Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([O:28]C)=[O:27])[CH2:21]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC=CC=1.O[C@@H]1CCC[C@H](C(OC)=O)C1.C1(C2C(C3C=CC=CC=3)=CN=C(O)N=2)C=CC=CC=1.N(C(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=O)=NC(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=O>O1CCCC1.CN(C)C=O>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([OH:28])=[O:27])[CH2:21]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H]1CCCC(Oc2ncc(-c3ccccc3)c(-c3ccccc3)n2)C1
Agent: COC(=O)[C@H]1CCC[C@@H](O)C1
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)P(F)(F)(c1ccccc1)c1ccccc1
Agent: O=C(N=NC(=O)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1CCCC(Oc2ncc(-c3ccccc3)c(-c3ccccc3)n2)C1
Reaction time: 0.5 h
Yield: 3.5 %

Procedure:
Methyl (1S)-3-(4,5-diphenylpyrimidin-2-yloxy)cyclohexanecarboxylate 1.5 g (2.12 mmol) of diphenylperfluorodecylphosphine were added to a solution of 280 mg (1.76 mmol) of methyl (1S,3R)-3-hydroxycyclohexanecarboxylate in 2 ml of tetrahydrofuran. After 30 minutes, 525 mg (2.12 mmol) of 4,5-diphenylpyrimidin-2-ol and 2 ml of tetrahydrofuran were added, and the mixture was again stirred for 30 minutes. A solution of 1.77 g (2.12 mmol) of bis(perfluorononyl) azodicarboxylate in 2 ml of tetrahydrofuran was slowly added dropwise (exothermic reaction) and stirred at room temperature for 2 hours. It was not possible to convert the suspension into a solution by adding 1 ml of dimethylformamide. The reaction mixture was filtered with suction (precipitate corresponds to 408 mg of 4,5-diphenylpyrimidin-2-ol). The filtrate was filtered twice through a FluoroFlash cartridge and washed with methanol/water=4/1, and the filtrate was concentrated. The residue was separated on a silica gel column (heptane/ethyl acetate, 10 minutes 100% heptane, gradient from 0% to 45% ethyl acetate in 45 minutes). 28 mg (4%) of the desired product were obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[N:37][N:36]=[CH:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]3[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH:35]=[N:36][N:37]=[CH:38]5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cnnc3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-morpholin-4-yl-2-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M33) (360 mg, 0.627 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (176 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[S:10]1[C:11]2[C:3]([CH:2]=[O:1])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=[N:9]1
Reactant: OCc1cccc2nnsc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc2nnsc12
Yield: 91.5 %

Procedure:
To a solution of 16.6 g of 7-hydroxymethylbenzo-1,2,3-thiadiazole in 100 ml of chloroform there are introduced with stirring at room temperature 35 g of manganese dioxide, during which process the internal temperature rises briefly to 31° C. When the temperature has dropped again to 25° C., the mixture is heated and refluxed overnight. Another 5 g of manganese dioxide are subsequently added, and heating of the mixture is continued until the reaction is complete. The hot mixture is filtered over Hyflo and the filtrate is then evaporated. The residue is digested in a little hexane and then filtered, which gives 15 g (91.4%) of the title compound of m.p. 134°-136° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.O>[CH2:1]([NH:8][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 5.358 g (0.05 mole) of benzylamine and 7.755 g (0.06 mole) of N,N-diisopropylethylamine in 80 mL of CH2Cl2 at room temperatue was added slowly 11.365 g (0.055 mole) of 4-methoxybenzenesulfonyl chloride. The resulting mixture was stirred for 18 hr at room temperature and diluted with water. The organic layer was separated, washed with NaHCO3, water, brine, dried over MgSO4, filtered and concentrated. The residue was boiled in CH2Cl2 :Hexane (1:4), cooled and filtered to provide 11.79 g (85%) of the desired product as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(c2cccc(F)c2)CCC=CCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(c2cccc(F)c2)CCCCCC1
Yield: 99.2 %

Procedure:
1-(3-Fluoro-phenyl)-cyclohept-4-enecarboxylic acid methyl ester (Example 12b) (1.09 g) was dissolved in methanol (20 mL), palladium on carbon (50 mg) added and mixture stirred under 4 atm of hydrogen overnight. The solution was filtered and evaporated to afford the sub-titled compound (1.09 g).
Reaction SMILES: CN(C)CCC=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.N#CBr>C1C=CC=CC=1>[CH:17]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:6][C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Agent: N#CBr
Solvent: c1ccccc1
Product: C1=Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 23.06 g. (0.0834 mole) of 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene in 61 ml. of benzene is added dropwise to a stirred solution of 9.80 g. (0.0917 mole) of cyanogen bromide in 38 ml. of benzene. Some heat is evolved. The mixture is stirred for 3 hours at room temperature, and filtered to remove any precipitate which forms. The filtrate, together with a benzene wash of the precipitate, is evaporated to dryness on a steam-bath under reduced pressure to remove excess cyanogen bromide and solvent. The residual crude cyanamide is dissolved in benzene, and the solution is washed with dilute hydrochloric acid to remove any unchanged amine, then with water. The benzene solution is then evaporated under reduced pressure leaving 5-[3-N-cyano-N-methyl)aminopropylidene]-5H-dibenzo[a,d]cycloheptene as a yellow oil weighing typically 19.6 g.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[O:1][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1cccc(C=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 104.2 %

Procedure:
A mixture of 2-hydroxy-3-methoxybenzaldehyde (3.04 g), ethyl 2-bromopropionate (5.85 g), and potassium carbonate (4.14 g) in dimethylsulfoxide (20 ml) was stirred at 70° C. for 5 hours. The mixture was diluted with water, neutralized with 1N hydrochloric acid, and was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The crude product (0.93 g) was purified on a silica gel column (60 g) eluting with a mixed solvent of n-hexane and toluene (from 6:1 to 5:1) to give ethyl 2-(2-formyl-6-methoxyphenoxy)-propionate (5.25 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([CH3:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[C:5]1=[O:20])[CH:2]=[CH2:3].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH3:19])[C:5]1=[O:20])[CH:2]=[CH2:3]
Reactant: C=CCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: C=CCN1CC2C(C1=O)C2(C)c1cccc(N)c1
Yield: 99 %

Procedure:
To a solution of 3-allyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Preparation 50, 10.2 g, 37.5 mmol) in ethanol (850 ml) and water (150 ml) was added iron powder (18.9 g, 337.5 mmol) and calcium chloride (2.1 g, 18.7 mmol). The reaction mixture was refluxed for 5 h, and then filtered to remove the iron powder. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane:methanol (85:15), filtered and then concentrated in vacuo, dissolved in tetrahydrofuran, filtered and then concentrated in vacuo to give the title compound as a pale yellow foam (9 g, 99%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25]([OH:27])=O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH2:31]([NH2:33])[CH3:32].Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl.CN(C=O)C>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25]([NH:33][CH2:31][CH3:32])=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: CCN
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)O)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)NCC)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 107 mg (0.24 mmol) of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoic acid (Example 33, Step A) and ethylamine (31.4 μL, 0.479 mmol) in DCM (539 μL) and DMF (59.9 μL) was treated at 0° C. with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (138 mg, 0.719 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (98 mg, 0.719 mmol), and sodium bicarbonate (60.4 mg, 0.719 mmol), successively. Then the reaction was stirred at 25° C. for 12 h. The reaction was diluted (1 N aq. HCl), extracted (2×EtOAc), the combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by chromatography on silica gel (30% to 40% EtOAc/Hexanes, a gradient elution) provided the title compound as a mixture of diastereomers (dr=5:1) as a white solid: MS (ESI) 473.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=O)[CH2:20]Br.C(=O)(O)[O-].[Na+].O>C(O)C>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:1]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]2[CH:20]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: Nc1nccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1cn2ccc3ccccc3c2n1
Yield: 81.9 %

Procedure:
A mixture of 3.0 g of 1-aminoisoquinoline, 6.7 g of 2'-methyl-2-bromoacetophenone and 17.5 g of sodium bicarbonate in 50 ml of ethanol was refluxed for 2 hours. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from dichloromethane/petroleum ether to give 4.4 g of the title compound as pale brown prisms.
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:12]=1)[CH:10]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])[CH:12]=1
Reactant: Cc1ccc(F)cc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(F)ccc1C
Reaction time: 1 h

Procedure:
To a mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100 ml) was added dropwise at room temperature a solution of 5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:25]>CCO>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[C:6]([C:4]([NH2:25])=[O:3])[O:10][N:9]=2)=[CH:12][CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: N
Reactant: CCOC(=O)c1cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)no1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 35 %

Procedure:
3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 12; 500 mg, 1.4 mmol) was dissolved in a saturated solution of NH3 in EtOH (200 mL). The mixture was stirred at room temperature for 60 h. The solvent was evaporated and the residue was purified by chromatography (50-60% EtOAc/hexanes) to give 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (160 mg, 35%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17].O>CN(C=O)C.C(OCC)(=O)C>[CH2:16]([O:8][C:7]1[C:2]([F:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1)[CH3:17]
Reactant: CCI
Reactant: Cc1ccc(O)c(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C)nc1F

Procedure:
2-Fluoro-3-hydroxy-6-picoline (500 mg) was initially introduced in absolute DMF (20 ml) and potassium carbonate (1 g) was added. After this, ethyl iodide (0.6 ml) was added dropwise with stirring and the mixture was stirred for 1 h. Subsequently, water and ethyl acetate were added to the reaction mixture. After separating off the organic phase, the mixture was additionally extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product obtained (477 mg) was reacted directly in the next stage.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24](O)=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1(C)C=CC=CC=1>[F:27][C:2]([F:28])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(=O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-cyclopropanecarboxylic acid (C20) (2.49 g, 6.40 mmol) in toluene (30 mL) was added triethylamine (2.20 mL, 16.0 mmol), followed by diphenyl phosphorazidate (1.70 mL, 8.00 mmol). The yellow solution was stirred overnight at room temperature. The reaction was quenched with water and saturated aqueous sodium bicarbonate, extracted with 1:1 ethyl acetate/hexanes (2×), dried over anhydrous sodium sulfate, and filtered. The crude compound was adsorbed onto silica gel and purified by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent to afford the title compound as a yellow oil (1.94 g, 73%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.03 (m, 2H), 7.83-7.72 (m, 2H), 7.44-7.34 (m, 2H), 7.20 (d, J=8.2 Hz, 2H), 2.70 (ddd, J=9.3, 6.8, 4.1 Hz, 1H), 1.98 (ddd, J=8.4, 5.3, 4.1 Hz, 1H), 1.78 (dt, J=9.4, 5.0 Hz, 1H), 1.53 (ddd, J=8.3, 6.8, 4.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.03.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([CH:19]=[O:20])=[CH:17][N:16]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC1C=CC(S([CH2:39][N+:40]#[C-:41])(=O)=O)=CC=1.[OH-].[K+].Cl>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]4[O:20][CH:41]=[N:40][CH:39]=4)=[CH:17][N:16]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(-c2cnco2)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (135 mg, 0.339 mmol), tosmic (73 mg, 0.37 mmol) and potassium hydroxide (38 mg, 0.68 mmol), was added methanol (10 mL). The resulting solution was stirred for 12 hours at 25° C. and then the pH was adjusted to pH=6 with hydrogen chloride (1M aqueous solution). The reaction was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography using silica gel, eluting with 25% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford 5-(4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)oxazole as a yellow oil. LRMS (ESI) calc'd for C21H24N5O4Si [M+H]+: 438, found 438.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[OH-].[Pd+2].[OH-].CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(C2=CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C2CCN(C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
A 25 mL glass microwave tube was charged with potassium phosphate tribasic (3.00 g, 13.05 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-isopropyl-1,1′-biphenyl (Strem Chemicals, Newburyport, Mass., 83 mg, 0.174 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, Newburyport, Mass., 80 mg, 0.087 mmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Acros Organics, New Jersey, 971 mg, 4.35 mmol) followed by 5-chloro-2-nitroanisole (Sigma Aldrich, 816 mg, 4.35 mmol). The solids were purged with argon and treated with 1,4-dioxane (12 mL) and water (4 mL), scaled and heated at 110° C. in a heating block for 1 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (3×30 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (80 g Thomson SingleStep column, using a gradient of 0-20% MeOH in DCM) affording 4-(3-methoxy-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (19a; 970 mg, 3.91 mmol, 90% yield) as a rust-brown solid which crystallized upon standing. m/z (ESI, +ve ion) 249.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, d, J=8.4 Hz), 6.99-7.08 (2H, m), 6.17-6.24 (1H, m), 3.97 (3H, s), 3.15 (2H, q, J=2.8 Hz), 2.65-2.74 (2H, m), 2.53-2.62 (2H, m), 2.38-2.46 (3H, m). In a 50 mL glass reactor, 4-(3-methoxy-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (940 mg, 3.79 mmol) was treated with palladium hydroxide (20 wt % Pd, dry basis, on wet carbon, degussa type e101 ne/w, 266 mg, 0.38 mmol) and anhydrous EtOH (20 mL). The reactor was purged with hydrogen (5×) and allowed to stir under 50 psi hydrogen at RT for 4 h. The reaction mixture was filtered through a 0.45 urn acrodisc to remove the catalyst residues washing with MeOH and concentrated to dryness under high vacuum affording 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (19b; 830 mg, 3.77 mmol, 99% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 221.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.56-6.74 (3H, m), 3.76-3.89 (3H, m), 3.54-3.76 (2H, m), 2.97 (2H, d, J=11.2 Hz), 2.34-2.47 (1H, m), 2.23-2.34 (3H, 1.95-2.12 (2H, m), 1.70-1.90 (4H, m).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:10]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
Thionyl chloride (14.5 mL, 198 mmol) was added to a solution of 2-amino-6-methylbenzoic acid (10.0 g, 66.1 mmol) in benzene (250 mL). The resulting suspension was heated to reflux and stirred overnight. After cooling, the reaction was concentrated in vacuo, and the resulting residue was dissolved in chloroform (300 mL). Aniline (15 mL, 165 mmol) was added, and the mixture heated to reflux. After three hours, the reaction was allowed to cool and the resulting suspension was filtered. The filtrate was subjected to flash chromatography, and the crude product recrystallized from isopropanol to provide compound 15 as a yellow crystalline solid. MS (ES): m/z 227 (M+H), 134. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz), 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 15 are shown below.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7](F)(F)F)[N:6]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=[O:16].Cl>C1COCC1.N1C=CC=CC=1>[Br:11][C:4]1[S:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[C:13]([F:12])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[N:6][C:5]=1[CH3:7]
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1Br
Temperature: 0 °C
Yield: 83 %

Procedure:
2-Amino-5-bromo-4-trifluoromethylthiazole (0.8 g) was dissolved in 3 mL of 1:1 mixture of THF and pyridine. 2,6-difluorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on silica gel gave the title compound as a white solid. Yield 83%.