Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([OH:24])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:33][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.5 g 4-{2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 23 ml DMF were added 1.87 g benzyl bromoacetate and 5.31 g cesium carbonate. After stirring at room temperature for 12 h the solution was diluted with 100 ml ethyl acetate and extracted with aqueous LiCl (4 w/w), 0.1 M HCl and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the following reactions. Yield: 3.6 g
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[C:13]([CH3:26])[CH:12]=2)=[C:5]2[CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH2:31][C:4]=12)[CH3:2].[NH3:34]>CO>[NH2:34][CH2:20][CH2:19][CH2:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][C:5]=23)=[O:27])=[CH:12][C:13]=1[CH3:26]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(CCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Reactant: N
Solvent: CO
Product: CCc1sc(C(=O)CCc2cc(C)c(CCCN)c(C)c2)c2c1CC(C)(C)CC2

Procedure:
A solution of methanesulfonic acid 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenyl}-propyl ester (160 mg, 0.326 mmol) in 7 N NH3 in methanol is stirred at 70° C. for 16 h in a sealed vial. The solvent is removed and the residue is purified by CC on silica gel eluting with DCM containing 7% of methanol to give 3-[4-(3-amino-propyl)-3,5-dimethyl-phenyl]-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (101 mg) as a pale yellow resin; LC-MS: tR=0.95 min, [M+1]+=412.36; 1H NMR (CDCl3): δ 6.87 (s, 2H), 3.09-3.00 (m, 4H), 2.97-2.88 (m, 4H), 2.76-2.60 (m, 6H), 2.30 (s, 2H), 2.28 (s, 6H), 1.80-1.70 (m, 2H), 1.54 (t, J=7.0 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H), 0.96 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].C[O-].[Na+].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].Cl>C(OCC)C.C(OCC)(=O)C>[F:10][C:6]1[CH:5]=[C:4]([C:11](=[O:13])[CH2:12][C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[CH:3]=[C:2]([F:1])[C:7]=1[S:8][CH3:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CSc1c(F)cc(C(C)=O)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CSc1c(F)cc(C(=O)CC(=O)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-[3,5-difluoro-4-(methylthio)phenyl]ethanone (4.84 g, 23.9 mmol) was dissolved in diethyl ether (200 mL). Sodium methoxide (24 mL of 25% in methanol, 30 mmol) was added and stirred 10 min at ambient temperature. Ethyl trifluoroacetate (3.79 g, 23.9 mmol) was added. The solution was stirred for 1 hour then aqueous hydrochloric acid was added (100 mL, 1 M). The layers were separated and the organic layer collected. The organic layer was washed with water (2×100 mL), saturated ammonium chloride (2×200 mL) and dried over sodium sulfate. The solvent was removed in vacuo to afford a yellow oil. The 1-[3,5-difluoro-4-(methylthio)phenyl]-4,4,4-trifluorobutane-1,3-dione was isolated by crystallization from ethyl acetate and hexanes (5.50 g, 77%). 1H NMR (CDCl3/300 MHz) 7.49 (m, 2H), 6.50 (s, 1H), 2.62 (s, 3H). ESHRMS m/z 297.0012 (M+H+, Calcd 297.0009). Anal. Calcd for C11H7F5O2S: C, 44.30; H, 2.37. Found: C, 44.36; H, 2.26.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](=[CH:21]\[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)/[C:18](O)=[O:19])=[CH:13][CH:12]=1.CO>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](=[CH:21]\[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)/[CH2:18][OH:19])=[CH:15][CH:16]=1
Reactant: O=C(O)/C(=C/C1CCCCC1)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: OC/C(=C/C1CCCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
Add DIBAL in toluene (673 mL, 1.0 M, 673 mmol) to a solution of (E)-2-(4-bromo-phenyl)-3-cyclohexyl-acrylic acid (52 g, 168 mmol) in toluene (1.6 1) maintained at −78° C. Then allow the reaction mixture to slowly warm to room temperature, and stir, it for 18 h. Cool reaction mixture to 0° C. and add MeOH to destroy excess amounts of DIBAL. Add Rochelle's salt (100 mL) and HCl (2 N). Separate the layers and wash the organic layer with brine. Filter through hydrophobic filter and concentrate to obtain the title compound (48.8 g) as a white solid. MS (m/e): 277 (M+H−H2O).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[S:5].[C:26]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](O)=[O:41])=[CH:36][C:35]=1[OH:45])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40]([O:25][CH2:24][CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][CH:7]=3)=[C:2]([OH:1])[CH:21]=2)=[O:41])=[CH:36][C:35]=1[OH:45])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Product: O=C(COc1ccc(C(=O)c2ccccc2)c(O)c1)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
Following the general procedure of Example 17, the title compound is prepared by reacting equimolar amounts of the alcohol compound of Example 7 and 4-benzoyl-3-hydroxy-phenoxyacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:9](=[O:13])[CH2:10][CH2:11][I:12])[C:5]([F:8])=[CH:6][CH:7]=1.[Na+].[I-]>C(#N)C.O>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C@H:9]([OH:13])[CH2:10][CH2:11][I:12])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C(CCI)c1c(F)ccc(Cl)c1F
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O[C@H](CCI)c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
1-(3-Chloro-2,6-difluorophenyl)-3-iodopropan-1-one: (Ref: Synthesis, 366-399 (1998)) To a stirred solution of NaI (0.153 g, 1.019 mmol) in ACN (0.637 ml) was added TMS-CI (0.130 mL, 1.019 mmol) dropwise. A precipitate was formed, and the mixture turned yellow. Water (0.015 mL, 0.849 mmol) was added (which re-dissolved the precipitate), followed by addition of Intermediate 2B (0.172 g, 0.849 mmol). The mixture was diluted with additional ACN (0.637 mL), and stirred at rt under argon for 15 min. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with 10% Na2S2O3 and brine, dried over anhydrous MgSO4, filtered, and concentrated to yield the desired product as a light yellow oil (0.265 g, 94%), MS (ESI) m/z: 330.7 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.50 (ddd, J=8.9, 8.1, 5.7 Hz, 1H), 6.96 (td, J=8.8, 1.8 Hz, 1H), 3.59-3.53 (m, 2H), 3.45-3.40 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([S:21](Cl)(=[O:23])=[O:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:21]([CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
To a solution of 10.0 g (50 mmol) of 4-bromophenethylamine and 7.6 mL (55 mmol) of triethylamine in 150 mL of dichloromethane was added a solution of 6.2 mL (55 mmol) of isopropylsulfonyl chloride in 40 mL of dichloromethane dropwise. The mixture was stirred at room temperature for 18 hr. The mixture was washed with 100 mL of 1N aqueous hydrochloric acid, the organic layer was separated and the aqueous layer extracted one time with 100 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford 6.7 g (44%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[C:37]([OH:42])=[C:36]([O:43][CH3:44])[CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[C:36]([O:43][CH3:44])[C:37]([OH:42])=[C:38]([O:40][CH3:41])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COc1cc(CCN)cc(OC)c1O
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: COc1cc(CCNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)cc(OC)c1O

Procedure:
Intermediate 4 was coupled with 4-(2-Amino-ethyl)-2,6-dimethoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.26 (d, 1H) 8.21 (s, 1H) 8.12 (d, 1H) 7.68 (d, 1H) 7.58 (d, 1H) 7.33 (d, 1H) 6.53 (s, 2H) 4.50 (s, 2H) 3.76 (s, 6H) 3.37 (m, 2H) 2.97 (s, 3H) 2.9 (m, 2H) 2.81 (m, 2H) 1.70 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]([CH3:28])([CH3:27])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:13][N:12]=2)=[CH:5][CH:4]=1)#[N:2]>ClC1C=CC=CC=1Cl>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([C:11]3[N:12]=[CH:13][C:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[CH:15][CH:16]=3)[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)(C#Cc1ccc(C(=O)OCc2ccccc2)cn1)Oc1ccc(C#N)cc1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2ccc(C(=O)OCc3ccccc3)cn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
9 g of benzyl 2-[3-(4-cyanophenoxy)-3-methyl-1-butyn-1-yl]pyridine-5-carboxylate were dissolved in 300 ml of 1,2-dichlorobenzene and the solution was added dropwise over a period of 5 hours to 100 ml of 1,2-dichlorobenzene heated at reflux. After a further 2 hours the mixture was allowed to cool to room temperature and was then evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:9), (1:6) and (1:4) for the elution. There were obtained 5.5 g of benzyl 6-(6 -cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylate which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].Cl[CH:15]([Cl:19])[CH:16](Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Cl:19][C:15]1[CH:4]=[CH:3][C:2]([C:5]([C:4]2[C:10]([F:13])=[CH:11][CH:12]=[C:2]([F:1])[C:3]=2[C:8]([OH:7])=[O:9])=[O:6])=[CH:12][CH:16]=1
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: ClC(Cl)C(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.3 %

Procedure:
To a solution of 3,6-difluorophthalic anhydride (3.0 g, 16.00 mmol) in 1,1,2,2-tetrachloroethane (30 mL) chlorobenzene (2.0 mL, 18.00 mmol) was added followed by the addition of aluminum chloride (4.40 g, 33.00 mmol). The reaction mixture was stirred at room temperature for 120 minutes followed by the stirring at 60° C. for an additional 90 minutes. It was cooled to room temperature, poured into ice water (300 mL) and diluted with 1M aqueous hydrochloric acid. The aqueous slurry was extracted with ethyl acetate (300 mL) and the organic layer was washed with water (70 mL), brine (70 mL) and dried over anhydrous sodium sulfate. Filtration and concentration resulted in a crude product, which was crystallized from ethyl acetate by the addition of hexane. The product was collected by filtration and dried in vacuo to give 2-[(4-chlorophenyl)carbonyl]-3,6-difluorobenzoic acid (3.52 g, 73% yield). 1HMR (400 MHz, CD3OD): 7.77 (s, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.53-7.34 (m, 2H). MS (EI) for C14H7ClF2O3: 281 (M−H2O).
Reaction SMILES: [OH-].[K+].[CH:3]1([C:6]([CH:14]2[CH2:16][CH2:15]2)([C:8]2[S:9][C:10]([SH:13])=[N:11][N:12]=2)[OH:7])[CH2:5][CH2:4]1.Br[C:18]1[CH:27]=[C:26]2[C:21]([C:22]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1>CO>[CH:14]1([C:6]([CH:3]2[CH2:5][CH2:4]2)([OH:7])[C:8]2[S:9][C:10]([S:13][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:23][C:24](=[O:28])[O:25]4)=[CH:20][CH:19]=3)=[N:11][N:12]=2)[CH2:15][CH2:16]1
Reactant: OC(c1nnc(S)s1)(C1CC1)C1CC1
Reactant: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1cc(-c2cccnc2)c2ccc(Sc3nnc(C(O)(C4CC4)C4CC4)s3)cc2o1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
KOH (0.089 g, 1.59 mmol) was added to a solution of dicyclopropyl(5-mercapto-1,3,4-thiadiazol-2-yl)methanol (0.363 g, 1.60 mmol) in dry MeOH. When a solution was obtained, the reaction mixture was concentrated to dryness. Dry toluene was then added and the mixture was concentrated to dryness again. The residue was dissolved in NMP, 7-bromo-4-pyridin-3-yl-2H-chromen-2-one (400 mg, 1.32 mmol) was added and the resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was cooled and partitioned between aqueous NH4OAc and EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated and purified on silica gel column (toluene-acetone, 90:10 to 70:30) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.82 (d, 1H), 8.72 (s,1H), 7.81 (dt, 1H), 7.64 (s, 1H), 7.58-7.50 (m, 1H), 7.48-7.41 (m, 2H), 6.46 (s, 1H), 2.57 (s, 1H), 1.40-1.31 (m, 2H), 0.69-0.57 (m, 6H), 0.50-0.44 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 83.2 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, a 100 g (0.413 mol) of a mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 43.8 g (0.413 mol) of sodium carbonate were charged, and the mixture was reacted at 130° C. for 5 hours with vigorous stirring. Then, the reaction mixture was subjected to distillation to obtain 75.6 g of tetrafluorophthalic anhydride. The yield was 83.2%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]([OH:13])=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1>>[Br:5][C:6]1[C:7]([OH:13])=[N:8][C:9]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: Cc1ccc(Br)c(O)n1
Reactant: O=[N+]([O-])O
Product: Cc1nc(O)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a 500 ml single-necked round-bottomed flask, 230 ml of a 65% aqueous HNO3 solution is added and stirred under cooling (ice/water cooling bath). 7.00 g of 3-bromo-6-methyl-pyridin-2-ol 2 at ambient temperature is introduced portion-wise. Stirring is continued for 3.5 hours at ambient temperature. After pouring the mixture into 200 ml of an ice/water mixture (pH 1), the water phase is extracted with AcOEt. The organic phase is washed twice with water brought to pH 4 by adding aqueous NaOH solution (pH meter), then dried over sodium sulfate, filtered and concentrated in vacuo to give 7.52 g of a yellow solid. This crude material is suspended in diethyl ether and stirred for 1 hour at ambient temperature, filtered, washed with the same solvent and dried to give 3.89 g of the compound as a yellow-orange solid (m.p. >220° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[C:7](OCC)(=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O-]CC.[Na+]>C(O)C>[OH:5][C:3]([CH:2]([CH3:6])[CH3:1])=[CH:4][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C=C(O)C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
To a mixture of 17.2 g of 3-methyl-2-butanone, 27.1 g of diethyl oxalate and 130 ml of ethanol was added 95 ml of sodium ethoxide (20% ethanol solution), and the resulting mixture was stirred at 60° C. for 5 hours. After allowed to cool to room temperature, a deposited precipitate was collected by filtration and washed with ethanol. The filter cake was partitioned between 2N hydrochloric acid and methyl t-butyl ether. The organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 28.8 g of ethyl 4-hydroxy-5-methyl-2-oxo-3-hexenoate of the formula:
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:30]=1)[C:22]1[CH:21]=[C:20]([OH:23])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.CCOC(C)=O>[C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:30]=1)[C:22]1[CH:21]=[C:20]([O:23][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)COc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 100 °C

Procedure:
To a solution of 2-(tert-butylamino)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (0.075 g, 0.179 mmol) in DMF (2 mL) was added cesium carbonate (0.175 g, 0.538 mmol) followed by 1-iodo-2,2-dimethylpropane (0.048 mL, 0.358 mmol). The mixture was heated to 100° C. After 6 hrs the mixture was cooled to RT, diluted with EtOAc, and washed with water and brine. The organic fraction was concentrated in vacuo and purified by silica gel chromatography using 40-60% Hexanes:EtOAc to afford N-tert-butyl-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine as an off-white foam. MS: MH+=489.2.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([S:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[NH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([S:31]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[O:9])[NH:22][C:23]=2[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(-c2nc(Sc3cccs3)[nH]c2-c2ccc(Cl)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.90 g of 4,5-bis(4-chlorophenyl)-2-(2-thienylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 3.83 g of 4,5-bis(4-chlorophenyl)-2-(2-thienylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Na+].[I-:17]>CC(=O)CC.CCOCC>[I:17][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)C1(CCCCCl)CC1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(CCCCI)CC1
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.6 g, 45.7 mmol) in 2-butanone (50 mL) was added NaI (8.23 g, 54.5 mmol). The reaction mixture was stirred under reflux overnight, diluted with Et2O (100 mL), washed with a mixture of H2O (100 mL) and aqueous Na2S2O4 (0.5 M, 10 mL) and brine (50 mL). The organic phase was dried (Na2SO4) and evaporate in vacuo to give tert-butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate (14.8 g, 94% pure by GC, 94%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=3.18 (t, J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.62-1.45 (m, 4H), 1.43 (s, 9H), 1.12 (dd, J=6.7 Hz, 3.8 Hz, 2H), 0.60 (dd, J=6.6 Hz, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=173.9, 80.0, 33.8, 33.3, 28.9, 28.2 (3×), 24.2, 15.5 (2×), 7.2. HRMS calcd for C12H21IO2 (M+): 324.0587, found: 324.0587.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#N)[CH:6]=1.C(O)=[O:15]>[Al].[Ni]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:15])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C#N)c1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: COC(=O)Cc1cccc(C=O)c1
Temperature: 25 °C

Procedure:
A mixture of (3-cyano-phenyl)-acetic acid methyl ester (1.56 g, 8.91 mmol), aluminum-nickel alloy (1.63 g) and 75% formic acid (25 mL) was heated at reflux for 1.75 h. The mixture was cooled to room temperature and the solids were removed by filtration through Celite with the aid of boiling EtOH. Water was added and the aqueous solution was washed with CH2Cl2 (3×). Aqueous saturated NaHCO3 was carefully added to the organic solution until the pH was about 8-9. The organic solution was washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (5:1 hexanes:EtOAc) provided the title compound as a clear and colorless oil (870 mg). 1H NMR (400 MHz, CDCl3) δ9.98 (s, 1H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]1=[O:9].[C:10](=O)([O-:12])[O-:11].[K+].[K+]>>[C:10]([C:5]1[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:9])[C:4]=1[OH:8])([OH:12])=[O:11]
Reactant: Cn1cccc(O)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(C(=O)O)c(O)c1=O
Yield: 87.7 %

Procedure:
1-Methyl-3-hydroxy-2(1H)-pyridinone (1) (6.25 g, 50 mmol) is mixed with anhydrous potassium carbonate (36 g, 0.26 mol). The vacuum dried mixture is put in a Parr bomb which is then filled with dry carbon dioxide gas (850 psi) and heated to 175°-185° C. for 3 days. The cooled bomb is opened and the resultant pale yellow solid is dissolved in ice water and acidified with 6N HCl to produce a beige crystalline product (7.42 g, 87.5%), m.p. 243°-245° C. (dec). 1H NMR (250 MHz, DMSO-d6): δ3.469 (s, 3H), 6.357 (d, 1H, J=7.33), 7.166 (d, 1H, J=7.19), 7.27 (s,br, 1H). 1H NMR (250 MHz, D2O-NaOD): d 3.342 (s, 3H), 6.176 (d, 1H, J=6.94), 6.487 (d, 1H, J=7.00). Anal. for C7H7NO4 (169.14): Calcd. (found): C, 49.71 (49.74); H, 4.17 (4.30); N 8.28 (8.16).