. The more nonpolar amide was obtained as a colorless oil in a yield of 474 mg (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=c1[nH]c2cc(F)cc(Cl)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
The Method of Cheeseman, supra. was adapted. 5-Chloro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (30 mg, 0.14 mMol) was dissolved in concentrated H2SO4 (0.5 ml) at 0° C. for 30 min, and KNO3 (17 mg, 0.17 mmole, Baker) was added in one portion to this solution. The mixture was stirred at 0° C. for 3 h, then at room temperature for 30 h. It was poured into ice water (5 g) and the precipitate was collected by filtration. The precipitate was dissolved in 1N NaOH (5 mL), then was acidified to pH=2 with 4N HCl to give a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording the pure (by NMR) title compound 5-chloro-6-nitro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (31 mg, 85.4%), as a white amorphous solid. mp: decomposed from 280° C. IR (KBr, cm-1): 3600, 3462, 3131, 1712, 1612, 1550. NMR (1H, DMSO-d6): δ7.106 (d, J=10.2 Hz, 1H), 11.800 (s, 1H), 12.371 (s, 1H). HRMS: calcd. for C8H3N3O4ClF (M+) m/z: 258.9795, found: 258.9790.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8](O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:9]=[C:8]([O:14][CH2:11][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:3]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (17.5 g), potassium carbonate (42 g) and benzyl bromide (35 mL) in dimethyl formamide (100 mL) is stirred at room temperature for 18 hours. The reaction mixture is poured into vigorously stirred ice-water (300 mL) and stirring is continued for 30 minutes. The resulting brown solid is filtered and dried to give 2,4-dibenzyloxybenzaldehyde (28.5 g), m.p. 80-81° C. [Elemental analysis:- C,79.5; H,6.10%. Calculated:- C,79.2; H,5.70%].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH3:20]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:20]
Reactant: CCBr
Reactant: COc1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(OC)ccc1C#N

Procedure:
30.0 g (201 mmol) of 2-hydroxy-4-methoxybenzonitrile are refluxed with 83.4 g of potassium carbonate (603 mmol) and 32.88 g (301 mmol) of bromoethane in 550 ml of acetone for 18 hours. After filtration, the solvent is removed under reduced pressure and the residue is purified by silica gel chromatography (cyclohexane:ethyl acetate=10:1): 35.9 g of an oil Rf=0.37 (cyclohexane:ethyl acetate=3:1)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2F)CC1
Reaction time: 2 h

Procedure:
A mixture of 3,6-dihydro-4-[4-amino-2-fluorophenyl]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 3, 11.44 g) and 10% palladium-on-carbon (4 g) in methanol (400 mL) in four Parr bottles is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for two hours, the catalyst is removed by filtration through Celite, and the filtrate is concentrated under reduced pressure to give the 4-[4-amino-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester intermediate. A mixture of this intermediate (11.17 g) and sodium bicarbonate (6.57 g) in dry tetrahydrofuran (390 mL) is treated with benzyl chloroformate (5.86 mL), and the resulting mixture is stirred at ambient temperature for 15 hours and washed with water (200 mL). The aqueous phase is extracted with methylene chloride (150 mL), and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (70-230 mesh, 800 g), eluting with a gradient of ethyl acetate/hexane (15/85-25/75). Pooling and concentration of those fractions with an Rf=0.38 by TLC (ethyl acetate/hexane, 25/75) gives the title compound, mp 96-98° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:14][C:15]1[CH:20]=[C:19]([CH2:21]P(OCC)(=O)OCC)[CH:18]=[CH:17][C:16]=1[CH2:30]P(OCC)(=O)OCC.[CH3:39][C:40]([O-:43])(C)[CH3:41].[K+]>C1COCC1>[Br:14][C:15]1[CH:20]=[C:19](/[CH:21]=[CH:10]/[C:9]2[CH:12]=[CH:13][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)[CH:18]=[CH:17][C:16]=1/[CH:30]=[CH:12]/[C:9]1[CH:10]=[CH:41][C:40]([O:43][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:39][CH:8]=1
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)c(Br)c1)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOc1ccc(/C=C/c2ccc(/C=C/c3ccc(OCCCC)cc3)c(Br)c2)cc1

Procedure:
To a solution of p-butoxybenzaldehyde (71) (2.0 g, 11.2 mmol) and tetraethyl 2-bromo-α,α′-p-xylenebisphosphonate (70) (2.55 g,. 5.5 mmol) in dry THF (70 ml) at 0° C. was added 12 ml of 1 M solution of KOtBu in THF. After 2 hours the reaction was quenched by addition of 70 ml of methanol. A light yellow solid was collected by filtration and washed three times with methanol to afford NMR-pure product in 2.36 g (84.5%) yield.1H NMR (CDCl3, 500 MHz) δppm: 7.70 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.4 (d, J=7.5 Hz, 1H), 7.32 (d, J=16.5 Hz, 1H, ═CH), 7.06 (d, J=16.5 Hz, 1H, ═C), 7.01 (d, J=16.0 Hz, 1H, ═CH), 6.85-6.95 (m, 5H, 4 Ar—H, 1 ═CH), 4.0 (m, 4H, CH2), 1.80 (m, 4H, CH2), 1.52 (m, 4H, CH2), 1.0 (t, J=7.5 Hz, 6H, CH3)13C NMR (CDCl3, 125.7 MHz) δppm: 159.1, 138.1, 135.7, 130.5, 130.4, 129.7, 129.4, 129.2, 128.0, 127.8, 126.2, 125.2, 124.7, 124.5, 124.3, 114.7, 67.7, 31.3, 19.2, 13.9.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.[C:19](O)(=[O:22])[CH:20]=[O:21]>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[C:10]2[O:11][C:20](=[O:21])[CH:19]([OH:22])[C:9]=2[CH:8]=[C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reaction time: 7 h
Yield: 100 %

Procedure:
23.6 g of methyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate, 10.1 g of glyoxylic acid monohydrate and 0.08 g of p-toluenesulfonic acid are boiled in 80 ml of 1,2-dichloroethane under a water separator for 7 h. The reaction solution is then cooled down, washed 3 times with 50 ml of water each time and freed of solvent in a rotary evaporator to leave 29.2 g of methyl 3-(7-tert-butyl-3-hydroxy-2-oxo-2,3-dihydrobenzofuran-5-yl)propionate in the form of a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:9]=2[NH:8][C:7]1=[O:24])=[O:5])[CH3:2].[CH2:25]1[O:27][CH2:26]1.[OH-].[NH4+]>C(Cl)CCl>[CH2:1]([O:3][C:4]([CH:6]1[N:12]2[CH2:25][CH2:26][O:27][C:11]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:9]=2[NH:8][C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Reactant: C1CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCOC(=O)C1C(=O)Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12

Procedure:
To a solution of 3.1 g. (0.0118 M) of stannic chloride in 35 ml of dry ethylene dichloride under nitrogen was added 1.5 g. (0.00438 M) of 7-chloro-1,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-carboxylic acid ethyl ester. The reaction was stirred in an ice bath, when a solution of 1.0 g. (0.0233 M) of ethylene oxide in 5 ml. of ethylene dichloride was added. The mixture was stirred at room temperature for 3 hr. and then made basic with mixture of ammonium hydroxide and ice. The mixture was filtered, and the filtrate was dried with anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether. Recrystallization from a mixture of dichloromethane and petroleum ether gave 10-chloro-11b-phenyl-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one-5-carboxylic acid ethyl ester as white rods, m.p. 205°-207°.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([NH:15][CH2:16][C:17]#[CH:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:18]=[C:17]([CH2:16][NH:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C#CCNc1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CNc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 18 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with phenyl prop-2-ynyl amine to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 18% yield: mp 159-162° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.42-7.35 (m, 5H), 7.30-7.21 (m, 2H), 6.82-6.77 (m, 1H), 6.73-6.69 (m, 2H), 6.18 (t, J=6.0 Hz, 1H), 4.66 (d, J=6.0 Hz, 2H), 4.58 (d, J=6.0 Hz, 2H), 4.32 (br s, 1H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) 160.9, 155.4, 153.1, 147.7, 147.1, 137.4, 129.4, 128.9, 127.9, 127.9, 124.5, 119.3, 118.3, 113.1, 44.3, 39.6, 17.4; MS (ES+) m/z 405.3 (M+1).
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].[C:7]([NH:17][C@H:18]([C:27]([OH:29])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].CN(C=O)C.CI>CCOC(C)=O>[CH3:1][O:28][C:27](=[O:29])[C@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:17][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
A suspension of Cs2CO3 (0.65 g, 2.0 mmol), N-Cbz-L-tyrosine (1.3 g, 4.0 mmol; Bachem) and DMF (40 mL) at ambient temperature was treated with methyl iodide (0.5 mL, 4.0 mmol). After 2.0 h the reaction mixture was diluted with EtOAc and then washed with H2O and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 6-4 as a white solid.
Reaction SMILES: O[CH:2]([N:10]1[C@H:13]([S:14][CH2:15][C:16]([CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[O:17])[C@H:12]([NH:23][C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]1=[O:33])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].S(Cl)(Cl)=O.N1[C:43]([CH3:44])=[CH:42][CH:41]=CC=1C.[Cl-].[CH2:47]([PH2:51])[CH2:48][CH2:49][CH3:50]>C1COCC1.O1CCOCC1>[C:26]1([CH2:25][C:24]([NH:23][C@H:12]2[C@@H:13]([S:14][CH2:15][C:16]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[O:17])[N:10]([C:2](=[P:51]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:15][CH2:16][CH2:18][CH3:19])[CH2:47][CH2:48][CH2:49][CH3:50])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:11]2=[O:33])=[O:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCOC1
Reactant: CCCCP
Reactant: Cc1cccc(C)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCCCP(CCCC)(CCCC)=C(C(=O)OC(C)(C)C)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCOC1

Procedure:
t-Butyl (RS)-2-hydroxy-2-[(3R,4R)-3-phenylacetamido-4-[(RS)-tetrahydrofuran-3-ylcarbonylmethylthio]azetidin-2-on-1-yl]acetate (2.719 g) in THF (20 ml) was treated with thionyl chloride (1.01 g, 0.615 ml) and 2,6-lutidine (0.913 g, 0.989 ml) as described in Example 1(d). Following work-up the crude chloride in dioxan (30 ml) was then treated with n-butylphosphine (2.53 g, 3.11 ml). After purification by flash chromatography with 50, 70% ethyl acetate/hexane then ethyl acetate the title compound was obtained as a pale yellow foam (1.496 g, 40%); νmax (CH2Cl2) 3420, 1762, 1717 (shoulder), 1681 and 1625 cm-1. [Mass spectrum: +ve ion (3NOBA, Na+), MH+ (663), MNa+ (685)].
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Yield: 107.4 %

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 71 g (0.217 mole) of 1,2-diphenyl-4-p-tolylbutane-1,4-dione, 100 ml of xylene, and 45 g (0.101 mole) of phosphorus pentasulfide. The autoclave was sealed, chilled in a Dry Ice-acetone bath, and charged with 120 g (3.52 moles) of hydrogen sulfide. The autoclave was then heated at 160°-190° C. (920-1130 psig) for 225 minutes. The autoclave was cooled to room temperature and the hydrogen sulfide vented into an aqueous sodium hydroxide solution. The residue in the autoclave was stirred with 150 ml of absolute ethanol. The slurry thus formed was filtered. The residue was dried to give 35.4 g (50.0%) of crude 2,3-diphenyl-5-p-tolylthiophene, m.p. 110°-112° C. Recrystallization from 190 ml. of toluene and 625 ml. of ethanol gave 30.1 g (42.5%) of pure 2,3-diphenyl-5-p-tolylthiophene, m.p. 114°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[OH:11][C:12]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][O:31][C:28]2[CH:27]=[CH:26][C:25]([C:12]3([OH:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:21])=[O:20])=[CH:30][CH:29]=2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(O)cc1
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCc2cc(F)cc(F)c2)cc1
Yield: 85 %

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in Example 48 from 3,5-difluorobenzyl bromide and [2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine to provide 511 mg as a brown oil. This material was purified via silica gel chromatography employing the Chromatotron® using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 4:1 to yield the title compound (360 mg, 85%) as a white solid. Ion spray M.S. 438.3 (M*−1). Calculated for C22H27NO4SF2: Theory: C 60.12, H 6.19, N 3.19. Found: C 59.32, H 6.14, N 3.26.