Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:29](=[O:45])[CH:30]([NH:37]C(OC(C)(C)C)=O)[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:29](=[O:45])[CH:30]([NH2:37])[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(C(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(N)C1CCCCC1)C1CCCCC1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution containing 121 (370 mg, 0.51 mmol) in DCM (10 mL) at 0° C. was added TFA (4 mL). After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM and the organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 210 mg of 122 which was used without further purification. Mass spectrum, m/z [523.3] (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[N:25]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:32][CH2:31][CH2:30][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCN1CCCC1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCN4CCCC4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-benzoic acid 14 (100 mg, 0.39 mmol) in DCM (2 mL) was heated with thionyl chloride (0.11 mL, 0.77 mmol) at 80° C. for 1 hour, the mixture was cooled to room temperature and concentrated to dry, 2-pyrrolidin-1-ylethanamine (CAS 7154-73-6) (0.05 mL, 0.58 mmol) was then added, and was stirred overnight. The reaction mixture was purified with prep HPLC to give pure 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide 24. LC/MS (ESI+): m/z 363 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7](O)=[O:8].S(Cl)([Cl:16])=O>ClC(Cl)C.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([Cl:16])=[O:8])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc(F)c(F)c1

Procedure:
To 0.27 mol of 3,4-difluorocinnamic acid dissolved in dichloroethane there are added 20 drops of dimethylformamide and 100 ml of thionyl chloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:7][CH:8]=1)=[O:30]
Reactant: COC(=O)c1ccc2ncn(-c3ccc(SC)cc3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2ncn(-c3ccc(S(C)=O)cc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of methyl 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carboxylate (4.44 g, 14.88 mmol) in dichloromethane (50 mL) was added m-chloroperbenzoic acid (3.07 g, 12.40 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 30 min. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 15 min. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1-0/1) to give the title compound (3.89 g, yield 83%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH3:10])([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([CH2:12][CH2:13][C:14]1([CH3:16])[O:8][CH2:7][C:4]([N+:1]([O-:3])=[O:2])([CH2:9][CH3:10])[CH2:5][O:6]1)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]
Reactant: CCC(CO)(CO)[N+](=O)[O-]
Reactant: CCCCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)CCC1(C)OCC(CC)([N+](=O)[O-])CO1
Yield: 90 %

Procedure:
7.46 g of 2-nitro-2-ethyl-1,3-propanediol, 8.61 g of butyl levulinate, 50 mg of p-toluenesulfonic acid in 50 ml of toluene was refluxed until no more water separated. The reaction mixture was cooled, washed with 2% sodium bicarbonate and water, dried and concentrated to give 13.65 g of 2-carbobutoxyethyl-2-methyl-5-nitro-5-ethyl-1,3-dioxane as a light yellow oil. This was dissolved in 50 ml of ethanol and hydrogenated over 1 g Raney Nickel catalyst at 60 under pressure. Distillation of the crude material at 160° C./3mm gave 11 g of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]=[C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[S:22][C:23]([C:32]#[N:33])=[C:24](NC3C=CC=CC=3)[C:13]=2[CH:12]=[CH:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:13]3[CH:12]=[CH:11][C:10](=[O:9])[N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]=3[S:22][C:23]=2[C:32]#[N:33])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Reactant: Nc1cccc(Br)c1
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1cccc(Br)c1

Procedure:
The title compound was prepared from 3-bromoaniline (155 mg, 0.9 mmol) following the method described for the compound of Example 18 to give the product as a pale yellow solid (183 mg). δH (CDCl3) 7.91-7.83 (3H, m), 7.83-7.66 (2H, m), 7.62 (1H, d, J 9.7 Hz), 7.52-7.44 (3H, m), 7.23 (1H, dt, J 7.1, 1.7 Hz), 6.81 (1H, d, J 9.7 Hz), 6.74 (1H, bs). LCMS (ES+) 422 (M+H)+ 79Br, 424 (M+H)+ 81Br.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO>[CH3:18][C:16]1[N:17]=[C:10]2[C:9](=[O:8])[CH2:14][CH2:13][CH2:12][N:11]2[CH:15]=1
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Reactant: [H][H]
Solvent: CO
Product: Cc1cn2c(n1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
60 g (251.8 mmol) of 8-benzyloxy-2-methylimidazo[1,2-a]pyridine (Kaminski et al, J. Med. Chem. 1985, 28, 876–892) are hydrogenated on Pd-carbon in 400 ml of methanol at a hydrogen pressure of 55 bar and 70° C. After completion of the hydrogenation, the catalyst is filtered off and the filtrate is concentrated. The residue (38 g) is taken up in dichloromethane and the solution is treated in portions at room temperature with manganese dioxide (109.5 g). The reaction mixture is stirred at room temperature for 22 h and then filtered through silica gel. The filtrate is concentrated to a residue and the crystallizate is dried in vacuo at 60° C. 25.13 g (66% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O.[F-].[Cs+]>COCCOC.C(OCC)(=O)C.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>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(C)cc2C)cccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 47.5 %

Procedure:
A mixture containing 0.5 g (2.3 mmol) of methyl 2-chloro-6-nitrobenzoate, 0.76 g (3.5 mmol) of 2,4-dimethylphenyl boronic acid, 0.7 g (4.6 mmol) of cesium fluoride, and 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine)palladium(0) in 10 ml of 1,2-dimethoxyethane was heated to 100° C. under a nitrogen atmosphere overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 20% ethyl acetate/hexanes gave 0.312 g (47%) of product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(N)nc2n1

Procedure:
A mixture of 2-chloro-7-amino-1,8-napthyridine (Newkome, G. R. et al, J. Org. Chem., 1981, 46, 833-39) (180 mg, 1 mmol) and a methanolic solution of sodium methoxide (458 μL, 25 wt. %) in methyl alcohol (2 mL) was heated at 50° C. for 19 hours. The reaction mixture was allowed to cool, filtered through Celite using dichloromethane, concentrated in vacuo and the residue purified on Silica gel (1:9:0.2 methyl alcohol/dichloromethane/ammonium hydroxide) to afford 2-methoxy-7-amino1,8-naphthyridine as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].C[C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1>C(O)C>[CH3:18][C:16]1[S:17][C:13](=[N:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[OH:10])[CH2:14][CH:15]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Cc1ccc(C=O)s1
Solvent: CCO
Product: CC1=CCC(=Nc2cc([N+](=O)[O-])ccc2O)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4Nitro-o-aminophenol (30.8 g, 0.2 mole) and 5-methyl-2-thiophenecarboxaldehyde (25.2 g, 0.2 mole) are dissolved in 250 ml of absolute ethanol and stirred at room temperature for 0.5 hour. The precipitated material is filtered and washed with additional ethanol yielding 49.8 g of product, melting point 202°-204°C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C1C(=O)N([I:36])C(=O)C1>C(O)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:10]=[C:11]([I:36])[C:12]=1[O:13][CH3:14]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)c(F)c2)c1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2cc(F)c(OC)c(I)c2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
Sulfuric acid (3 mL) was added into a cold (ice bath) mixture of ethyl 1-(3-fluoro-4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 1.505 mmol) and NIS (339 mg, 1.505 mmol) in acetic acid (10 mL). The resulting mixture was stirred in an ice bath and was allowed to warm to ambient temperature overnight. The reaction was then heated in a 55° C. oil bath for 5 hrs. The crude mixture was combined with the reaction crude from an identical probe reaction (32 mg scale). The combined crude was poured into an ice/water mixture and extracted with EtOAc. The separated organic phase was dried over Na2SO4, filtered and evaporated to afford a dark mixture. This dark mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 30%). Related fractions were pooled and evaporated to afford a colorless oil as the titled compound. LCMS calc.=457.98. found=459.06 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:16]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:17])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)C(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)C(F)F
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (880 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (820 mg, 3.1 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=1[S:15][CH3:16].C[O:18][B:19](OC)[O:20]C>O1CCCC1>[F:14][C:9]1[C:8]([S:15][CH3:16])=[C:7]([B:19]([OH:20])[OH:18])[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: CSc1c(F)cc(F)cc1Br
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1c(F)cc(F)cc1B(O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Charge a flask with isopropyl magnesium chloride (145 mL, 2M in THF, 290 mmol) and dilute with tetrahydrofuran (150 mL) and heat to 40° C. under nitrogen. Add 1-bromo-3,5-difluoro-2-methylsulfanyl-benzene (28 g, 117 mmol) slowly over 5 minutes. After 30 minutes, cool the reaction to 0° C. and add trimethylborate (46 mL, 410 mmol) diluted with tetrahydrofuran (100 mL) via an addition funnel over 5 minutes. Partition the resulting gelatinous mixture between methylene chloride and 1N HCl. Acidify the aqueous layer to pH˜1 (if needed) and vigorously stir the biphasic mixture until all solids are dissolved. Separate the organic layer. Dry over sodium sulfate, filter and concentrate. Triturate with hexanes and filter to yield 14.7 g (61%) of the title compound.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([O:15][C:16]2[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=2)=[CH:10][N:9]=1.C(=O)(O)[O-].[Na+].[CH2:36](I)[CH3:37]>O.O1CCOCC1>[CH2:36]([S:22]([C:20]1[C:19]([O:26][CH3:27])=[CH:18][C:17]([CH:28]([CH3:30])[CH3:29])=[C:16]([CH:21]=1)[O:15][C:11]1[C:12]([NH2:14])=[N:13][C:8]([NH2:7])=[N:9][CH:10]=1)(=[O:24])=[O:23])[CH3:37]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1S(=O)(=O)Cl
Reactant: CCI
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Temperature: 80 °C
Yield: 19.6 %

Procedure:
To a solution of sodium sulfite (541 mg, 4.29 mmol) in water (20 mL) was added 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonyl chloride (400 mg, 1.07 mmol) and the reaction was heated at 80° C. for 1 hour. Sodium bicarbonate (361 mg, 4.29 mmol-dissolved in 5 mL water), dioxane (20 mL), and ethyl iodide (0.10 mL, 1.29 mmol) were added and the reaction was heated at 80° C. for 2 hours. The reaction was concentrated, extracted with dichoromethane (150 mL) and water (20 mL). The dichloromethane layer was dried using anhydrous sodium sulfate, concentrated, and purified via silica gel column chromatography (95/5/0.1 dichloromethane/methanol/ammonium hydroxide) to yield 5-(5-ethanesulfonyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (77 mg, 20%) as white solid, MS (M+H)=367.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10](Br)[N:9]=1)=[O:7].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>>[F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:31]2[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][CH:32]=2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=1[NH2:14])=[O:7]
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NCC(O)(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2nc(C(=O)NCC(O)(C(F)(F)F)C(F)(F)F)c(N)cc2C(F)(F)F)cn1

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide (Ex. 1.28) and 2-methylpyridine-5-boronic acid analogously to Example 8. LC-MS Rt 1.28 min; 477[M+H]+; (Method 2minLC_v002); 1H NMR (400 MHz, MeOD) δ 8.50 (1H, s), 7.85 (1H, dd), 7.69 (1H, s), 7.40 (1H, d), 4.00 (2H, s), 2.62 (3H, s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[C-:10]#[N:11].[Na+].CS(C)=O>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][C:10]#[N:11])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(CC#N)OCC
Reaction time: 5 h

Procedure:
A mixture of 8 g of bromo-acetaldehyde diethyl-acetal, 3 g of sodium-cyanide and 20 ml of dimethyl-sulfoxide is admixed at a temperature of 80° C. for 5 hours. The reaction mixture is poured on 80 ml of water, then twice extracted with 50 ml of chloroform. The chloroform extract is washed twice with 30 ml of water, dried on magnesium sulfate, then distilled in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1.[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:22](=[O:23])[N:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc(CO)c1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)COc1cccc(COC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 73.5 %

Procedure:
(3-Hydroxymethylphenoxy)acetic acid methyl ester (400 mg, 2 mmol) and diphenylcarbamyl chloride (580 mg, 2.5 mmol) were combined in pyridine (2 ml). The resultant yellow solution was allowed to stand for ten days under nitrogen. The mixture was then poured into water, extracted with dichloromethane, and evaporated. Purification of the residue by silica gel chromatography, eluting with 5% acetone/dichloromethane, gave {3-[(diphenyl-carbamoyloxy)methyl]phenoxy}acetic acid methyl ester as a colorless solid (575 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].CCN(CC)CC.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:34]([NH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([F:25])([F:36])[F:37])=[O:35]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.11 g, 4.68 mmol) and Et3N (720 ml, 5.17 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (707 ml, 4.68 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and washed with n-hexane to give tert-butyl 3-methoxy-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.11 g, 56%) as a white crystalline powder. mp 131–133° C.; 1H-NMR (CDCl3) δ 1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.83–6.88 (m, 3 H), 6.98 (br s, 1 H), 7.17–7.21 (m, 1 H), 7.52–7.59 (m, 2 H), 7.89–7.91 (m, 1 H), 8.04–8.06 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[OH:7])[CH3:2].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[O:7][S:45]([CH3:44])(=[O:47])=[O:46])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCOC(C(=O)OCC)C(O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCOC(C(=O)OCC)C(OS(C)(=O)=O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxy-propionic acid ethyl ester (150 mg, 0.3 mmol) in dichloromethane (2 ml) at 0° C. was added successively triethylamine (55 μl, 0.4 mmol) and methanesulfonic acid chloride (42 μl, 0.36 mmol). The reaction was allowed to warm to ambient temperature over night and then quenched by the addition of sat. NaHCO3. The layers were separated and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford crude 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-methanesulfonyloxy-propionic acid ethyl ester which was dissolved in THF (2 ml). DBU (139 μl, 0.9 mmol) was added at ambient temperature and the mixture was stirred for 8 h at 50° C. The reaction was quenched by the addition of water, the layers were separated, and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure to afford a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 79 mg (0.166 mmol, 55%) of the title compound as bright yellow oil and 29 mg (61 μmol, 20%) 2E-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester as bright yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>ClC(Cl)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]([C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])[C:11](=[O:24])[C:10]=1[Br:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)cc(=O)n1-c1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Product: Cc1cc(OCc2ccccc2)c(Br)c(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one (0.1 g, 0.278 mmol) and N-bromosuccinimide (0.055 g, 0.3 mmol) in dichloroethane (3.0 mL) was stirred at room temperature for 1 h, and heated at 60° C. under argon for 30 min. The reaction mixture was then diluted with dichloroethane (15 mL), washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. 1H NMR (CD3OD) δ: 7.64 (m, 2H), 7.55 (m, 3H), 7.38 (m, 3H), 6.65 (s, 1H), 5.34 (s, 2H), and 2.00 (s, 3H); ES-MS m/z=439 (MH+); HR-MS, m/z calc C19H16NO2Cl2Br, 439.9635, found 439.9669.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])=[CH:2]1.[CH2:16]1CCN2C(=NCCC2)C[CH2:17]1.C(Br)C>C1C=CC=CC=1>[CH2:16]([O:13][C:12](=[O:14])[C:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:15])[CH3:17]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Solvent: CCBr
Solvent: c1ccccc1
Product: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Yield: 70 %

Procedure:
Following the same method as previously described, 1,0 g 3-indole-pyruvic acid were reacted with 1,5 ml DBU and 790 microliters ethylbromide. In this case the benzene solution appeared red orange. After flash chromatography purification the ethyl ester was obtained with a yield of about 70%.