Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)=[C:26]([F:35])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:31][CH2:32][CH2:33]2)=[C:26]([F:35])[CH:25]=1
Reactant: OC1(c2ccc(Br)cc2F)CCC1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)c(F)c3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (75 mg, 0.23 mmol), 1-(4-bromo-2-fluorophenyl)cyclobutanol (57 mg, 0.23 mmol), 4 M aqueous potassium carbonate (0.47 mL, 0.9 mmol), toluene (3 mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (9 mg, 0.011 mmol). The reaction mixture was placed in a pre-heated oil bath at 105° C. and stirred for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine (lx each), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid, which was purified by flash chromatography (12 g silica, 10-50% ethyl acetate/heptane, 21 column volumes). The product fractions were combined and concentrated in vacuo to afford the title compound as a colorless solid (49 mg, 56% yield). MS (ES−) 372.2 (M−H)−. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1 H), 8.10 (s, 1 H), 7.94 (d, J=2.93 Hz, 1 H), 7.54 (s, 1 H), 7.38-7.44 (m, 1 H), 7.18-7.28 (m, 2 H), 3.89 (s, 3 H), 2.66-2.77 (m, 2 H), 2.42 (m, 2 H), 2.11-2.22 (m, 1 H), 1.74-1.86 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([O:37][CH3:38])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=3[O:37][CH3:38])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1cc(F)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(F)ccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 110 °C
Yield: 53.2 %

Procedure:
To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.63 g, 1.7 mmol) and 4-fluoro-2-methoxy-phenylboronic acid (0.30 g, 1.8 mmol) in saturated sodium carbonate solution (4 ml) and 1,4-dioxane (4 ml) was added palladium(II) acetate (0.076 g, 0.34 mmol) followed by triphenylphosphine (0.089 g, 0.34 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and the reaction monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(4-fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XIX) (0.42 g, 53%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:25]=[CH:24][C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:26]1([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:25]=[CH:24][C:19]4[NH:20][C:21](=[O:23])[O:22][C:18]=4[CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)C3CCNC3)cc2o1
Reactant: O=CCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccc(S(=O)(=O)C3CCN(CCCCc4ccccc4)C3)cc2o1

Procedure:
The title compound, MS: m/e=401.4 (M+H+) was prepared from (RS)-6-(pyrrolidine-3-sulfonyl)-3H-benzooxazol-2-one trifluoroacetic acid and 4-phenyl-butyraldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15]CC)=[O:14])[C:9]=2[CH3:18])[CH:5]=[CH:6][CH:7]=1.Cl.NO>CCO>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]=2[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc(-c2cccc(Cl)c2F)c1C
Agent: Cl
Agent: NO
Solvent: CCO
Product: Cc1c(C(=O)O)noc1-c1cccc(Cl)c1F
Temperature: 90 °C
Reaction time: 5 h
Yield: 39 %

Procedure:
Ethyl 5-(3-chloro-2-fluorophenyl)-4-methylisoxazole-3-carboxylate: The mixture of Intermediate 47C (0.057 g, 0.199 mmol) and hydroxylamine hydrochloride (0.017 g, 0.239 mmol) in EtOH (1 mL) was heated in a sealed tube at 90° C. After 5 h, the reaction was cooled to rt and then it was concentrated. Purification by reverse phase HPLC afforded the desired product (0.022 g, 39%) as a white solid. MS(ESI) m/z: 284.0 (M+H)+. 1H NMR (500 MHz, MeOD) δ 7.73-7.68 (m, 1H), 7.56 (ddd, J=7.8, 6.2, 1.7 Hz, 1H), 7.37 (td, J=8.0, 1.1 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 2.24 (d, J=2.2 Hz, 3H), 1.42 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1cc(F)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2ccc(F)cc2N)c1
Yield: 88.2 %

Procedure:
Following General Procedure A, the title compound (750 mg, 88%) was prepared from 2-amino-4-fluorobenzenethiol (417 mg, 2.92 mmol) and methyl 3-(bromomethyl)benzoate (666 mg, 2.92 mmol), K2CO3 (1.21 g, 8.75 mmol) in DMF (10 ml).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 224 (0.500 g, 0.00102 mol) was taken in THF (8 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (0.213 g, 0.0051 mol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:10]=[C:11]([N:15]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl.O=[Mn]=O>[C:2]([C:9]1[CH:10]=[C:11]([N:15]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(O)c2ccccc2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(α-hydroxybenzyl)phenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.717 g, 1.87 mmol) in 10 mL DCM was added activated MnO2 (0.489 g, 5.62 mmol). The reaction was gently heated and sonicated for 5 min then stirred overnight. Another portion of MnO2 (0.489 g, 5.62 mmol) was added and it was sonicated and stirred overnight again. The mixture was filtered through Celite and concentrated to give a pure white solid. 1H NMR: 8.52 (dd,J=4.9, 1.5 Hz, 1H), 8.40 (d,J=2.0 Hz, 1H), 7.74-7.66 (m,5H), 7.61 (m,1H), 7.51-7.42 (m,4H), 7.25 (dd,J=7.8, 4.9 Hz, 1H), 4.93 (s,2H), 3.14 (q,J=7.3 Hz, 2H), 1.45 (t,J=7.3 Hz, 3H). MS calcd. 380.1; MS (M+1) 381.1.
Reaction SMILES: C([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[N:11]([C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>C1COCC1.O.[Pd]>[Cl:32][C:27]1[CH:26]=[C:25]([CH2:24][C:23]([N:11]2[CH:12]3[CH:17]([CH2:16][CH2:15][CH2:14][CH:13]3[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[NH:8][CH2:9][CH2:10]2)=[O:33])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)C2CCCC(N3CCCC3)C21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[(4aRS,8SR,8aRS)-4-Benzyl-8-(pyrrolidin-1-yl)perhydroquinoxalin-1-yl]-2-(3,4-dichlorophenyl)ethan-1-one (244 mg, 0.50 mmol) was dissolved in THF/H2O (1:1, 50 ml), and conc. HCl (5 ml) and palladium-on-carbon (Pd/C) (Merck) (98.4 mg) were added. The mixture was stirred under 1 bar of H2 at room temperature for 30 minutes. The catalyst was filtered off and THF was evaporated off in vacuo. The aqueous phase was brought to pH 8 with NaOH (2 N) and extracted by shaking five times with CH2Cl2. The combined organic phases were dried over Na2SO4 and evaporated. The yellowish residue was purified by column chromatography over silica gel 60 (40-63 μm, (Merck) column Ø 3 cm, CH2Cl2/MeOH/NH3 9:1:0.1, l=17 cm, V=10 ml) and gave a yellow resin.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.N1CCCCC1.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:37]#[C:36][C:34]([OH:38])([C:30]4[S:29][CH:33]=[CH:32][N:31]=4)[CH3:35])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a sealed tube was added 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide (55%, 113 mg, 0.172 mmol), followed by piperidine (2 mL), tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol), copper(I) iodide (7 mg, 0.034 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (105 mg, 0.688 mmol). The reaction mixture was purged with nitrogen gas, capped and stirred at 60° C. for 1.5 hr. Reaction mixture was concentrated in vacuo. EtOAc (5 mL) added. Concentration in vacuo was repeated. The residue was purified using column chromatography (Biotage, 100% DCM to 10% MeOH/DCM) to give a brown solid. Trituration of the solid with DCM gave the title compound: 1H NMR (500 MHz, DMSO) delta 1.95 (3H, s), 3.12 (3H, s), 3.33 (3H, s), 7.12 (2H, s), 7.13-7.19 (2H, m), 7.42 (1H, dd, J=8.35, 1.42 Hz), 7.71 (1H, d, J=3.31 Hz), 7.80 (1H, d, J=3.15 Hz), 7.97-8.07 (1H, m), 8.35 (1 H, d, J=5.52 Hz), 8.94 (1H, s); LC-MS: m/z=+434.45 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CC1=CCC(C(C)CC=O)CC1
Product: CC1=CCC(C(C)CCN2CCCC2)CC1

Procedure:
The procedure of Example 1 was followed using 50g (0.3 mole) of 3-(4-methyl-3-cyclohexenyl)butyraldehyde and 24g (0.33 mole) of pyrrolidine. Obtained following distillation was 48.5g of pure N-[3 . . . butyl]pyrrolidine as a clear, colorless liquid: bp 106°-108° (0.2mm) ir (τ max. film 3.5 (s), 6.9 (s), 7.3 (s), 8.7 (s), 12.5 (m) microns; nmr (δ, CDCl3) 5.36 (m, 1H), 2.45 (m, 6H), 2.1 to 0.8 (m, 20H) ppm; ms (molecular ion) 221.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.[Br-].[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Zn+].C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:11]2[S:10][CH:14]=[CH:13][N:12]=2)[CH:7]=1
Reactant: [Zn+]c1nccs1
Reactant: Fc1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccnc(-c2nccs2)c1
Reaction time: 3.5 h
Yield: 78 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2-chloro-4-fluoropyridine (99 mg, 0.75 mmol) and Pd(dppf)Cl2 (27 mg, 0.038 mmol). The vial was sealed with a septum screwcap and then was placed under N2 atmosphere. To the vial was added thiazol-2-ylzinc(II) bromide in THF (3.0 mL, 1.5 mmol). The vial was placed in a 60° C. heating block with stirring for 3.5 h. The reaction solution was transferred to a 125 mL reparatory funnel and was diluted with EtOAc (50 mL). The solution was washed with water:brine (25 mL:25 mL); then brine (50 mL). The organic solution was dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was subjected to silica gel chromatography (hexanes:EtOAc) to afford 2-(4-fluoropyridin-2-yl)thiazole as a white solid (106 mg, 78%). 1H-NMR (400 MHz, CDCl3-d) δ 8.59 (dd, J=8.3, 5.5 Hz, 1H), 7.98-7.92 (m, 2H), 7.49 (d, J=3.3 Hz, 1H), 7.07 (ddd, J=8.2, 5.6, 2.5 Hz, 1H): MS: MS m/z 181.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]=[CH:11][CH:10]2[OH:15])=[C:4]([CH3:16])[CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cc(C)c1C1C(=O)C=CC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1cc(F)cc(C)c1C1C(=O)C=CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 5-(4-fluoro-2,6-dimethylphenyl)-4-hydroxy cyclopent-2-enone (3 g, 13.6 mmol) in acetone (36 ml) is added freshly prepared Jones reagent (24 ml) at 0° C. The resulting solution is stirred at 0° C. for 60 minutes. The reaction mixture is quenched with ice cold isopropyl alcohol (25 ml) and stirred for one hour. The organics evaporated under vacuo and extracted with ethyl acetate, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo to give a residue which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(4-fluoro-2,6-dimethylphenyl)cyclopent-4-ene-1,3-dione (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][OH:13])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[O:10][CH2:11][CH2:12][OH:13]
Reactant: N#Cc1ccc(Cl)cc1OCCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(Cl)cc1OCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-2-fluoro-benzonitrile (1.00 g, 6.43 mmol), ethylene glycol (3.59 mL, 64.3 mmol) and K2CO3 (1.33 g, 9.64 mmol) in DMF (30 mL) is stirred at RT for 12 h. The reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4. Concentration in vacuo affords the corresponding 4-chloro-2-(2-hydroxy-ethoxy)-benzonitrile. A THF (6 mL) solution of 4-chloro-2-(2-hydroxy-ethoxy)benzonitrile (875 mg, 4.43 mmol) is added to a suspension of LAH (504 mg, 13.2 mmol) in THF (45 mL) at 0° C. The reaction is allowed to stir for 2 h at ambient temperature and then quenched by Na2SO4.10H2O, and the product is isolated by filtration with Celite and washed with THF and dried under reduced pressure to give the title compound as colorless solid; ES-MS: M+=202.1; HPLC: AtRet=1.90 min
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])(=[O:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:12](=[O:14])[CH3:13])[CH:16]=1)=[O:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: CC(=O)c1cccc(NC(=O)c2cc(Cl)ccc2O)c1
Yield: 80 %

Procedure:
Using 5-chlorosalicylic acid and 3-acetylaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Na+].Cl.ClCCl>CC1CCCO1.O.C(OC)(C)(C)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 23.5 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To a stirred mixture of crude (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (273 g, 0.512 mol, 83% pure) in 2-methyltetrahydrofuran (1030 mL) was added 2N sodium hydroxide (308 mL, 616 mmol) and the resulting mixture stirred at 21-26° C. for 20 min. To this mixture was added 2N sodium hydroxide (265 mL, 530 mmol) and the resulting mixture stirred vigorously for 2.5 h. The mixture was diluted with water (500 mL) and methyl t-butyl ether (300 mL) and stirred for 10 min. The aqueous layer was acidified with 2N hydrochloric acid (60.0 mL, 120 mmol) (pH=3) and extracted with ethyl acetate (300 mL). The organic layer was separated and washed with a sodium hydroxide solution (1N, 200 mL). The combined aqueous layers were washed with methyl t-butyl ether (500 mL). The aqueous layer was cooled to 15° C. before a hydrochloric acid solution (6N, 210 mL) was added over 20 min maintaining a temperature of 15-19° C. until a pH of 2.6 was obtained. To this solution was added dichloromethane (1000 mL) and the mixture was separated. The aqueous phase was extracted with dichloromethane (300 mL). The dichloromethane layers were combined and washed with an aqueous 20% sodium chloride solution (200 mL). The solution was evaporated and residue suspended in formic acid (1272 mL). The mixture was slowly stirred until a solution was achieved before water (1330 mL) and seed crystals (1 g) were added. The resulting mixture was stirred for 2.5 h at room temperature. The mixture was cooled to 5° C., filtered and the cake washed with water and dried under vacuum to give (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (111 g, 56.9%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 90.3 %

Procedure:
A suspension of the {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (45.7 mg, 0.1 mM) and 0.11 mL (0.11 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 22 hours at 25° C. A small volume of diethyl ether/hexanes was added, then cooled in the refrigerator. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH/diethyl ether/hexanes, then dried in vacuo to afford 40 mg (86%) of the {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.6-7.4 (m, 6H), 7.3 (t, 1H, J=8 Hz), 7.2 (t, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.9 (t, 1H, J=8 Hz), 6.5 (d, 1H, J=8 Hz), 5.8 (s, 2H), and 4.25 (s, 2H). MS (ES) m/e 441, 443, 445.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]N)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:14]=1>C(O)(=O)C>[CH2:22]([C:21]1[O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:20]=1[C:19](=[O:27])[C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)CC(=O)c1ccc(O)cc1
Reactant: NOc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
O-4-nitrophenylhydroxylamine (1.0 g), was suspended in acetic acid (10 ml) and 1-(4-hydroxyphenyl)-heptane-1,3-dione (1.36 g; see step (b) above) was added. The mixture was stirred for 3 h at 70° C. and then at 100° C. for an additional 22 h. The mixture was cooled to room temperature and the solvent evaporated under vacuum. Yield 80% of 2-Butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH2:27][CH3:28])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (2.0 g) was dissolved in ethanol (50 ml) and to the solution was added conc. sulfuric acid (0.5 ml). The mixture was heated under reflux for 5 hours. After dilution with water, the mixture was extracted with ethyl acetate and the extract was washed with water, dried (MgSO4) and concentrated under reduced pressure to obtain the title compound as crystals. The crystals were recrystallized from ethyl acetate to obtain prisms, yield 1.34 g (61.0%), m.p. 126°-127° C.