Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cc2[nH]cc(C3CCCCC3)c2s1
Yield: 98 %

Procedure:
A solution (0.1 M) of 6-cyclohex-1-en-1-yl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in MeOH/AcOEt (2:1) was treated with 20% Pd(OH)2/C (10% wt.). The resulting suspension was stirred for 18 h under 45 psi of hydrogen then purged with nitrogen and filtered. The filtrate was concentrated to afford the title compound (98%) as a solid.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([O:8][CH:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:10]#[C:11][CH2:12]O)(=[O:7])[CH3:6]>CCOCC>[C:5]([O:8][CH:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:10]#[C:11][CH2:12][Br:2])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C#CCO)COc1ccc(F)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(=O)OC(C#CCBr)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus tribromide (10.6 g., 0.039 mole) is added dropwise during 15 minutes to a solution of 4-acetoxy-5-(4-fluorophenoxy)-2-pentyn-1-ol (25.1 g., 0.10 mole) in ether (80 ml.). The resulting solution is stirred at room temperature for 1 hour and then heated at reflux for 30 minutes. The solution is poured into 100 ml. of ice water. The organic layer is separated, washed with water and dried over Na2SO4. The solvent is evaporated under reduced pressure to leave the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+]>C1COCC1.CO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([CH2:21][C:22]([OH:24])=[O:23])=[C:2]2[CH3:1])=[CH:17][CH:16]=1
Reactant: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[2-Methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid: 1M Aqueous NaOH (1.18 ml) is added to a stirring suspension of [2-methyl-1-(4-nitro-benzyl)-1-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.2 g, 0.54 mmol) in 4:1 THF/MeOH (5 ml). The reaction mixture is allowed to stir at room temperature for 4 hours and then the solvent is removed in vacuo. The crude residue is dissolved in 1:1 THF/water and acidified to pH 3-4 using 6M HCl. After stirring for 30 minutes the resulting suspension is filtered and dried in vacuo at 110° C. to yield the titled product as a yellow solid. (MH+ 326)
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][O:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C>CC(O)C.Cl>[ClH:21].[NH2:8][CH:9]([CH2:22][O:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COC(=O)NN)COc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: CC(C)O
Product: NNC(=O)OCC(N)COc1noc2ccc(Cl)cc12

Procedure:
In 10 ml of 2-propanol is dissolved 3-(2-tert-butoxycarbonylamino-3-hydrazinocarbonyloxypropoxy)-5-chloro-1,2-benzoisoxazole, and 12.8 ml of a 2-propanol solution (7.5N) of hydrogen chloride is added thereto, after which they are subjected to reaction at 20°-25° C. for 1.5 hours. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the crystals obtained are washed with 5 ml of ethyl acetate and then collected by filtration, to obtain 0.52 g of colorless, crystalline 3-(2-amino-3-hydrazinocarbonyloxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 190°-191° C.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[N:14][C:15]([N:19](C(OC(C)(C)C)=O)[NH:20][C:21](OC(C)(C)C)=O)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:35]([F:38])([F:37])[F:36])(=O)=O)C=CC=CC=1.[C:39](O)(=O)C>>[CH3:39][C:21]1[N:14]2[C:13]3[CH:12]=[C:11]([C:35]([F:38])([F:37])[F:36])[NH:10][C:18]=3[CH:17]=[CH:16][C:15]2=[N:19][N:20]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(F)(F)F)n2S(=O)(=O)c2ccccc2)n1
Product: Cc1nnc2ccc3[nH]c(C(F)(F)F)cc3n12

Procedure:
A solution of di-tert-butyl 1-[1-(phenylsulfonyl)-2-(trifluoro methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.66 g, 1.2 mmol, from Step 3) in acetic acid (20 mL) was heated at 180° C. for 5 minutes in the microwave. The acetic acid was removed in vacuo. The residue was dissolved in EtOAc and washed with an additional NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH in DCM. Yield: (0.14 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Clc1cc2cc[nH]c2cc1Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.2 %

Procedure:
To a mixture of 5,6-dichloro-1H-indole (1.0 g, 5.37 mmol), Cu(OTf)2 (194 mg, 0.537 mmol) in DCM (15 mL) at RT, ethyl 2-diazoacetate (918 mg, 8.05 mmol) was added dropwise. The resulting mixture was stirred at RT for 16 h, quenched with water, and then extracted dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the desired product (120 mg, 8.2% yield) as light yellow solid. ESI-MS m/z: 272.1[M+H]+.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: O=C1CSC(=O)C1
Reactant: CCCC/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a stirring solution of 855 mg (7.37 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 902 μL (6.47 mmol) of triethylamine and 240 mg (1.96 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.68 g (8.76 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (8.84 mmol) of myristoleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0 N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 785 mg (33%) of 4-hydroxy-3-[(Z)-1-oxo-9-tetradecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.CC1C=CC(S(O[CH:28]2[CH2:31][N:30]([C:32]([C:34]3[O:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[N:37][N:38]=3)=[O:33])[CH2:29]2)(=O)=O)=CC=1>>[CH2:3]1[C:4]2([CH2:5][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:28]4[CH2:29][N:30]([C:32]([C:34]5[O:35][C:36]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)=[N:37][N:38]=5)=[O:33])[CH2:31]4)=[C:11]([Cl:16])[CH:10]=3)[CH2:7]2)[CH2:1][O:2]1
Reactant: Oc1ccc(CN2CC3(COC3)C2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2Cl)C1
Yield: 51.6 %

Procedure:
Using a similar protocol as described in Example 2 but employing 8A (130 mg, 0.54 mmol) and 8B (220 mg, 0.55 mmol) as starting materials afforded 130 mg (51%) of 8 as a gum. 1H NMR (500 MHz, CD3OD): δ 3.38 (s, 4H), 3.48 (s, 2H), 4.25 (dd, 1H), 4.6-4.8 (m, 6H), 5.15 (m, 2H), 6.78 (d, 1H), 7.15 (d, 1H), 7.32 (s, 1H), 7.56 (t, 2H), 7.61 (t, 1H), 8.09 (d, 2H), MS (APCI+) m/z 467 [M+H]+, LC purity: 91%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:19][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[CH2:19]
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2c1cc(Cl)nc2F

Procedure:
To a solution of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (50 mg, 0.152 mmol) in 5 mL of dry THF at −78 C was added methylmagnesium chloride, 3.0 m solution in tetrahydrofuran (16.87 μL, 0.228 mmol) (0.07 mL) and the reaction was slowly warmed up to −30 C. Only half of conversion was detected. To this was added another batch of methylmagnesium chloride, 3.0 m solution in THF (16.87 μL, 0.228 mmol) (0.07 mL). The reaction was quenched at −30 C with sat. NH4Cl, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. It was then treated with 1 mg of PPTS in DCM at 25 C for 0.5 h. After cooling, 0.1 g of NaHCO3 was added the solvent was evaporated to dryness to give crude 7-bromo-3-chloro-1-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine which was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=2)=[C:4]([C:18](=[O:20])[NH2:19])[CH:3]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[C:6]([CH3:8])[CH:7]=1)[N:9]=[C:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[N:19]=[C:18]2[OH:20]
Reactant: Cc1cc(Br)cc(C(N)=O)c1NC(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Br)cc2c(O)nc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of N-(4-bromo-2-carbamoyl-6-methylphenyl)nicotinamide (1.74 g salt, 5.22 mmol, 1.0 eq) in EtOH (50 mL) was treated with NaOH (1.04 g, 26.1 mmol, 5.0 eq). The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the volatiles were removed in vacuo. Water (30 mL) was added to the residue and the mixture was adjusted to pH˜1 or 2 by slow addition of aqueous HCl. The resultant precipitate was collected and dried to give 870 mg of iv-h as a yellow solid (77% yield after two steps), LCMS m/z=315.7, 317.7 (M+1) (Method B) (retention time=1.74 min).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]2[CH2:23][C@H:22]2[CH2:24][CH2:25][F:26])[CH:20]=1)=O)(C)(C)C>CCOCC.CO>[ClH:1].[NH:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]2[CH2:23][C@H:22]2[CH2:24][CH2:25][F:26])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCF)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: FCC[C@@H]1C[C@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M HCl (anhydrous) in ether (2.0 mL) was added to a stirred solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1R,2S)-2-(2-fluoroethyl)cyclopropyl]pyridine (160 mg, 0.45 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h. The above solution was concentrated and purified by HPLC to obtain the title compound (97 mg). 1H NMR (CD3OD, 400 MHz) δ 8.40 (br s, 1H), 8.29 (br s, 1H), 7.75 (s, 1H), 4.91-4.85 (m, 1H), 4.63-4.47 (m, 4H), 4.17-4.04 (m, 2H), 2.79-2.58 (m, 2H), 2.04-1.97 (m, 1H), 1.91-1.77 (m, 2H), 1.46-1.34 (m, 1H), 1.26-1.19 (m, 1H), 1.16-1.09 (m, 1H). MS (ESI) m/z 273 (M+Na+).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([NH:8][S:9]([C:12]1[CH:22]=[CH:21][C:15]2[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.O>[CH3:6][CH:5]([CH3:7])[C@@H:4]([NH:8][S:9]([C:12]1[CH:22]=[CH:21][C:15]2[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(SC)sc2c1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2s1

Procedure:
(2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.35 g, 0.9 mmol) was dissolved in THF/H2O (2 mL/2 mL), and added LiOH (0.16 g, 5 equi.). After the reaction soluton was refluxed for 6 hours, the solution was distilled under reduced pressure and treated with 1N HCl. The product was extracted with ethylacetate (10 mL). The separated organic phase was washed with NaCl solution, dried over MgSO4, distilled under reduced pressure and dried under vacuum, to prepare the titled compound, (2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic acid (54 mg, 23%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12)=[O:53])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c4ccc(O)cc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Methoxybenzyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl)ceph-3-em-4-carboxylate (136mg, 0.35mmol) [See example 6] in THF (10ml) was stirred in an ice bath with dicyclohexylcarbodiimide (108mg, 0.52mmol) then (R)-2-t-butoxycarbonylamino-2-(4-hydroxyphenyl)acetic acid (139mg, 0.52mmol) in THF (3ml) was added dropwise over 2 min. The mixture was stirred at 0° C. for 30 min then at room temperature for 30 min. It was filtered and evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/hexane mixtures. The title compound was obtained as a white solid (212mg, 95%); δH (CDCl3) 1.10-2.0 (4H,m), 1.42 (9H,s), 3.18 and 3.43 (2H,ABq, J 17Hz), 3.80 (3H,s), 3.77-3.88 (2H,m), 4.89 (1H,d, J 5Hz), 5.10 (1H,t, J 7Hz), 5.11 (1H,d, J 5Hz), 5.19 (2H, s), 5.65 (1H,d, J 5Hz exch), 5.69 (1H,dd, J 4,9Hz), 6.72 (2H,d, J 8Hz), 6.81 (1H,d, J 9Hz exch), 6.88 (2H,d, J 9Hz), 7.10 (2H,d, J 8Hz) and 7.33 (2H,d,J 9Hz). (Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (938)].
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)#[N:17]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)=[O:23])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)c3ccc(C#N)cc3)s2)noc1C(F)(F)F
Yield: 36 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 4-cyanobenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (130 mg, 36%). 1H NMR (CDCl3) 2.42 (d, J=1.3, 3H), 7.62 (d, J=4.0, 1 H), 7.67 (d, J=4.0, 1H), 7.85 (d, J=8.3, 1H), 7.98 (d, J=7.9, 1H). 13C NMR 8.0, 114.9, 116.3, 118.7 (q, J=271), 118.0, 129.1, 129.8, 132.7, 135.3, 137.6, 141.1, 144.6, ˜155 (q, obscured due to baseline noise), 157.7, 186.4. 19F NMR −63.1. LC/MS 7.08 min, [M+1]+ 363.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11](C)[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[ClH:26]>C1COCC1.O1CCOCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[NH:11][C:10](=[O:25])[C:9]=2[Cl:26])[CH2:3]1
Reactant: Cl
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)c(Cl)c(=O)[nH]c1=O

Procedure:
Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl in dioxane (1 mL) at RT for 1 h, concentrated, and then purified by LC-MS to give the title compound. 1H-NMR (400 MHz, DMSO-D6): 8 ppm 12.0 (s, 1H), 7.88 (d, J=7.6 Hz, 1 H), 7.68 (t, J=7.7 Hz, 1 H), 7.49 (t, J=7.7 Hz, 1 H), 7.36 (d, J=7.8 Hz, 1 H), 5.09-5.21 (m, 2 H), 3.17 (m, 2 H), 2.96 (t, J=11.1 Hz, 1 H), 2.86 (d, J=10.6 Hz, 1 H), 2.65 (m, 1 H), 1.90 (d, J=11.6 Hz, 1 H), 1.57 (d, J=13.1 Hz, 1 H), 1.19-1.31 (m, 1 H), 1.03-1.15 (m, 1 H). MS (ES) [m+H] calc'd for C17H19ClN5O2, 360.1; found, 360.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Reaction time: 0.05 h
Yield: 63.2 %

Procedure:
40% Methanolic Triton B (0.086 mL, 0.19 mM) was added to a solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (87.8 mg, 0.44 mM) Was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 44.0 mg (63%) of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CHCl3, cm−1) 3450, 3400, 1746, 1674, 1592, 1457, 1369, and 1151. MS (FD) m/e 448.
Reaction SMILES: N([C:8]1[C:9](=[O:21])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([CH3:19])=[C:12]([CH3:20])[CH:11]=2)C1C=CC=CC=1.S(=O)(=O)(O)[OH:23]>O>[CH3:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH3:20])[C:9](=[O:21])[C:8]([OH:23])=[CH:17][C:16]2=[O:18]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc2c(cc1C)C(=O)C(Nc1ccccc1)=CC2=O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)C(O)=CC2=O

Procedure:
A solution of 2-anilino-6,7-dimethyl-1,4-naphthoquinone (3.1; 0.014 mole) in concentrated sulphuric acid (70ml) was diluted with an equal volume of water and refluxed for 1 minute. After pouring into cold water the precipitated hydroxy derivative was filtered off and extracted into petrol ether (b.p. 100°-102° C). After treatment of the extract with charcoal the title compound separated as a yellow solid, 1.29g (55%), m.p. 175°-177° C (d). (Found; C, 71.29; H, 5.07; C12H10O3 requires; C, 71.28; H, 4.98%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH:9](O)=[O:10]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:9]=[O:10])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=CO
Product: O=CNc1ccc(Cl)cn1

Procedure:
Was prepared according to Example 2 from 2-amino-5-chloropyridine and formic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][NH:33][CH3:34])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:33]([CH2:32][CH:28]4[CH2:29][CH2:30][CH2:31][N:27]4[CH2:25][CH3:26])[CH3:34])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCCC1CNC
Product: CCN1CCCC1CN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(1-ethylpyrrolidin-2-yl)-N-methylmethanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.36 (m, 3 H) 1.60-1.96 (m, 2 H) 2.11 (br. s., 1 H) 2.43 (s, 3 H) 2.60-2.95 (m, 2 H) 3.06 (br. s., 3 H) 3.12-3.58 (m, 5 H) 3.58-3.84 (m, 1 H) 7.54 (d, J=8.08 Hz, 1 H) 7.59 (s, 1 H) 7.93 (s, 1 H) 7.98 (dd, J=8.72, 2.15 Hz, 1 H) 8.07 (br. s., 1 H) 8.48 (d, J=8.08 Hz, 1 H) 8.50-8.54 (m, 1 H); ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[C:32]([CH2:34]Cl)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[S:30][CH:31]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(C)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
A mixture of 150 mg of [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (0.59 mmol), 190 mg of 2-(4-tert-butyl-phenyl)-4-chloromethyl-thiazole (0.71 mmol) and 325 mg of cesium carbonate (1 mmol) in 5 ml of acetonitrile was stirred at 60° C. for 1 h. The solvent was then evaporated and the residue obtained was chromatographed on silicagel using a 98:2 (v/v) mixture of dichloromethane and diethyl ether as the eluent. Thus, 150 mg (52% of theory) of [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was obtained as a colorless viscous oil.