Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:20][CH3:21])[S:13][C:14]=2[C:15]([O:17]CC)=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:20][CH3:21])[S:13][C:14]=2[C:15]([OH:17])=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1sc(NC)nc1C(C)c1ccc(-c2ccc(F)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1nc(C(C)c2ccc(-c3ccc(F)cc3)c(F)c2)c(C(=O)O)s1
Yield: 64.5 %

Procedure:
Ethyl 4-(1-(2,4'-difluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarboxylate (1.00 g, 2.48 mmole) was dissolved in methanol (20 ml). After adding a solution of potassium hydroxide (420 mg, 7.49 mmole) in water (4 ml), the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and washed with ether. The water layer was acidified to about pH 4 with 1chloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure Recrystallization of the residue from methanol gave the desired 4-(1-(2,4'-difluoro-4-biphenylyl-)ethyl)-2-methylamino-5-thiazolecarboxylic acid (599 mg, 1.60 mmoles, yield 65%) as a white crystalline product.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[C:5]1([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]#[C:20][C:21]3[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:5]1([C:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]#[C:20][C:21]3[N:26]=[CH:25][C:24]([NH:27][CH2:1][CH2:2][CH3:3])=[CH:23][CH:22]=3)[CH2:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCNc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of propionaldehyde (0.18 mL, 2.5 mmol), 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.83 g , 2.7 mmon) and glacial acetic acid (0.14 mL, 2.5 mmol) in 20 mL of dichloroethane is treated with sodium triacetoxyborohydride (0.79 g, 3.7 mmol) under nitrogen and is stirred at room temperature for 18 hours. The reaction is quenched with saturated aqueous sodium bicarbonate, diluted with dichloromethane, and the organic layer is dried (sodium sulfate) and concentrated under reduced pressure. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.20 mol of water; mp 138°-139° C.
Reaction SMILES: CC[O:3][C:4]([C@H:6]1[CH2:11][N:10]([CH2:12][CH2:13][CH:14]=[C:15]([C:22]2[S:26][CH:25]=[CH:24][C:23]=2[CH3:27])[C:16]2[S:20][CH:19]=[CH:18][C:17]=2[CH3:21])[CH2:9][CH2:8][CH2:7]1)=[O:5].Cl>O>[CH3:27][C:23]1[CH:24]=[CH:25][S:26][C:22]=1[C:15]([C:16]1[S:20][CH:19]=[CH:18][C:17]=1[CH3:21])=[CH:14][CH2:13][CH2:12][N:10]1[CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCC=C(c2sccc2C)c2sccc2C)C1
Agent: Cl
Solvent: O
Product: Cc1ccsc1C(=CCCN1CCC[C@@H](C(=O)O)C1)c1sccc1C
Temperature: 88 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
To a 1 L flask, 50 g of tiagabine ethyl ester, 575 ml of water and 25 g of conc. hydrochloric acid were charged. The mixture was heated to reflux for 1 hour and then ethanol/water, a total of 200 ml, was distilled off over a period of 4 hours. The reaction solution was cooled to 88° C. and then an additional 23.5 g of conc. hydrochloric acid was added. The solution was gradually cooled to room temperature (22° C.) while the reaction was stirred for 18 hours. The resulting precipitate was collected by filtration and was washed with 20 ml of water. The product was dried under vacuum at room temperature to give 42.0 g of Tiagabine, hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[C:8]2=[O:25])[S:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]2=[O:25])[S:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCN(CCOS(=O)(=O)c3ccc(C)cc3)C2=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 3-methyl-5-(2-oxo-3-(2-(tosyloxy)ethyl)imidazolidin-1-yl)thiophene-2-carboxylate (0.16 g, 0.35 mmol), phenol (0.03 g, 0.36 mmol) and potassium carbonate (0.05 g, 0.35 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 16 h, cooled to ambient temperature, and partitioned between ethyl acetate (75 mL) and water (35 mL). The organic layer was washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-40% ethyl acetate in hexanes to afford the title compound as a colorless solid 72% yield (0.10 g): 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.00-6.94 (m, 1H), 6.89 (d, J=7.6 Hz, 2H), 6.14 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.17 (t, J=4.9 Hz, 2H), 3.81 (br s, 4H), 3.72 (t, J=4.9 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 375.2 (M+1).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9][C:8]1=[O:18].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH3:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:18])[CH:9]=1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n(CC=O)c2ccccc12
Temperature: 40 °C
Reaction time: 15 h

Procedure:
0.74 g of 1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one was dissolved in 6 mL of 67% aqueous trifluoroacetic acid solution, and stirred at room temperature for 15.5 hours, at 40° C. for 9.5 hours, further at room temperature for 15 hours. After the reaction mixture was alkalized by adding aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8](I)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (20 mmol, 1 equiv) in DMF was added NaN3 (2.5 equiv, 50 mmol), the resulting mixture was heated to 65 centigrade and stirred overnight. The mixture was diluted with water, extracted with AcOEt and dried over Na2SO4. After removal of solvent, the residue was purified by chromatography on silica gel to give title product (4.94 g) as colorless oil in 90% yield. MS m/e=271.5 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.Cl.[CH3:15]O>>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=C(O)c1ccc2[nH]nc(O)c2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2[nH]nc(O)c2c1
Temperature: 100 °C
Yield: 99 %

Procedure:
3-hydroxy-1H-indazole-5-carboxylic acid (1.5 g, 8.4 mmol) was suspended in methanol (17 mL). Concentrated hydrochloric acid (3.11 mL, 101 mmol) was added and the reaction was heated to 100° C. for 6 hours. The reaction was concentrated to provide the title compound (1.60 g, 99%). +ESI (M+H) 193.1; 1H NMR (400 MHz, DMSO-d6, δ): 12.00 (br. s., 1H), 8.35 (s, 1H), 7.83 (dd, J=8.9, 1.7 Hz, 1H), 7.33 (dd, J=8.9, 0.7 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.Cl.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH2:32])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester was treated with HCl according to General Procedure C and followed by aqueous NaHCO3 wash to give (S)-2-amino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester. This was subjected to alkylation with (1-bromo-propyl)-benzene according to General Procedure P.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([OH:17])[CH:3]=1.I[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([NH:26][CH3:27])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][S:23](=[O:25])(=[O:24])[NH:26][CH3:27])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1O
Reactant: CNS(=O)(=O)CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl 4-fluoro-2-hydroxybenzylcarbamate (Example 15; 12.2 mmol), 4-iodo-N-methylbutane-1-sulfonamide (Example 18; 18.3 mmol) and potassium carbonate (61 mmol) in DMF (60 ml) was stirred at 80° C. for 10 hours.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:20][S@](C(C)(C)C)=O)[C:11]1[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=1)(C(C)(C)C)(C)C.[ClH:27].O1CCOCC1>CO>[ClH:27].[ClH:27].[NH2:20][C@@H:10]([C:11]1[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:9][OH:8]
Reactant: COc1ncc(F)cc1[C@@H](CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ncc(F)cc1[C@H](N)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (S)-N-((S)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 3.46 mmol) in methanol (20 mL) was added 4N HCl/dioxane (8.65 mL, 34.6 mmol). The solution was stirred at ambient temperature for 16 hours, then concentrated and dried under vacuum to afford (S)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride as a yellow oil which was used without purification, assuming 100% yield. MS (apci) m/z=186.9 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C([Li])(CC)C.Cl.[C:26](OCC)(=[O:28])C>C1COCC1.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:26]=[O:28])=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1ccc(-c2cccc(F)c2F)c(F)c1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C=O)c(F)c2F)c(F)c1F
Reaction time: 2 h

Procedure:
4-Ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl (s-7) (28.0 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 109 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. N,N-Dimethylformamide (8.0 g) in a THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (300 ml) and ethyl acetate (300 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent and further purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:5 by volume) and dried to give 4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-carboxaldehyde (s-8) (28.0 g). The yield based on the compound (s-7) was 90.6%.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:30].[OH-].[Li+]>O1CCCC1>[C:24]1([S:21]([C:20]2[CH:19]=[CH:18][S:17][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]=2[CH3:30])(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A solution of [3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.19 g) in tetrahydrofuran (10 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.8 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a white solid (0.17 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[O:10]([CH2:17][C:18](N)=[NH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:18]([CH2:17][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:19]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COc1ccccc1
Solvent: CCO
Product: Nc1nc(COc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 3.0 g (0.025 mole) of 3-amino-2-pyrazinecarbonitrile and 3.8 g (0.025 mole) of 2-phenoxyacetamidine [prepared according to C. Djerassi and C. R. Scholz, J. Am. Chem. Soc., 1947, 69, 1688] in 100 ml if absolute ethanol. Refluxing time: 4 hours. Yld: 5.4 g (85%), m.p. 202°-204° C. (ethanol).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][C:15]1=[O:26]>>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18]([N:17]=[CH:16][C:15](=[O:26])[N:14]2[CH2:13][CH:9]=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc2ncc(=O)n(CC3OCCO3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into 200 mL of an 80% aqueous trifluoroacetic acid solution, 13g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxyquinoxalin-2(1H)-one was dissolved, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, the reaction mixture was alkalified with an aqueous saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain (7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [CH2:1]([C:4]1([O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:8]([O:9][CH3:10])[C@H:6]1[OH:7])[OH:5])[CH:2]=[CH2:3].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:1]([C:4]1([O:14][C@H:13]([CH2:15][O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:11]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:8]([O:9][CH3:10])[C@H:6]1[O:7][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:5])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCC1(O)O[C@H](CO)[C@@H](O)[C@H](OC)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OC)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Allyl-3-O-methyl-glucopyranose (4.5 g) was dissolved in anhydrous DMF (120 mL) and sodium hydride (1.84 g, 50% dispersion in oil) was added thereto. The resulting solution was stirred for 0.5 hours at 0° C. Benzyl bromide (6.8 mL) was added dropwise at 0° to 5° C. and the reaction mixture was then stirred for 4 hours at room temperature. The reaction mixture was quenched by adding methanol, diluted with dichloromethane (250 mL) and washed with water (3×250 mL), dried over Na2SO4, filtered and evaporated. The material was purified by chromatography on silica gel using hexane-ethyl acetate (5:1) as eluent. The evaporated fractions from column were crystallized from a mixture of dichloromethane and hexane to provide for allyl-3-O-methyl-2,4,6-tri-O-benzyl-glucopyranose (8 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[F:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[F:28][C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:29])[CH:18]3[CH3:30])=[CH:15][C:14]=1[O:13][C:10]1([CH3:12])[CH2:9][NH:8][CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(F)c(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(F)c(OC4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 3-(7-fluoro-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.033 g, 0.078 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 7-fluoro 4-methyl-6-(3-methyl-azetidin-3-yloxy)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a white solid (0.017 g, 67%). LC/MS (Table 1, Method 5) Rt=1.806 min; MS m/z: 321 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:23][C:24](=[O:26])[CH3:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
1-Amino-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (60 mg, 0.19 mmol) prepared in Example 20 was dissolved in dichloromethane (10 mL), and acetyl chloride (76.15 mg, 70.0 μl, 0.97 mmol) and triethylamine (130.00 mg, 0.18 mL, 128 mmol) were added thereto in order at 0° C. The mixture was stirred for 1 hr at RT, washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 48 mg of the titled compound (yield: 71%).
Reaction SMILES: C[C:2]1(C)[O:6][CH2:5][CH2:4][O:3]1.[F:8][C:9]([F:16])([F:15])[C:10]([F:14])=[C:11]([F:13])[F:12]>>[F:12][C:11]([CH:4]1[CH2:5][O:6][CH2:2][O:3]1)([F:13])[CH:10]([F:14])[C:9]([F:16])([F:15])[F:8]
Reactant: CC1(C)OCCO1
Reactant: FC(F)=C(F)C(F)(F)F
Product: FC(C(F)(F)F)C(F)(F)C1COCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Example 1 was prepared by combining 2,2-dimethyl-1,3-dioxolane (200 g, 1.96 moles, Fluka Chemie GmbH, Deisenhofen, Germany) and Luperox 575 (10 g, 0.041 moles) (Arkema, Oakville, Ontario, Canada) were combined in a 600 mL Parr reactor (Parr Instrument Co., Moline, Ill.). The reactor was warmed to 75° C. and hexafluoropropene (300 g, 2.0 moles) (MDA Manufacturing Inc., Decatur, Ala.) was added at a constant rate. The reactor was allowed to stir at this temperature for 16 h. The crude reaction material was distilled using a ten plate Oldershaw column to afford 4-(1,1,2,3,3,3-hexafluoropropyl)-1,3-dioxolane (boiling point (b.p.) of 144° C.).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7](OCC)=[O:8])[CH2:2]1.[NH2:19][NH2:20]>CO>[NH:19]([C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1)=[O:8])[NH2:20]
Reactant: NN
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NN)C1

Procedure:
Stirred a solution of (R)-1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (5 g, 19.4 mmol), hydrazine (anhydrous; 2 ml) in MeOH (5 ml) in a microwave oven at 100° C. for 3 hours. Cooled and solvent was evaporated. Chromatographed residue on silica gel eluting with 3% MeOH: DCM to yield (R)-tert-butyl 3-(hydrazinecarbonyl)piperidine-1-carboxylate as colorless oil (5.1 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][CH:20]=1)[CH3:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][CH:20]=1)[CH3:18]
Reactant: CCc1cnc(C(=O)O)[nH]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCc1cnc(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)[nH]1
Yield: 55 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.20 g, 0.87 mmol), 5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1b) (85 mg, 0.44 mmol), WSC hydrochloride (0.55 g, 2.87 mmol) and DMAP (115 mg, 0.94 mmol), to obtain 85 mg of the title compound as a pale yellow solid (55%).