Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C@@H:8]([NH2:10])[CH3:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Si]([O:24][CH2:25][CH:26]=O)(C(C)(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:42]CCl>>[ClH:42].[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C@@H:8]([NH:10][CH2:26][CH2:25][OH:24])[CH3:9])=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: C[C@H](N)COc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Synthesis of (2S)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[(4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C8). To a solution of (2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C7) (785 mg, 3.31 mmol) in dichloromethane (15 mL) was added {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (577 mg, 3.31 mmol). After 2 hours, sodium triacetoxyborohydride was added portion-wise. The reaction mixture was allowed to stir at room temperature overnight, then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was concentrated in vacuo, then purified via silica gel chromatography (Gradient: 0 to 7% methanol in ethyl acetate) to afford the title compound as a clear liquid. Yield: 466 mg, 1.18 mmol, 36%. LCMS m/z 396.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.19 (d, J=6.4 Hz, 3H), 2.73-2.86 (m, 2H), 3.11-3.19 (m, 1H), 3.74 (dd, J=5.6, 5.4 Hz, 2H), 3.92 (d, J=5.5 Hz, 2H), 6.94 (dd, J=9.0, 4.0 Hz, 1H), 7.15-7.21 (m, 1H), 7.29 (dd, J=8.4, 3.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C>[C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N+:27]([O-:29])=[O:28])=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1NC(=O)C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1cc([N+](=O)[O-])c2ccccc2c1NC(=O)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of 1,2-diethoxalylaminonaphthalene (10.8 g, 0.03 mol) in 150 ml of acetic acid was treated dropwise with nitric acid (1.24 ml, 0.03 mol, d 1.52) and stirred over night at room temperature. Then an additional amount of nitric acid (2.0 ml, d 1.52) was added dropwise and the mixture was stirred for 17 h at room temperature. The mixture was poured into 200 ml of ice/water and the resulting precipitate was isolated by filtration and washed with water, a small amount of cold ethanol and ether affording 3.3 g (27%) of pure product, m.p. 183.0-184.0° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:33]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[CH:34][C:35]2[N:36]([C:38](OCC(F)(F)F)=[N:39][N:40]=2)N=1>C1COCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:33]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[CH:34][C:35]2[N:36]([C:38]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:39][N:40]=2)[CH:7]=1
Reactant: FC(F)(F)COc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: OCC(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)COc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Yield: 48 %

Procedure:
The title compound (21 mg, 48% yield) as a white powder was prepared from 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridine (38 mg, 0.1 mmol), 2,2,2-trifluoroethanol (72 μL, 1.0 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (144 μL, 0.5 mmol) and anhydrous THF (0.5 mL)in a manner analogous to that in which 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[4,3-a]pyridazine (Example 6) was prepared. HPLC/MS: retention time=3.86 min, [M+H]+=438.1.
Reaction SMILES: [Na].[CH2:2]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[C:12]=2[OH:18])=[CH:8][CH:7]=1)[C:3]([CH3:5])=[O:4].[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([CH:29]([OH:32])[CH2:30][NH2:31])=[CH:24][C:23]=1[Cl:33].C([BH3-])#N.[Na+]>CO>[OH2:4].[NH2:21][C:22]1[C:23]([Cl:33])=[CH:24][C:25]([CH:29]([OH:32])[CH2:30][NH:31][CH:3]([CH3:5])[CH2:2][C:6]2[CH:20]=[CH:19][C:9]([O:10][C:11]3[C:15](=[O:16])[NH:14][C:13](=[O:17])[C:12]=3[OH:18])=[CH:8][CH:7]=2)=[CH:26][C:27]=1[Cl:28].[NH2:21][C:22]1[C:23]([Cl:33])=[CH:24][C:25]([CH:29]([OH:32])[CH2:30][NH:31][CH:3]([CH3:5])[CH2:2][C:6]2[CH:20]=[CH:19][C:9]([O:10][C:11]3[C:15](=[O:16])[NH:14][C:13](=[O:17])[C:12]=3[OH:18])=[CH:8][CH:7]=2)=[CH:26][C:27]=1[Cl:28]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(=O)Cc1ccc(OC2=C(O)C(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(Cc1ccc(OC2=C(O)C(=O)NC2=O)cc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Product: O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the sodium salt of 4-(4-acetonylphenoxy)-3-hydroxy-1H-pyrrole-2,5-dione (1.41 g) and 2-(4-amino-3,5-dichlorophenyl)-2-hydroxy ethylamine (1.0 g) in methanol was treated with sodium cyanoborohydride (0.35 g) and stirred at ambient temperature for 18 hours. The solvent was removed in vacuo, the residue dissolved in acetone and purified by column chromatography on silica using acetone as eluent followed by methanol after the elution of fast-running impurities. The solid obtained was washed with acetone and filtered to give 4-[4-[2-[(4-amino-3,5-dichloro-β-hydroxyphenethyl)amino]propyl]phenoxy]-3-hydroxy-1H-pyrrole-2,5-dione hemihydrate as a (34:66) mixture of diastereoisomers.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:24][C:25]([O:27]C)=[O:26])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:6]1)=[O:4].O1CCCC1.[OH-].[Li+].Cl>O>[C:25]([CH2:24][C:5]1([C:3]([OH:4])=[O:2])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:11]=2)[CH2:6]1)([OH:27])=[O:26]
Reactant: COC(=O)CC1(C(=O)OC)CC(c2ccc(OC)c(OC3CCCC3)c2)=NO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=NOC(CC(=O)O)(C(=O)O)C2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
To a solution of the compound obtained from step c in tetrahydrofuran (1.0 eq), was added and lithium hydroxide (5.0 eq) in water (as 5N solution). The mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the residue thus obtained was diluted with water and acidified with drops of concentrated hydrochloric acid. The organic compound was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and finally concentrated under reduced pressure to afford title organic compound.
Reaction SMILES: [H-].[K+].CCCCCC.[C:9](#[N:13])[CH2:10][C:11]#[N:12].[CH2:14]([C:21]1[C:22](=[O:32])[C:23]2[C:28]([C:29](=[O:31])[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.CCCCCC.C(OCC)(=O)C>[NH2:12][C:11]1[O:31][C:29]2[C:28]3[C:23]([C:22]([OH:32])=[C:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:30]=2[C:10]=1[C:9]#[N:13])=[CH:24][CH:25]=[CH:26][CH:27]=3
Reactant: N#CCC#N
Reactant: O=C1C=C(Cc2ccccc2)C(=O)c2ccccc21
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(N)oc2c1c(Cc1ccccc1)c(O)c1ccccc12
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A mixture of potassium hydride (7.56 g, 63 mmol, 35% oil dispersion) and hexane (250ml) was stirred at room temperature under nitrogen. Solvent was decanted off and substituted with dry tetrahydrofuran (250ml). Malononitrile (4.16 g, 63 mmol), dissolved in tetrahydrofuran (50 ml), was then added to the slurry dropwise. A mixture of 2-benzyl-1,4-naphthoquinone (15.62 g, 63 mmol) and tetrahydrofuran (50 ml) was then added dropwise. The reaction mixture was set at reflux for 2h, allowed to cool to room temperature and quenched with methanol (50 ml). The mixture was poured into water (100 ml) and extracted into ethyl acetate (3 x 250 ml). The organic layer was dried (magnesium sulfate) and evaporated to an oil. Chromatography (silica gel: hexane/ethyl acetate (2 : 1) as eluant) of the oily residue afforded 7.48 g (23 mmol, 38%) of product as green crystals, m.p. 224°-225 ° C.; 1H NMR (d6DMSO): 4.5(s,2H), 7.1-7.6 (m, 7H), 7.9(d, 1H), 9.25(s, 1H); IR (nujol): 3460, 3310, 3240, 3190, 2220; High resolution mass spectrum: calculated 314.1055, measured 314.1061.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: CN(CCN)S(C)(=O)=O
Product: CN(CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O)S(C)(=O)=O
Yield: 23.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and N-(2-aminoethyl)-N-methylmethanesulfonamide (100 mg, 0.657 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-N-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 24% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.31 (br s, 1 H), 8.58 (s, 1 H), 7.49 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-6.99 (m, 2 H), 4.37 (m, 2 H), 4.14 (s, 2 H), 3.67 (m, 2 H), 3.51 (m, 2 H), 3.41 (m, 2 H), 2.95 (s, 3 H), 2.83 (s, 3 H), 1.83 (m, 2 H); HRMS m/z calcd for C23H28N4O6FS: 507.1714. Found: 507.1712.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14](C(OC)=O)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:21][Mg]Br.CC[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([C:27]([OH:26])([CH3:28])[CH3:21])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (4.0 g, 0.014 mol) in toluene (300 mL) and THF (70 mL) was cooled to 0° C. and treated with a 3.0 M solution of methylmagnesium bromide in ether (14 mL) maintaining the temperature at 0° C. The mixture was stirred at rt for 1.5 hours then cooled to 0° C. and an additional 3 eq of 3.0 M of methylmagnesium bromide in ether was added. The mixture was stirred at rt for 15 minutes then cooled 0° C. and quenched with 1:1 NH4Cl sat.: H2O (50 mL total volume). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo and the crude product thus obtained, chromatographed over silica gel eluting with EtOAc to afford desired 2-[trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]propan-2-ol. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14-1.39 (m, 8 H), 1.41-1.60 (m, 1 H), 1.77-1.98 (m, 2 H), 2.01-2.20 (m, 4 H), 2.78-3.06 (m, 1 H), 7.35 (d, J=5.05 Hz, 1 H), 7.64 (d, J=5.05 Hz, 1 H) and 7.83 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:18])([CH3:17])[CH2:11][C:12](=[O:16])[C:13]([OH:15])=O)[C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[C:32](=[O:33])[O:31][N:30]=[C:29]([CH2:34]C)[C:28]=2[CH:36]=1.O>CC(N(C)C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:18])([CH3:17])[CH2:11][C:12](=[O:16])[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[O:33])[O:31][N:30]=[C:29]([CH3:34])[C:28]=4[CH:36]=3)=[O:15])[C:4]=2[O:3][CH2:2]1
Reactant: CCc1noc(=O)c2ccc(N)cc12
Reactant: CC(C)(CC(=O)C(=O)O)c1cccc2c1OCO2
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3cccc4c3OCO4)cc12
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
10 g of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-pentanoic acid is dissolved in 125 ml of dimethylacetamide and mixed with 3.5 ml of thionyl chloride under argon at −0° C. After 20 minutes of stirring at −3 to +3° C., 7.6 g of 6-amino-4-ethyl-2,3-benzoxazin-1-one (WO00/32584) is added. It is stirred for 96 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2SO4), and after the solvent is concentrated by evaporation and after chromatography of the crude product on silica gel with hexane/ethyl acetate (100:0→60:40), 6.56 g of 6-[4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxo-valeroyl-amino]-4-methyl-2,3-benzoxazin-1-one is obtained as a beige solid.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[CH:11]1[CH2:16]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[C:11]1=[CH2:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1CC(CO)C1CBr)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1C(CO)CC1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
1-Benzoyloxy-2-bromomethyl-3-hydroxymethylcyclobutane (2.5 g, 8.36 mmol) from Step F and tetra-n-butylammonium fluoride ((8.1 g, 25 mmol) were combined in 200 mL of freshly distilled THF and the reaction mixture was stirred at ambient temperature, under a nitrogen atmosphere, overnight. The volume of the reaction mixture was then reduced to 25 mL and this was dissolved in 250 mL of methylene chloride. The methylene chloride solution was washed with 150 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (4.9 g) was dissolved in ~5 mL of methylene chloride and purified on a 2.5×35 cm silica gel column eluted @ 5 psi with a step-wise (4×200 mL steps) of methanol in methylene chloride from 0% to 3% methanol to give 1.54 g (85% yield) of the title compound as a syrup; 1H NMR (CDCl3) δ 2.38 (m, 2H), 3.22 (m, 1H), 3.69-3.85 (m, 2H), 5.13 (t, 1H), 5.32 (t, 1H), 5.79 (M, 1H), 7.45 (m, 2H), 7.58 (m, 1H), 8.08 (m, 2H); MS DCI-NH3M/Z: 219 (M+H)+, 236 (M+NH4)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)N>>[OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH:4][C:25]1[CH:24]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:26]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-trifluoromethylaniline [Aldrich, product #A41801] as the starting materials. LCMS for C13H16F3N6O4S (M+H)+: m/z=409.1. 1H NMR (500 MHz, DMSO-d6): δ 11.63 (s, 1H), 9.08 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21 (m, 2H), 7.10 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.28 (t, J=5.4 Hz, 1H), 3.36 (q, J=5.8 Hz, 2H), 3.17 (q, J=5.8 Hz, 2H), 2.91 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Cl)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(O)C>[C:1]([NH:4][C:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCC=CCCCCCCCCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCC=CCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 4 %

Procedure:
Diethyl 2-acetamidomalonate (15 g) was dissolved in 200 ml of dry ethanol and 5.6 g of sodium ethoxide was added thereto. To the reaction mixture, 22 g of 9-octadecenyl chloride was added while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with ethanol-concentrated hydrochloric acid (11:1) and concentrated. The concentrate was purified by silica gel column chromatography to give 1.3 g of diethyl 2-acetamido-2-(9-octadecenyl)malonate as a colorless, oily and viscous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.C(OC1C=[CH:29][C:28]([NH:31][C:32]2[N:37]=CN=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45]C(=O)CC(NC4C=CC(F)=CC=4)=O)=[CH:41][C:40]=3[F:59])[CH:33]=2)=CC=1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:37][C:32]1[CH:33]=[C:34]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:13]([CH:10]3[CH2:11][CH2:12][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:16])=[O:15])=[CH:41][C:40]=2[F:59])[CH:29]=[CH:28][N:31]=1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)C3CCN(c4ccc(F)cc4)C3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.3 mol), 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 21.9 mg, 0.1 mmol) in DMF (0.5 ml), was added HATU (76 mg, 0.2 mmol) and followed by diisopropylethylamine (0.1 mL, 0.57 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with 2 mL of methanol. The reaction mixture was purified by prep HPLC. The desired fractions were combined, neutralized with sat. aq. NaHCO3 solution, and concentrated in vacuo to afford the title compound (18 mg, 43%) as a white solid. 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 7.95 (d, 1H, J=7.2 Hz), 7.91 (m, 1H), 7.68 (m, 2H), 7.50 (m, 1H), 7.44 (t, 1H, J=10.0 Hz), 7.24 (m, 2H), 6.70 (m, 1H), 6.11 (d, 1H, J=2.8 Hz), 3.91 (m, 2H), 3.78 (t, 1H, J=5.0 Hz), 2.41 (m, 2H); MS(ESI+) m/z 425.15 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[CH:6]1[CH:11]([CH3:12])[C:10](=[O:13])[O:9][C:7]1=[O:8].[C:14]1(=[O:33])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1.Cl.[C:35](=S)=S>>[C:14]1(=[O:33])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH:24]1[CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[C:28]([C:7](=[O:8])[CH2:6][C:11]([C:10]([OH:9])=[O:13])([CH3:12])[CH3:35])[CH:27]=2)[CH2:32]1
Reactant: S=C=S
Reactant: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Reactant: CC1C(=O)OC(=O)C1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(CC(=O)c1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
in 30 ml of carbon disulfide was suspended 1.60 g of anhydrous aluminum chloride, and to the suspension were added under ice cooling 580 mg of dimethyl succinic anhydride and then 790 mg of 2-(1,3-isoindolinedion-2-yl)indane. The mixture was stirred at 0° C. to room temperature for 3 hours and then refluxed under heating for 4 hours. The reaction mixture was poured into ice water, and hydrochloric acid was added thereto. The mixture was extracted with dichloromethane-tetrahydrofuran (3:1), the extract was dried, and then the solvent was removed. The resulting crystals were washed with ethyl acetate and dried to obtain 580 mg of 2-(1,3-isoindolinedion-2-yl)-5-(3-carboxy-3,3-dimethylpropionyl)indane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2.[H-].[Na+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CN(C)C=O>[O:31]1[CH2:30][CH:29]1[CH2:27][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: ClCC1CO1
Reactant: COc1cc(-c2cc(=O)c3ccc(O)cc3o2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC

Procedure:
Reaction of 3′,4′,5′-trimethoxy-7-hydroxy-flavone, 25 (8.2 g, 25 mol), 50% sodium hydride (3 g, 125 mmol) and epichlorohydrin (7.8 mL, 100 mmol) in dry dimethyl formamide (145 mL) using identical procedure as described for 28 furnished 31. Yield 8 g (83%); mp 187-188° C.; MS (FAB) 385 (M++1); IR (KBr) 1651; 1H NMR (200 MHz, CDCl3) δ 8.14 (d, J=9.3 Hz, 1H), 7.10 (s, 2H), 7.02 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.70 (s, 1H), 4.39 (dd, J=11.0 Hz, 2.8 Hz, 1H), 3.98 (dd, J=11.0 Hz, 5.7 Hz, 1H), 3.43-3.39 (m, 1H), 3.96 (s, 6H), 3.93 (s, 3H), 2.97 (t, J=4.5 Hz, 4.2 Hz, 1H), 2.82 (dd, J=4.7 Hz, 2.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[O:14]C(Cl)(Cl)Cl>O1CCOCC1>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: CSc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CSc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred mixture of 9.16 parts of 2-amino-5-(methylthio)benzoic acid and 100 parts of 1,4-dioxane were added dropwise slowly 9.8 parts of trichloromethyl carbonochloridate. Upon completion, stirring was continued for 2 hours. The reaction mixture was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 8 parts (76%) of 6-(methylthio)-2H-3,1-benzoxazine-2,4(1H)-dione; mp. 219.4° C. (intermediate 153).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:27][CH2:26][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=4)=[CH:3][CH:2]=1.C(O)C.Cl>[Pt]=O.O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:27][CH2:26][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][C:16]([C:22]([F:25])([F:23])[F:24])=[CH:15][CH:14]=4)[CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccncc3)CC12
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCC3CCNCC3)CC12

Procedure:
A mixture of 5 g. (0.014 mole) of 2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 60 ml. of ethanol, 120 ml. of water, 12 ml. of concentrated hydrochloric acid and 1 g. of platinum oxide catalyst was hydrogenated in a Parr apparatus for 2 hours. The catalyst was filtered and the solvents removed. The residue was crystallized two times from methanol to yield 42 g. of the title compound as the dihydrochloride salt, m.p. 279°-282° C.