Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:17][N:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]1=[O:26]>FC(F)(F)C(O)=O>[C:1]1([C:7]2[C:15]([CH2:17][N:18]3[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]3=[O:26])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: c1ccc(-c2cc3ncccn3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cccnc23)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
To a solution of 2-phenylpyrazolo[1,5-a]pyrimidine x124 (25.6 mmol, 1 eq, 5 g) in trifluoroacetic acid (150 ml) is added 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (38.4 mmol, 1.5 eq, 6 g). The resulting solution is stirred at room temperature for three days. The solvent is removed under reduce pressure, ice is added and the mixture is alkalinized by solid NaHCO3. The mixture is extracted by AcOEt, the organic layers are washed with brine and dried over Na2SO4. The solvent is removed under reduce pressure and the crude reaction mixture purified by chromatography on silicagel (AcOEt/hexane 40/60). After crystallisation in AcOEt/hexane, to afford 2.06 g of 1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 191 are obtained.
Reaction SMILES: C[N:2]1[CH2:8][CH:7]=[C:6](C2C=CC(C)=CC=2)[C:5]2[CH:16]=[CH:17][C:18](N3CCN(C4N=CC=CN=4)CC3)=[CH:19][C:4]=2[CH2:3]1>C(O)C.[OH-].[Pd+2].[OH-]>[NH:2]1[C:3]2[CH:4]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:5]=[CH:6][CH:7]=[CH:8]1
Reactant: Cc1ccc(C2=CCN(C)Cc3cc(N4CCN(c5ncccn5)CC4)ccc32)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C1=CNc2ccccc2C=C1
Reaction time: 1 h
Yield: 121.2 %

Procedure:
To a solution of the dihydrobenzazepine (0.20 g, 0.49 mmol) from step I above in ethanol (30 mL) was added palladium(II) hydroxide (0.20 g, 0.28 mmol). The reaction solution was shaken under hydrogen (35 psi) for 1 h. The resultant reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude product was purified by preparative HPLC to give the desired racemic benzazepine (85 mg, 42%) as an off-white foam: 1H NMR (CDCl3, 500 MHz) δ 8.33 (d, J=5.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 6.81 (d, J=2.5 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 6.62-6.53 (br, 1H), 6.51 (t, J=5.0 Hz, 1H), 4.21 (d, J=9.0 Hz, 1H), 3.96 (t, J=5.0 Hz, 4H), 3.89 (br d, J=12.5 Hz, 1H), 3.70 (d, J=14.0 Hz, 1H), 3.20 (t, J=5.5 Hz, 4H), 3.15-3.08 (br, 1H), 2.93 (t, J=10.5 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H), 2.32-2.25 (m, 1H), 2.12-2.04 (br, 1H); ESI MS m/z 414 [M+H]+.
Reaction SMILES: Br[CH2:2]C1C=CC(C(O)=O)=CC=1.[H-].[Na+].[CH2:14]([O:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:15]C=C>C(O)(C)C>[CH:14]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=1)([CH3:15])[CH3:2]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OCc1ccc(C(=O)O)cc1

Procedure:
The reaction of isopropanol and 4-Bromomethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 4-Isopropoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (d, J=8.2, 2 arom.H); 7.41 (d, J=8.2, 2 arom.H); 4.51 (s, OCH2C6H4—); 3.63 (m, CH(CH3)2); 1.14 (d, CH(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 144.47; 129.52; 129.23 (2 arom.C); 126.93 (2 arom. C); 70.67; 68.47; 22.00 (2 C).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:15]1[CH2:18][CH2:17][CH2:16]1>COCCOC>[N:15]1([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Br:1])[CH2:18][CH2:17][CH2:16]1
Reactant: Clc1ccncc1Br
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Brc1cnccc1N1CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a 16×100 mm reaction tube under N2 was added, 3-bromo-4-chloropyridine (320 mg, 1.663 mmol), cesium carbonate (1.65 g, 5.06 mmol), and 1,2-dimethoxyethane (3 mL). The reaction mixture was flushed with nitrogen and then treated with azetidine (210 μL, 3.12 mmol). The reaction mixture was securely capped, stirred at room temperature for 5 min, then heated at 90° C. for 18 h. The reaction mixture was filtered through a small Celite plug by gravity, washed with dichloromethane (30 mL) and the volatiles were evaporated in vacuo to give 350 mg (99%) of the title compound as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=1.O.[N+:14]([CH:17]([CH:20]=O)[CH:18]=O)([O-:16])=[O:15].[Na]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]2[C:10](=[N:12][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:20]=2)[NH:9][N:8]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1cc(-c2ccccn2)n[nH]1
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]nc(-c3ccccn3)c2c1
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A 50 mL reaction vessel was charged with 3-(pyridin-2-yl)-1H-pyrazol-5-amine (1.5 g, 9.4 mmol), sodium nitromalonaldehyde monohydrate (1.54 g, 9.8 mmol) and water (9 mL). The flask was heated to 100° C. overnight, and the cooled reaction mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (MgSO4), to provide crude 3-(pyridin-2-yl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (2.0 g, 88% yield) as a solid.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:15][C:16]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[CH:19]=[C:18]([Cl:25])[N:17]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([NH:22][C:23]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:24])[CH:19]=[C:18]([Cl:25])[N:17]=1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Reactant: Cc1cc(NN)nc2c(C)cccc12
Product: Cc1cc(NNC(=O)Nc2cc(Cl)nc(Cl)c2)nc2c(C)cccc12

Procedure:
A solution of 2-hydrazinyl-4,8-dimethylquinoline (110 mg, 0.60 mmol) and 111 mg (1.0 eq) of 2,6-dichloro-4-isocyanatopyridine was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.50 (s, 3 H) 2.56 (s, 3 H) 6.79 (s, 1 H) 7.18 (t, J=7.62 Hz, 1 H) 7.41 (d, J=7.03 Hz, 1 H) 7.70 (d, J=8.20 Hz, 2 H) 8.72 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[C:10]2=[O:32])=[CH:5][CH:4]=1.[CH3:33][O:34]C=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH:26]3[CH2:31][CH2:30][CH2:29][N:28]([CH:33]=[O:34])[CH2:27]3)[C:10]2=[O:32])=[CH:7][CH:8]=1
Reactant: COC=O
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCNC3)C2=O)cc1
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCN(C=O)C3)C2=O)cc1
Reaction time: 8 h

Procedure:
3-(4-Methoxy-phenyl)-7-phenylamino-1-piperidin-3-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (95 mg, 0.22 mmol) (from Example 4b supra) was dissolved at room temperature in methylformate (5 mL) (Aldrich). After stirring overnight the reaction mixture was concentrated to the crude product, which was purified by silica gel column chromatography with a 0–100% ethyl acetate in hexanes and then a 0–20% tetrahydrofuran in ethyl acetate gradient. After a precipitation out of dichloromethane with excess of pentane, 3-[3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carbaldehyde was isolated as an off-white solid. (Yield 90 mg, 89%).
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[N-:9]=[N+:10]=[N-:11].[Na+]>CC(C)=O.[Cl-].[Na+].O>[N:9]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[N+:10]=[N-:11]
Reactant: CC(C)(C)C(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A mixture of 1-bromopinacolone (0.5 mL, 3.7 mmol) and NaN3 (0.48 g, 7.38 mmol) in 50 mL acetone was stirred overnight at room temperature. It was then poured into brine and extracted with dichloromethane. The extracts were washed with brine, were dried over Na2SO4, filtered, and were evaporated to afford the title compound as a yellow oil (524 mg, 100%). 1H NMR (DMSO-d6) δ 4.39 (s, 2H), 1.10 (s, 9H); MS (DCI+) m/z 142 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[I-:14].[Na+].Cl[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([I:14])[N:7]=1
Reactant: [I-]
Reactant: COC(=O)CCc1ncccc1O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COC(=O)CCc1nc(I)ccc1O
Temperature: 15 °C
Yield: 32.7 %

Procedure:
A solution of 15 g of 3-(3-hydroxy-2-pyridyl)-propionic acid methyl ester in 250 ml of methanol is mixed with 12.4 g of sodium iodide, cooled to 15° C., and 74 ml of aqueous sodium hypochlorite solution (6.5% active chlorine) is instilled. The yellow suspension is concentrated by evaporation, the residue is taken up in water, acidified to pH 4 with 2n sulfuric acid and shaken out with ethyl acetate. The organic phase is washed with 10% sodium thiosulfate solution, dried with sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-50% ethyl acetate. 8.3 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester of melting point 145°-148° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](SC)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])([O-])=O.[Na+].[Na+].[C:43]1([C@@H:49]([NH2:51])[CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:51][C@H:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH3:50])[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1)c1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine (110 mg, 0.31 mmol) is dissolved in CH2Cl2/HOAc 1:1 (6.2 ml), combined at 0° C. with mCPBA (84 mg 70% 0.34 mmol) and stirred for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude sulfoxide (110 mg). 50 mg are dissolved in 1-(S)-phenylethylamine (0.5 ml) and heated to 120° C. for 1 h. Purification over RP18 (CH3CN/Water 70/30 to 10/90) yielded the title compound as light brown foam (30 mg 52%)
Reaction SMILES: CC1(C)O[CH:5]([CH2:7][N:8]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]3[CH:19]=[CH:20][S:21][C:10]=3[S:9]2(=[O:23])=[O:22])[CH2:4][O:3]1.O.FC(F)(F)C(O)=O>>[OH:3][CH2:4][CH:5]1[O:16][C:14](=[O:15])[C:13]2[N:8]([S:9](=[O:22])(=[O:23])[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[CH:12]=2)[CH2:7]1
Reactant: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CC1COC(C)(C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1OC(CO)CN2C1=Cc1ccsc1S2(=O)=O
Yield: 193.5 %

Procedure:
A solution of the product from Step B (18 g, 21.4 mmol) in a water/trifluoroacetic acid mixture (1:9) was stirred for 12 h. The solid which formed was collected by filtration, washed with hexane, and dried to give 11.9 g (86%) of a colorless solid: mp 210°-212° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:14][O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19][CH2:20][CH2:21]Br>[OH-].[K+].C(O)C>[CH3:18][S:19][CH2:20][CH2:21][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:14][O:15][CH2:16][CH3:17])=[CH:8][CH:9]=1
Reactant: CCOCC(COc1ccc(O)cc1)OCC
Reactant: CSCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOCC(COc1ccc(OCCSC)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A 2.40 g quantity of 4-(2,3-diethoxypropoxy)phenol was dissolved in 0.56 g of potassium hydroxide and 10 ml of 90% ethanol. To the solution was added 1.55 g of 2-methylmercaptoethyl bromide. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water, dewatered with Glauber's salt and concentrated. The residue was distilled at reduced pressure, giving 2.95 g of 2-{4-(2,3-diethoxypropoxy)phenoxy}ethyl methyl sulfide in 93.9% yield, b.p. 176° to 177° C./l to 2 mmHg.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC(C)=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:46])[C:14]2=[O:15])[N:3]=1.O.NN>C(O)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:28]2[CH2:29][C@H:30]([NH2:34])[CH2:31][CH2:32][CH2:33]2)=[N:18][C:17]2[N:16]([CH3:46])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccc(C)cc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: NN
Solvent: CCO
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 79 °C

Procedure:
In a clean round bottom flask, 9 ml of ethanol, 90 mg of 1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-4-methylphthalimidopiperidin-1-yl)-xanthine & 0.9 ml of hydrazine hydrate were charged. The temperature of the reaction mass was raised to 78-80° C. & the reaction mass was maintained for 3 hours. The reaction mass was cooled to 50° C. & ethanol was distilled off. 9 ml methylene dichloride was added to the obtained residue & stirred at RT to get the solid. Undesired solid was filtered. The filtrate was concentrated & 9 ml methyl tert butyl ether was added to the residue to get the solid Linagliptin. Reaction mass was stirred at RT & filtered. Wet cake was washed with 2 ml IPA. Dry wt 45 mg
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:18]Br>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:18])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Oc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a refluxing (250 watt infra-red lamp) and stirred solution of 4-(4-nitrophenoxy)toluene (229.25 g; 1 mol) in CCl4 (2.5 l) under nitrogen, bromine (247.46 g; 1.55 mol) in CCl4 (250 ml) was added dropwise over a period of 4 hours. After refluxing an additional 8 hours, followed by stirring at room temperature overnight, the reaction mixture was washed with 10% sodium bisulphite (1×1 l), saturated sodium bicarbonate (2×2 l) and saturated sodium chloride. The organic layer was dried over magnesium sulphate and evaporated to give a yellow solid which was recrystallised from benzene-hexane (250 ml:350 ml) to yield 4-(4-nitrophenoxy)α-bromotoluene as light yellow crystals. m.p. 68°-70° C. NMR (CDCl3): 8.15 (d,2H), 7.45 (d,2H), 7.0 (d,4H); and 4.49 (s,2H). Analysis: calculated for C13H10BrNO3 : C, 50.67; H, 3.27; N, 4.55; Br, 25.93; found: C, 50.38; H, 3.24; N, 4.58; Br, 26.02.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:25][O:24][C:11]1[C:12]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(Sc2ccccc2Cl)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(Sc2ccccc2Cl)cccc1C(C)C(=O)O
Yield: 67 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenylthio)phenyl]propionate (3.3 g) and potassium hydroxide (1.5 g) in ethanol (60 ml) and water (30 ml) was refluxed under heating for 48 hours. After cooling, ethanol was distilled off from the reaction mixture. To the residue was added water, and the aqueous solution was washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily 2-[2-methoxy-3-(2-chlorophenylthio)phenyl]propionic acid (1.9 g).
Reaction SMILES: C[Mg]Br.CC[O:6][CH2:7][CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:20]([CH2:30][CH:31]2[CH2:35]C[C:33](=O)[CH2:32]2)[C:21]([NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:22])[CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:18])=[O:17]>O1CCCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:20]([CH2:30][CH:31]2[CH2:32][CH2:33][C:7]([OH:6])([CH3:8])[CH2:35]2)[C:21]([NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:22])[CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:17])=[O:18]
Reactant: CCOCC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
3.0M solution of methylmagnesium bromide in ether (2.53 mL, 7.59 mmol) cooled to 0° C. was treated dropwise with a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 0.10 g, 0.237 mmol) in tetrahydrofuran (1 mL). The resulting solution was stirred at 0° C. for 30 min, quenched with a saturated aqueous ammonium chloride solution (3 mL), and partitioned between a saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 80% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxy-3-methyl-cyclopentyl)-N-pyrazin-2-yl-propionamide (37 mg, 35%) as a yellow foam: mp 78-84° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H24ClN3O4S (M+H)+ 438.1249. found 438.1254.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:28](=[O:30])[NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:32]>C(O)C>[Na+:32].[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]([O-:26])=[O:25])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:28](=[O:30])[NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)[O-])c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Yield: 56 %

Procedure:
A solution of the {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (83.5 mg, 0.207 mM) and 1.0 mL (2.0 mM) of 2 N NaOH in 10 mL of ethanol was stirred for 45 minutes at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 48 mg (56%) of the {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid sodium salt as a white powder. MS (ES) m/e 314, 372, 389, 411. The filtrate was acidified with 1N HCl to pH=1. After cooling to 5° C., the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 24 mg (29%) {9-[(phenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ 1.2 (bs, 1H), 7.8 (bs, 1H), 7.6 (d, J=8 Hz, 1H), 7.45 (bs, 1H), 7.4-7.05 (m, 8H), 6.45 (s, 1H), 5.65 (s, 2H), 4.9 (s, 2H), 2.4 (s, 3H). MS (ES) m/e 314, 372, 389.
Reaction SMILES: [S].[SH:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>>[F:8][C:9]([F:13])([S:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH:10]([F:12])[F:11]
Reactant: Sc1ncc[nH]1
Reactant: FC(F)=C(F)F
Agent: [S]
Product: FC(F)C(F)(F)Sc1ncc[nH]1

Procedure:
The appropriate R1 moiety can then be introduced onto the sulfur by a suitable alkylating agent such as tetrafluoroethylene or difluorocarbene. For example, the 2-mercaptoimidazole derivative of Reaction (2) can be reacted with tetrafluoroethylene to form the 2-(1,1,2,2-tetrafluoroethylthio)imidazole derivative. ##STR10## The reaction is carried out under heat and pressure with a slight excess of the fluorocarbon reactant. Typically, the reaction is carried out in a closed reaction vessel at a temperature of 50° C. at an initial pressure of about 50 p.s.i. which falls to about 13 p.s.i. as the reaction proceeds. Similar addition reactions of tetrafluoroethylene and other fluorinated olefins are described by England, D. C. et al., J. Am. Chem. Soc., 82, 5116 (1960) and Rapp, K. E., et. al., J. Am. Chem. Soc., 72, 3642 (1950). Within the context of the invention, tetrafluoroethylene and other fluorinated olefins used are considered alkylating agents.
Reaction SMILES: [CH2:1]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[N:36](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:35]=[N:34][N:33]=2)=[CH:22][CH:21]=1)[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(O)(=O)C>O>[CH2:1]([N:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[NH:36][N:35]=[N:34][N:33]=2)=[CH:24][CH:25]=1)[C:7]([N:9]1[C:18]2[CH:13]([CH2:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)N1CCCc2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1CCCC2CC=CC=C21
Temperature: 60 °C
Reaction time: 16 h
Yield: 3.1 %

Procedure:
A mixture of 29.3 mg (0.405 mmole) of 1-[N-pentyl-N-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step E), 400 μL of glacial acetic acid, and 180 μL of H2O was stirred under N2 at 60° C. for 16 hours, then cooled, and concentrated to dryness in vacuo. The residual oil was flash chromatographed on silica gel (elution with 3% and then 5% MeOH in CH2Cl2) to yield 6.0 mg (31%) of the title compound as a stiff foam, homogeneous by TLC (95:5 CH2Cl2 --MeOH); FAB-MS m/e 481 (M+1)+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:15]=[N-:16]>C(O)C>[N:14]([C:17](=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:4]=1[O:3][CH3:2])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:15]=[N-:16]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1cccc(C=O)c1OC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc(OC)c1OC)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Pieces of sodium (3.678 g, 160 mmol) were added to ethanol (200 ml) over a period of 30 minutes. The resulting solution was cooled to −18° C. and a mixture of 2,3-dimethoxybenzaldehyde (4.832 g, 40 mmol) and ethyl azidoacetate (20.64 g, 160 mmol) was then added, over one hour, at a rate which allowed the temperature to be maintained below −15° C. After three hours, the solution was stored at 5° C. for two days in order to give a crystalline product which was collected. and washed with cold hexane in order to give a pure product in the form of a yellow oil.