Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]2[CH2:9][CH2:10][CH2:11][CH:2]12.[OH-].[Na+].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>CN(C=O)C>[C:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:1]2[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:3]3[CH2:9][CH2:10][CH2:11][CH:2]23)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])[CH3:15]
Reactant: O=C(O)C1CC2CCCC2N1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(S(=O)(=O)N2C(C(=O)O)CC3CCCC32)cc1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
1 g of octahydrocyclopenta[b]pyrrole-2-carboxylic acid (6.45 mmol) was dissolved in 20 ml of DMF, after which 3 equivalents of a 3N solution of NaOH (6.45 ml) were added at 0° C. After 10 min, a solution of 1.55 g of 4-acetylbenzenesulfonyl chloride (1.1 equivalents, 7.1 mmol) in 8 ml of DMF was slowly added dropwise; after it had reached RT, the mixture was stirred at 40° C. for a further 6 h and, after that, the solvent was removed under reduced pressure. The crude product was purified chromatographically.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][C@H:8]([C:16](OC)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].[Cl-].[Li+].[BH4-].[Na+]>O1CCCC1.C(O)C>[CH3:3][C:2]([CH3:20])([O:4][C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:16][OH:17])=[O:6])[CH3:1]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester (10 g, 35.8 mmole) dissolved in a mixture of tetrahydrofuran (190 ml) and absolute ethanol (190 ml) is added lithium chloride (6.09 g, 143.2 mmole). The resulting homogeneous solution is treated with sodium borohydride (5.42 g, 143.2 mmole) and the reaction is stirred at room temperature under argon for 24 hours. The reaction mixture is next filtered using ether (~700 ml) to rinse the filter cake. The resulting filtrate is rinsed with water (3×200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated in vacuo to give 9 g of crude product. Recrystallization from ether/hexane gives 7.59 g of the title D compound,; m.p. 94°-96°.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH3:15][N:16]1C(=O)CCC1.C([Cu])#N>CCOC(C)=O>[N+:8]([C:7]1[C:2]([C:15]#[N:16])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Solvent: CCOC(C)=O
Product: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A microwave reaction vial was charged with 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (2 g, 8.83 mmol), NMP (4.41 ml) and CuCN (0.830 g, 9.27 mmol). The vial was sealed and the mixture was irradiated in the MW at 175° C. for 15 min. Upon cooling to RT, the reaction mixture was poured onto ice and EtOAc was added. The mixture was filtered through Celite, washing with EtOAc and a small amount of MeOH. The layers of the filtrate were separated, and the aqueous portion was extracted again with EtOAc. The combined organic portions were dried with sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography, using a gradient of 0-30% EtOAc in heptane to provide 3-nitro-5-(trifluoromethyl)picolinonitrile (645 mg, 2.97 mmol, 33.7% yield) as a yellow oil that solidified upon standing. LC/MS (ESI) m/z=218.1 (M+H).
Reaction SMILES: C[C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:38])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][CH2:32][S:33]4(=[O:37])=[O:36])=[CH:28][CH:27]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(O)(=[O:42])C>O>[CH:2]([O:7][C:6]1[CH:8]=[CH:9][C:10]([C@@H:12]([OH:38])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32][S:33]3(=[O:36])=[O:37])=[CH:28][CH:27]=2)=[CH:11][C:5]=1[CH2:4][OH:42])=[O:3]
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3ccc4c(c3)S(=O)(=O)CCC4)ccc2O1
Reactant: CC(=O)O
Solvent: O
Product: O=COc1ccc([C@@H](O)CNCCCCCCOCCCCc2ccc3c(c2)S(=O)(=O)CCC3)cc1CO

Procedure:
A solution of (1R)-1-(2,2-dimethyl4H-1,3-benzodioxin-6-yl)-2-({6-[4(1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl)butoxy]hexyl}amino)ethanol (134 mg) in glacial acetic acid (10 ml) and water (5 ml) was heated at 80° C. for 40 min. The mixture was concentrated in vacuo and the residue purified by mass directed autoprep to give the title compound (79 mg). LCMS RT=2.46 min, ES+ve 520 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[C:6]([N+:14]([O-])=O)[C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[H][H]>[Pd]>[NH2:14][C:6]1[CH:5]=[C:4]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)c1cc(Cl)c(C2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: CCOC(=O)C(=O)c1cc(N)c(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 17.6 g. (0.05 moles) of ethyl 3-chloro-5-nitro-4-cyclohexylphenylglyoxylate in 100 ml. of methanol containing 0.05 moles of citric acid and 1.5 g. of 5% palladium-on-carbon is shaken with hydrogen at 3 atm. pressure and 27° C. until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl 3-amino-5-chloro-4-cyclohexylphenylglyoxylate isolated as the citrate salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixed solution of the compound (1.5 g, 4.2 mmol) obtained in Example 36a in ethanol/tetrahydrofuran (v/v=1/1, 20 mL) was added palladium-carbon (10% wet., 150 mg), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere (1 atm). Palladium-carbon was removed by filtration and the solvent was evaporated under reduced pressure to give a crude title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>C1COCC1>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][NH:1][S:18]([C:16]1[S:17][C:13]([Cl:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1)(=[O:20])=[O:19])([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 71.9 %

Procedure:
To a stirred solution of tert-butyl N-(2-aminoethyl)-carbamate (0.46 g, 2.87 mmol) in THF (6 ml) was added at 0° C. (ice water bath) 5-chloro-4-nitrothiophene-2-sulfonyl chloride (0.5 g, 1.91 mmol) and triethylamine (0.29 ml, 2.1 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/heptane), and subsequent crystallization from ethyl acetate/hexane to yield [2-(5-chloro-4-nitro-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (0.53 g, 72%) as a light yellow solid. MS (ISP) 384.1 [(M−H)−], mp 147° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].CS(Cl)(=O)=O.[Br:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([N:27]2[C:31]([CH2:32][CH3:33])=[C:30]([CH2:34]O)[C:29]([CH2:36][CH3:37])=[N:28]2)=[C:22]([CH3:38])[CH:21]=1.C(N(CC)CC)C.C1C=C2C(C=C([O-])C=C2)=CC=1.[Na+]>C(OCC)C>[Br:19][C:20]1[CH:21]=[C:22]([CH3:38])[C:23]([N:27]2[C:31]([CH2:32][CH3:33])=[C:30]([CH2:34][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][C:2]=3[OH:11])[C:29]([CH2:36][CH3:37])=[N:28]2)=[C:24]([CH3:26])[CH:25]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CO
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1Cc1c(O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.4 %

Procedure:
A solution of 2-naphthol (2.28 g, 15.8 mmol) in 20 ml of diethylether was treated with sodium hydride (60% mineral oil dispersion, 0.632 g, 15.8 mmol) and the mixture was stirred at ambient temperature for 20 minutes. Methanesulfonyl chloride (0.677 ml, 8.7 mmol) was added dropwise to an ice bath cooled solution of [1-(4-bromo-2,6-dimethyl-phenyl)-3,5-diethyl-1H-pyrazol-4-yl]-methanol (2.68 g, 7.9 mmol) and triethylamine (1.38 ml, 9.9 mmol) in diethylether (25 ml). The mixture was stirred at 0°-5° C. for 15 minutes; and then stirred at ambient temperature for 20 minutes. The mixture was then added to the above-described sodium 2-napthoxide suspension. After 16 hours stirring at ambient temperature, the reaction mixture was extracted with methylene chloride/dilute aqueous sodium bicarbonate (150 ml and 100 ml, respectively). The aqueous phase was extracted twice with 50 ml portions of methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (5.65 g). Trituration of the entire sample with ethyl acetate/hexanes (5 ml and 45 ml, respectively) followed by filtration afforded the title compound 1.15 g as a colorless solid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.ClC(Cl)([O:20][C:21](=[O:27])[O:22]C(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:21](=[O:20])([O-:27])[O-:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: OCCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C([O-])[O-]
Reaction time: 0.25 h

Procedure:
In a 500 mL 3-necked round-bottomed flask equipped with a mechanical stirrer, and a liquid addition device were placed 10 g (0.073 mol) of tyrosol, 24 ml (0.298 mol) of pyridine, 200 mL of DCM and stirred for 15 min to get a clear solution. Triphosgene (7.7 g, 0.078 mol of phosgene) was dissolved in 25 mL of DCM and the solution was introduced into the reaction flask over 2-3 hours. After the addition was complete, 250 mL of water was added to the reaction mixture and stirred for 5 min. After allowing the layers to separate, the top aqueous layer was removed and discarded. The washing was repeated with two additional 250 mL portions of DI water. The reaction mixture was then precipita-ted with 300 mL of IPA. The resulting gel was ground twice with 200 mL portions of IPA in 1 L laboratory blender. The product was isolated by vacuum filtration and dried in a vacuum oven at 60° C. The polymer had a HPSEC polystyrene equivalent molecular weight of 126 Kda (THF as mobile phase) and glass transition temperature (Tg) of 58° C. Compression molding at 195° C. gave a uniform transparent film which gave tensile modulus, tensile stress at yield, and elongation at break respectively of 19.1 ksi, 5 ksi and 450%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH2:8][S:9][CH3:10])[O:6]C(=O)[NH:4]1>CC(O)C.[OH-].[K+]>[NH2:4][C@@H:3]([C@H:7]([OH:6])[CH2:8][S:9][CH3:10])[CH2:2][OH:1]
Reactant: CSC[C@H]1OC(=O)N[C@@H]1CO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CSC[C@@H](O)[C@H](N)CO
Temperature: 80 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
The product from Example 6.5 (1.16 g, 6.55 mmol) was dissolved in a mixture of iPrOH (32 ml) and 2M aq. KOH (14 ml) and stirred at 80° C. for 4 h. The solvent was evaporated and the residue chromatographed on silica gel (CH2Cl2-MeOH-28% aq. NH4OH, 9:1:0.1) to give (2R,3S)-2-amino-4-(methylthio)butane-1,3-diol (0.932 g, 94%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:20])[N:9]=2)[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(F)c2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c2nn(C)cc12
Reaction time: 5 h
Yield: 66.8 %

Procedure:
To a solution of methyl 7-fluoro-1H-indazole-4-carboxylate (2.93 g, 15.1 mmol) in ethyl acetate (60 mL) was added trimethyloxonium tetrafluoroborate (2.90 g, 19.6 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.10 g, yield 67%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](O)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=[O:3])[CH3:2].[Cl:23]CCl.C(Cl)(=O)C(Cl)=O>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([Cl:23])=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)O)ccc21
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reaction time: 8 h
Yield: 84 %

Procedure:
To a flask containing 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (1.5 g, 5.9 mmol) was added dichloromethane (80 mL) and oxalyl chloride (1.02 mL, 11.7 mmol). The reaction was allowed to stir under a nitrogen atmosphere overnight. To the flask was added a catalytic amount of DMF. The reaction was allowed to stir for three hours. TLC indicated reaction was complete. The solvent was removed and a solid formed to yield the title compound (1.57 g, 84% yield).
Reaction SMILES: [CH2:1]([C:4]1([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=C.[O:19]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[N:14]1([C:4]2([CH2:1][CH:2]=[O:19])[CH2:13][C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[O:7][CH2:6][CH2:5]2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: O=[O+][O-]
Reactant: C=CCC1(n2cccn2)CCOC2(CCCC2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=CCC1(n2cccn2)CCOC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
To a solution of 1-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]-1H-pyrazole (80 mg, 0.32 mmol) in DCM (5 mL) at −78° C. was bubbled with O3 until the solution turned blue. The resulting solution was bubbled with N2 for 5 min. To it was added PPh3 (168 mg, 0.64 mmol). And the solution was stirred for 4 h at rt. After removal of the solvent, the residue was purified by flash column chromatography to give 2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (15 mg, 23% yield). LCMS m/z 249 (M+1) observed.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br:25][C:26]1[CH:27]=[C:28]([CH:42]=[C:43]([CH3:45])[CH:44]=1)[C:29]([C:31]1[NH:36][C:35](=[O:37])[NH:34][C:33](=[O:38])[C:32]=1[CH:39]([CH3:41])[CH3:40])=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]([CH:42]=[C:43]([CH3:45])[CH:44]=1)[C:29]([C:31]1[N:36]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=2)[C:35](=[O:37])[NH:34][C:33](=[O:38])[C:32]=1[CH:39]([CH3:40])[CH3:41])=[O:30]
Reactant: Cc1cc(Br)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(=O)Nc1cc(CO)ccn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Cn2c(C(=O)c3cc(C)cc(Br)c3)c(C(C)C)c(=O)[nH]c2=O)ccn1
Yield: 46.9 %

Procedure:
N-(4-Hydroxymethyl-pyridin-2-yl)-acetamide (166 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 6-(3-Bromo-5-methyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (28) (351 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (2:1); Rf˜0.2 fraction was collected.) to afford 234 mg (47%) of a white solid.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[OH-:27].[Na+]>CN1CCCC1=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:3]([CH2:2][OH:27])=[C:4]([CH3:5])[N:6]=2)=[N:10]1
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)oc1CO
Yield: 60 %

Procedure:
730 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (1.86 mmol) and 3.75 ml of NaOH, 1N (3.75 mmol) were stirred in 7.4 ml of N-methylpyrrolidone at 50° C. under argon overnight. After cooling, the mixture was poured onto ice-water and the product which had precipitated out was filtered off and dried. Finally, it was purified by column chromatography (SiO2, cyclohexane:ethyl acetate 2:1). 375 mg (60%) of 2-[1-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-methyl-oxazole were obtained as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:16][C:17]=1[Cl:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[C:20]([F:21])([F:22])[F:23])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: OC(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)nc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
Under a dry argon atmosphere a solution of 2-chloro-5-nitropyridine (1.6 g, 0.010 mole) and 1-(3,4-dichlorophenyl)-2,2,2-trifluoroethanol (2.5 g, 0.010 mole) in dimethyl sulfoxide (50 ml) was stirred for five minutes. Potassium carbonate (1.6 g, 0.011 mole) was added to the mixture in one portion. The resultant mixture was stirred at room temperature for approximately 18 hours. The mixture was transferred to a separatory funnel to which was added 50 g of ice and 75 ml of a 2N aqueous sodium hydroxide solution. This aqueous mixture was extracted with two 200 ml portions of diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving an oil. Purification of this oil by column chromatography on silica gel yielded 3.3 g of 2-[1-(3,4-dichlorophenyl)-2,2,2-trifluoroethoxy]-5-nitropyridine.
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:15])([C:12](=[O:14])[CH3:13])[CH3:11])[CH:7]=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:15])([C:12](=[O:14])[CH3:13])[CH3:11])[CH:7]=[CH:6][C:5]=1[S:16]([NH2:1])(=[O:18])=[O:17]
Reactant: [NH4+]
Reactant: CC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)c1ccc(S(N)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of NH4OH (30 mL) was added a solution of 2-chloro-4-(2-methyl-3-oxobutan-2-yl)benzene-1-sulfonyl chloride (9.8 g, 33.2 mmol) in THF (150 mL) at 0° C. After stirring 2 h, volatiles were removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (100 mL×2). The combined extracts were dried over MgSO4, concentrated and purified by column chromatography (Hex/EtOAc=4:1 to 2:1) to give 2-chloro-4-(2-methyl-3-oxobutan-2-yl)benzenesulfonamide (8.9 g, 96% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.27 (d, J=2.2 Hz, 1H), 5.09 (s, 2H), 2.04 (s, 3H), 1.52 (s, 6H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[F:15].C([Li])CCC.[C:21](=[O:23])=[O:22].[F-].[Cs+]>C(#N)C>[F:15][C:3]1[C:4]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:5]([F:10])[C:6]([F:9])=[C:7]([CH3:8])[C:2]=1[C:21]([OH:23])=[O:22]
Reactant: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1Br
Reactant: O=C=O
Agent: [Cs+]
Agent: [F-]
Agent: [Li]CCCC
Solvent: CC#N
Product: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1C(=O)O
Yield: 62 %

Procedure:
This preparation route is very expensive. The first and the second synthesis step each involve reaction with butyllithium and diisopropylamine in tetrahydrofuran at −78° C., and the third synthesis step involves reaction with butyllithium in ether, likewise at −78° C. In the first step, 1-bromo-2,4,5-trifluorobenzene is reacted first with lithium diisopropylamide and then with trimethylsilyl chloride, the resulting 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (88% yield) is once more reacted with lithium diisopropylamide and subsequently with methyl trifluoromethanesulfonate, the resulting 1-bromo-2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzene (75% yield) is reacted with butyllithium and subsequently with CO2 in the form of dry ice, and the resulting 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)- benzoic acid (62% yield) is reacted with cesium fluoride in acetonitrile to give 6-methyl-2,4,5-trifluorobenzoic acid (89% yield).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)([OH:3])=O.Cl.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: CNC
Reactant: CC/C(Nc1ccc(CC(=O)O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21
Agent: Cl
Product: CC/C(Nc1ccc(CC(=O)N(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone and dimethylamine-hydrochloride