Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20].C(O)C(N)(CO)CO>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:8][S:19](=[O:21])(=[O:20])[N:18]([CH3:23])[CH3:17])[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: NC(CO)(CO)CO
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)Oc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A flask is charged with 5-bromo-pyridin-3-ol (0.200 g, 1.126 mmol), potassium phosphate (0.631 g, 2.884 mmol) and acetone (5 mL) and cooled to 0° C. Dimethylsulfamoyl chloride (0.261 g, 1.802 mmol) is then added dropwise and the cooling bath is removed. After 2 h, the mixture is diluted with acetone, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in THF (30 mL) and polymer-supported trisamine (3.85 mmol/g, 0.7 g, 2.7 mmol) is added. After 1 h, the mixture is filtered. Concentration in vacuo gives a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 9:1 to 4:1) to give dimethyl-sulfamic acid 5-bromo-pyridin-3-yl ester as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.05 (s, 3H), 7.86 (m, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.62 (d, J=1.9 Hz, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 92.1 %

Procedure:
A slurry of 5.00 g (15.6 mmoles) of methyl 4-(4-phenoxyphenoxy)benzoate from Example A, 0.28 g (50.0 mmoles) of potassium hydroxide, 50 ml of methanol and 50 ml of deionized water is refluxed for 48 hours. Methanol is added until the mixture is homogeneous. Aqueous hydrochloric acid is added until the solution is strongly acidified, and the slurry is cooled. The resulting precipitate is filtered, washed with 300 ml of deionized water and dried in air. It is recrystallized from a minimum volume of hot 2-1 by volume methanol and water solution to yield 4.40 g (92 percent yield) of 4-(4-phenoxyphenoxy)benzoic acid having a melting point of 185° C. as measured by DSC.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(OCC2CC2)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A reaction flask was charged with 4-cyclopropylmethoxypiperidine-1-carboxylic acid t-butyl ester (6.80 g, 26.6 mmol) in DCM (15 mL). TFA (7 mL) was added and the reaction was stirred at rt for 4 h. The reaction mixture was quenched with 1 M NaOH and the product extracted into diethyl ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the title compound (3.949 g, 95%). 1H NMR (CD3CD) d 3.34-3.24 (m, 1H), 3.15 (d, 2H), 2.88-2.82 (m, 2H), 2.44-2.37 (m, 2H), 1.78-1.70 (m, 2H), 1.31-1.21 (m, 2H), 0.89-0.79 (m, 1H), 0.37-0.32 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CD3OD) d 76.2, 73.6, 44.7, 33.2, 11.7, 3.5.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[N:1]/[C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h
Yield: 103.1 %

Procedure:
A mixture of methyl 4-aminobenzoate (1.51 g, 10 mmol) and 4-nitrobenzaldehyde (1.51 g, 10 mmol) in ethanol (30 mL) was stirred overnight to give the yellow slurry. The precipitated off-white solid was collected and dried in vacuo to give (E)-methyl 4-(4-nitrobenzylideneamino)benzoate (2.93 g, 95% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH3:11])[CH3:2].CN1C([N+]([O-])=[O:19])=CN=C1C>>[CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]=[O:19])[CH3:2]
Reactant: Cc1ncc([N+](=O)[O-])n1C
Reactant: CCn1c([N+](=O)[O-])cnc1C
Product: CCn1c([N+](=O)[O-])cnc1C=O

Procedure:
With regard to the dimethylamino compound, said compound is prepared by employing the procedure set forth in Example 3, with the exception that 1-ethyl-2-methyl-5-nitroimidazole is utilized instead of 1,2-dimethyl-5-nitroimidazole. The process yields 1-ethyl-5-nitro-2-imidazolecarboxaldehyde, 4',4'-dimethyl-3'-thiosemicarbazone, which is cyclized as in Example 3 to 2-(2-dimethylamino-5-thiadiazoly)-1-ethyl-5-nitroimidazole.
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]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]([NH:25][O:26]C4CCCCO4)=[O:24])[CH:19]=3)[CH2:14]2)=[O:12])=[CH:2]1.[ClH:33]>CO.O>[ClH:33].[OH:26][NH:25][C:23]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=1)[CH2:22][CH2:21]2)=[O:24]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1c[nH]c3ccccc13)C2
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)Cc1c[nH]c3ccccc13)C2
Reaction time: 8 h
Yield: 63 %

Procedure:
180 mg 2-(1H-indol-3-ylacetyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide are dissolved in methanol and 6 ml of a solution of 0.1 M HCl in water are added drop wise. The mixture is stirred overnight. The mixture is evaporated in vacuo and the residue is treated with a mixture of water and acetonitrile and lyophilized. 92 mg (63%) of the title compound are obtained. MH+=350.0
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[O:4])[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
4.3 g of 2-Chloro-4′-fluoroacetophenone and 8.0 g of 1-ethoxycarbonylpiperazine were dissolved in 30 ml of chloroform and refluxed with heating for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and 25% aqueous ammonia solution was added, followed by extraction with ether. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give a crude 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-oxoethyl]piperazine, which was then dissolved in 40 ml of ethanol, and a solution prepared by adding 1 drop of 5% potassium hydroxide and 1.0 g of sodium borohydride to 5 ml of water was added, followed by heating at 50° C. for an hour. After concentration of the reaction solution under reduced pressure, water was added, followed by extraction with ether, and the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. To the residue was poured 50 ml of 4M hydrogen chloride/ethyl acetate solution, the solution was concentrated under reduced pressure, and the resulting solid was washed with ether to give 8.3 g of 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-hydroxyethyl]piperazine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:32])[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:13]1[C:12](=[O:32])[C:11]2[C:15](=[CH:16][CH:17]=[CH:18][C:10]=2[NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[C:14]1=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.53 g (7.39 mmol) of tert-Butyl 4-(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butylcarbamate are dissolved in 150 ml of dichloromethane, and a solution of 10 ml of trifluoroacetic acid in 50 ml of dichloromethane is added at 0° C. The reaction mixture is slowly warmed to RT and stirred overnight. The reaction mixture is then concentrated and the oily residue is stored at 5° C. overnight. Dichloromethane and a little ethanol are added to the residue, which is now partially crystalline, and the mixture is filtered. This gives 3.44 g (95% of theory) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([NH2:11])=[N:19][C:17]3[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=3[CH:20]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: Cc1cc(C)cc(CC#N)c1
Product: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2N)c1

Procedure:
The title compound was prepared according to Example 1, starting from 2.0 g of 3,5-dimethylphenyl-acetonitrile and 1.81 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 298-302° C., MS(CI).
Reaction SMILES: CO[CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[SH:16][CH2:17]CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:6]([O:5][CH2:4][CH:3]1[S:16][CH2:17][CH2:15][O:14]1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCS
Reactant: COC(COC(=O)c1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
Aliquots of 2-benzoyloxyacetaldehyde dimethyl acetal (50.0 g) prepared according to Example 1, 2-mercaptoethanol (20.4 g), p-toluenesulfonic acid monohydrate (0.90 g) and toluene (250 mL) were placed in a three-neck flask, followed by heating. By-produced methanol was distilled off with the solvent. After distilling off about 150 mL, the reaction mixture was cooled to room temperature, was washed with a saturated aqueous sodium hydrogen carbonate solution and water and was dried over anhydrous sodium carbonate. After filtration and vacuum distillation at 144-147° C. and at 0.60 mmHg, the target compound (54.9 g) was obtained in a yield of 100%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)([O-])=O.[H][H]>[Pd].C(O)C>[C:12]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1Nc1ccccc1-c1ccccc1

Procedure:
N-(2-nitrophenyl)biphenyl-2-amine (19.69 g, 67.8 mmol), 10% palladium on carbon (0.29 g, 0.27 mmol), and 150 mL of ethanol was added to a Parr hydrogenator bottle. The mixture was hydrogenated on a Parr hydrogenator until no more hydrogen was taken up by the solution. The solution was filtered through Celite to remove the catalyst, Celite was washed with dichloromethane, the filtrate was evaporated to yield a brown oil, 14.8 g (84%). The product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH3:10])[CH:6]=1)[C:2]([CH3:4])=[O:3].[CH3:11][C:12]1[O:17][C:16](=[O:18])[CH2:15][CH2:14][CH:13]=1.C(=O)([O-])[O-].Cl>C(#N)C>[CH3:10][C:7]1[CH:6]=[C:5]([CH2:1][C:2](=[O:3])[CH2:4][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[CH3:11])[O:9][N:8]=1
Reactant: CC1=CCCC(=O)O1
Reactant: CC(=O)Cc1cc(C)no1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)CCCC(=O)CC(=O)Cc1cc(C)no1
Temperature: 0 °C
Yield: 80.9 %

Procedure:
1.39 g of 5-acetonyl-3-methylisoxazole, 1.68 g of 3,4-dihydro-6-methyl-2H-pyran-2-one and 3.42 g of cecium carbonate were added to 20 ml of acetonitrile to heat at reflux for 3 hours. After returning to room temperatrure, the reaction solution was poured into 100 ml of ice water with hydrochloric acid added, and extracted with ethyl acetate. The organic layer was washed with water and then with saturated salt water, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The obtained crude product was purified on silica gel column chromatography to give 2.03 g of the title compound as a colorless viscous liquid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:9]=1[NH2:10].Cl.[C:25](=N)(OC)[CH3:26].O>CO>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[C:12]1[CH:13]=[CH:14][C:8]2[N:7]([CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)[C:25]([CH3:26])=[N:10][C:9]=2[CH:11]=1
Reactant: COC(C)=N
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCC1CCCO1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC1CCCO1
Yield: 127.5 %

Procedure:
To a solution of 2-(tetrahydrofuran-2-yl)methylaminoanilin-5-yl)benzoxazole (see Working Example 95-1) (0.15 g, 0.4 mmol) in methanol (5 mL) was added methyl acetimidate hydrochloride (0.05 mg, 0.4 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.17 g, 79% yield) as white crystals.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][N:5]=1.CN(C)C(=O)C.[SH:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>CC(C)=O>[ClH:2].[CH3:10][C:9]1[C:4]([CH2:3][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
12.71 g (0.0459 mole) of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine hydrochloride were suspended in 322 ml of acetone in the presence of 2.52 ml N,N-dimethylacetamide. Then 7.24 g (0.0597 mole) of 2-mercaptobenzimidazole were added. The mixture was heated to reflux and stirred for 5 hours. After cooling to room temperature, the resulting suspension was filtered to obtain the wet product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[C:3]=1[NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N)c21
Yield: 75.9 %

Procedure:
To a solution of ethyl N-[2-amino-6-({[(2,4-dichlorophenyl)amino]carbonothioyl}amino)phenyl]-beta-alaninate (Reference Example 26; 174 mg, 0.407 mmol) in tetrahydrofuran (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (234 mg, 1.22 mmol) at room temperature. The resultant mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as an oil (122 mg, 0.309 mmol, 76%).
Reaction SMILES: Br[CH:2]1[CH2:7][C@@H:6]2[CH2:8][C:3]1([C:9]([OH:11])=[O:10])[CH2:4][CH2:5]2>[Zn].C(O)(=O)C>[C:3]12([C:9]([OH:11])=[O:10])[CH2:8][CH:6]([CH2:5][CH2:4]1)[CH2:7][CH2:2]2
Reactant: O=C(O)C12CC[C@H](CC1Br)C2
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)C12CCC(CC1)C2
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A 2-L reactor equipped with an overhead mechanical stirrer, condenser, nitrogen gas inlet port, temperature probe and reagent charging port, was placed under an atmosphere of nitrogen. The reactor was charged with zinc powder (<10 micron) (298 g, 4560 mmol) and acetic acid (500 mL). While vigorously stirring the heterogeneous mixture, (4S)-2-bromobicyclo[2.2.1]heptane-1-carboxylic acid (100 g, 456 mmol) was then added. A second portion of acetic acid (500 mL) was then used to rinse the walls of the reactor. The reaction mixture was brought to a gentle reflux (ca. 30 min) and then held at this temperature for 5 h. The cooled (room temperature) reaction mixture was passed through a pad of Celite, which was washed with acetic acid (1 (300 mL) and ethyl acetate (1 (500 mL). The filtrate was concentrated, water (300 mL) was added, and then the mixture was stirred vigorously to induce precipitation. The precipitate was collected by filtration, washed with water, and dried under vacuum at 35° C. overnight. Pentane (50 mL) was then added, and the mixture was stirred vigorously for 20 min during which time a fine white precipitate formed. The resulting precipitate was filtered, washed with pentane (20 mL), and air dried to afford bicyclo[2.2.1]heptane-1-carboxylic acid (52 g) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:37])[O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:26](=[O:37])([O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[NH2:14])=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccc(N2CCC(O)CC2)nc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To the solution of 6-(4-hydroxypiperidin-1-yl)nicotinamide (3.32 g, 15 mmol) in pyridine (10 mL) was added DIPEA (3.87 g, 30.0 mmol) and 4-nitrophenyl carbonochloridate (6.03 g, 30 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated under reduced pressure to afford the crude product. The residue was further purified by silica gel chromatography (DCM: MeOH=100:0 to 20:1) to afford the title compound (3 g, 50%) as a white solid. [LCMS RtB=1.79 min, [M+H]+=387.0].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Oc2ccc(C(=O)O)cc2)cc1
Reaction time: 1 h

Procedure:
This step illustrates the addition of an aryl group to the compound of Step 2 to increase the stiffness and rod-like characteristics of the alkyl or alkoxy substituted cinnamoyl group. The compound of Step 2 (1.0 gm=5.1 mmole) was slurried under N2 in 10 mL dry pyridine. N,N-diisopropylethylamine (0.7 gm=5.6 mmole) was added, followed by a spatula tip of 4-dimethylaminopyridine. A solution of p-hydroxybenzoic acid (0.7 gm, 5.1 mmole) in 7 mL pyridine was added dropwise to the above slurry. An amber-orange solution soon developed. The solution was stirred for 60 minutes after addition was complete, and it was dropped slowly into 200 ml ice/H2O containing 25 mL concentrated HCl. The resulting precipitate was collected by suction filtration, slurried twice with H2O on the funnel, and dried in a 40° C. vacuum oven. The white solid was recrystallized from boiling acetone. White needles, K280° l.c. Yield 0.6 gm. Elemental Analysis: C17H14O 5, mol. wt. 298.3. Calcd: C, 68.5, H, 4.7, O, 26.8. Found: C, 68.5, H, 4.7. 1H NMR (DMSO-d6): δ (ppm) 6.7 (1H, d), 8.0 (1H, d).
Reaction SMILES: CS(O[CH:6]([CH2:28][F:29])[CH2:7][O:8][C:9]1[CH:13]=[C:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[CH:19][C:17]=3[N:18]=2)[O:11][N:10]=1)(=O)=O.[N-]=[N+]=[N-].[Na+].CS(C)=O>O>[CH:25]1([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:16]3[O:15][C:14]([C:12]4[O:11][N:10]=[C:9]([O:8][CH2:7][CH:6]([NH:10][C:9](=[O:8])[CH3:13])[CH2:28][F:29])[CH:13]=4)=[N:18][C:17]=3[CH:19]=2)[CH2:26][CH2:27]1
Reactant: CS(=O)(=O)OC(CF)COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NC(CF)COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1
Temperature: 100 °C
Reaction time: 4 h
Yield: 117.7 %

Procedure:
A mixture of 2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]isoxazol-3-yl}oxy)-1-(fluoromethyl)ethyl methanesulfonate (97.3 mg), sodium azide (29.7 mg) and dimethyl sulfoxide (2 mL) was stirred at 100° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with triphenylphosphine (71.8 mg), THF (3 mL) and water (1 mL), and the obtained mixture was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with acetic anhydride (1 mL), triethylamine (1 mL) and ethyl acetate (3 mL), and the obtained mixture was stirred at 60° C. overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained residue was separated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). A saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as white crystals (52.3 mg).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.