Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[F:16][C:17]([F:25])([F:24])[C:18]([C:19]1[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:20]=1[CH3:21])=[O:23]
Reactant: Nc1sccc1C(=O)c1ccc(F)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sccc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 18.1 %

Procedure:
To a stirred solution of 30 mg (0.13 mmol) (2-amino-thiophen-3-yl)-(4-fluoro-phenyl)-methanone in 1 ml acetic acid was added 0.017 ml (0.13 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 15 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 8 mg (17%) 2,2,2-trifluoro-1-[4-(4-fluoro-phenyl)-6-methyl-thieno[2,3-b]pyridin-5-yl)-ethanone as a yellow oil. ES-MS m/e (%): 340 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[CH:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH:13]([CH3:14])[C:12]([CH:11]=[O:15])=[CH:4][C:3]=2[CH:6]=1
Reactant: C/C=C/C=O
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1Oc2ccc(O)cc2C=C1C=O

Procedure:
The starting material is prepared as follows: A mixture of 2,5-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), crotonaldehyde (3.8 g, 54.3 mmol), and potassium carbonate (10.0 g, 72.4 mmol) in 75 ml of 1,4-dioxane is heated at reflux for 6 hours. The mixture is cooled and poured into water. This is extracted (3×) with dichloromethane, and the combined organic layers are dried (MgSO4) and concentrated to dryness to give 6-hydroxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde as a colored solid. Such is converted to 6-benzyloxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde, m.p. 107°-109° C., which is in turn converted to 3-(N-hydroxyaminomethyl)-6-benzyloxy-2-methyl-2H-1-benzopyran as described above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](I)[CH:25]=[CH2:26].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:26][CH:25]=[CH2:24])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=CCI
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To the solution was added 0.6 g of approximately 50 % sodium hydride and stirring was performed for 30 minutes. To this was added 3.4 g of allyl iodide and the mixture was reacted for 3 hours at room temperature. Then the solvent was evaporated from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.3 g of 1-(m-nitrophenyl)-3-allylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 188-189°C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)[N:4]=1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:53]([O:52][C:50]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:32])([F:33])[F:1])=[N:4]2)[CH:10]=1)(=[O:25])=[O:26])=[O:51])[CH2:54][CH2:55][CH3:56]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccc(C(F)(F)F)n3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 3-[3-(3-trifluoromethylpyrazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (43.5 mg, 0.087 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (25.8 mg, 0.174 mmol) and butyl chloroformate (110.7 μL, 0.87 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (40-100% CH3CN in water) to give the title compound in 88% yield, over two steps, (41.6 mg, 0.076 mmol).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:19]2[NH:20][CH:21]=[CH:22][C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:15]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:9])[C:19]3[NH:20][CH:21]=[CH:22][C:18]=3[C:17]=2[CH:16]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Reactant: O=C1CCC(=O)N1Br
Agent: CCC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
434 mg (2.44 mmol) of N-bromosuccinimide is added to 500 mg (1.95 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 1) dissolved in 10 ml of anhydrous dimethylformamide and the reaction mixture is stirred for 1 h at room temperature. The mixture is then diluted in 10 mL of ethyl acetate, the solid is filtered, rinsed with diethyl ether then recrystallized from acetic acid to give 360 mg (55%) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid in the form of a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(NC3C=CC(C)=CC=3)=O)=[CH:12][CH:11]=2)[CH:4]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>>[CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:36]([NH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:38])([F:39])[F:27])[CH:30]=3)=[O:37])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CNc1cc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)ncn1
Product: CNc1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Reaction time: 3 h

Procedure:
The title compound is prepared as described in Example 102 but using [6-(4-amino-benzyl)-pyrimidin-4-yl]-methyl-amine (Example 119) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 3 h. The title compound is obtained as a white solid: ES-MS: 402.0 [M+H]+; single peak at tR=7.34 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[O:30][CH2:31][CH:32]=O.[BH4-].[Na+]>CO>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[O:30][CH2:31][CH2:32][NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(CCN)cc1S(N)(=O)=O
Reactant: COc1ccc(F)cc1OCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1OCCNCCc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A suspension of 1.50 g of 5-(2-aminoethyl)-2-methoxybenzenesulfonamide hydrochloride and 0.8 ml of triethylamine in 50 ml of methanol was heated for 30 minutes at 75° C. To the reaction mixture was added 1.00 g of 2-(5-fluoro-2-methoxyphenoxy)acetaldehyde and the reaction mixture was heated for 10 minutes at 75° C. To the solution was added 0.45 g of sodium borohydride under ice cooling and the solution was stirred for 1 hr at room temperature. The reaction mixture was evaporated, acidified with 10% hydrochloric acid and washed with ether. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was solidified with a mixture of methanol and ether and the precipitate was filtered to give 0.46 g of the desired compound as pale brown crystals which were recrystallized from N,N-dimethylformamide as pale yellow crystals, m.p. 201°-205° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[CH3:18])=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.C(O)C>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17](=[N:16][O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:10][CH:9]=2)[CH3:18])=[CH:24][CH:23]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)Cc1ccc(OCCCON=C(C)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=NOCCCOc1ccc(CC(=O)O)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a solution of (4-{3-[1-(4-tert-butyl-phenyl)-ethylideneaminooxy]-propoxy}-phenyl)-acetic acid methyl ester (3.55 mmol) in tetrahydrofuran/ethanol (3/2) (20 mL) was added 1 M sodium hydroxide solution (6 mL, 6 mmol) and the reaction was stirred overnight at room temperature. It was concentrated to a small volume, acidified to pH 1 with 1M hydrochloric acid solution and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80)+1% formic acid to afford the title compound (0.620 g, 46%) as a light yellow solid. mp=98.7-99.7° C.; mass spectrum (−ESI, M−H) m/z 382. 1H NMR (400 MHz, DMSO-d6); δ 12.20 (bs, 1H), 7.55 (d, 2H), 7.38 (d, 2H). 7.14 (d, 2H), 6.87 (d, 2H), 4.25 (t, 2H), 4.05 (t, 2H), 3.47 (s, 2H), 2.16 (s, 3H), 2.09 (m, 2H), 1.25 (s, 9H). Elemental analysis: Calcd. for C23H29NO4: C, 72.04; H, 7.62; N, 3.65, Found: C, 71.43; H, 7.87; N, 3.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([O:16][CH3:17])[C:4]=1B(O)O.[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[CH3:22].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][N:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)=[CH:6][C:5]=2[O:16][CH3:17])=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=1[Cl:34])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CN2CCSCC2)cc(OC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CN3CCSCC3)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture of 2,6-dimethoxy-4-(thiomorpholinomethyl)benzeneboronic acid (1.1 g), N-(2,6-dichlorobenzoyl)-4bromo-L-phenylalanine ethyl ester (0.71 g), Pd(PPh3)4 (1.0 g) and K2CO3 (1.00 g) in DME/H2O (10 mL/0.5 mL) was heated at 80° C. for 6 h under N2. The mixture was worked up and purified according to the procedure described in Example 8-3) to yield 0.15 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(thiomorpholinomethyl)phenyl]-L-phenylalanine ethyl ester. mp. 86-89° C. ESMS: m/z 616 (MH+). HCl salt: mp. 204-205° C.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](O)=[O:26])[CH:6]=1)[CH2:3][OH:4].[NH2:28][C@@H:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([NH:28][CH:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31])=[O:26])[CH:6]=1)[CH2:3][OH:4]
Reactant: NC(=O)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC(NC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid (assume 0.44 mmol) in DMF (5 mL) was added (S)-2-aminosuccinamide (0.076 g, 0.45 mmol), DIEA (0.20 mL, 1.1 mmol) and HBTU (0.203 g, 0.54 mmol). The reaction was stirred overnight then partitioned between 50 mL EtOAc and 50 mL brine. The aqueous layer was extracted once more with 25 mL EtOAc and combined. The organics were dried over Na2SO4, filtered and evaporated in vacuo. The residue was crystallized from 4 mL warm acetone, the solid filtered off, rinsed with additional acetone and dried under vacuum at 50° C. to yield the product S)-2-(4-((S)-1,2-Dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamido)succinamide as a light tan powder (0.125 g, 0.26 mmol, 59% yield, LC/MS: m/z=483.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 9.29 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.40 (s, 1H), 7.32-7.25 (m, 2H), 7.21-7.15 (m, 2H), 7.14-7.07 (m, 3H), 6.99 (s, 1H), 5.64 (d, J=4.8 Hz, 1H), 4.85 (t, J=6.0 Hz, 1H), 4.75-4.64 (m, 2H), 3.62-3.49 (m, 2H), 2.79-2.70 (m, 1H), 2.61-2.53 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3.[OH:20]O>CC(O)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:20])[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3
Reactant: OO
Reactant: FC(F)(F)c1nnc2cnc3cc(Cl)c(Cl)cc3n12
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n2c(C(F)(F)F)nnc12
Temperature: 55 °C

Procedure:
800 mg (2.3 mmol) of the quinoxaline (9) was stirred in 22 ml HOAc, and 7 ml of 30% H2O2 was added. The reaction mixture was heated to 55° C. for 16 hours, and then cooled to room temperature. Filtering and drying the product yielded 330 mg of 1-trifluoromethyl-7,8-dichloro-1,2,4-triazolo [4,3-a]quinoxalin-4(5H)-one (10).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[F:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)cc(F)cc1N1CCOCC1
Temperature: 10 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
2,4,6-Trifluoronitrobenzene (4.95 g) and potassium carbonate (4.63 g) were mixed in dry dimethyl sulfoxide (40 mL) and cooled to 10° C. under argon. Morpholine (2.56 mL) was added and the reaction mixture was allowed to warm to 25° C. and stirred under argon for 16 hours. The reaction mixture was concentrated in vacuo, brine (50 mL) was added and the product was extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography to furnish 3.69 g (54% yield) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:51][NH:52][CH3:53]>ClCCl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9]([N:52]([CH3:53])[CH3:51])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 91 %

Procedure:
A solution of compound 50.3 (50 mg, 0.1 mmol) in dichloromethane (2 mL) was treated with 1-hydroxybenzotriazole (15 mg, 0.11 mmol) and EDC (21 mg, 0.11 mmol) sequentially. The resulting mixture was stirred for 1 h. before dimethylamine (9 mg, 0.2 mmol) was added dropwise. The reaction was quenched 30 min. later with water (5 mL). The reaction mixture was extracted with dichloromethane (2 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure to yield amide 50.4 (48 mg). The product was used in the next step without further purification. MS ESI (pos.) m/e: 527 (M+).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2
Reactant: CC1=C(N2CCC3(CCN(C(CO[Si](C)(C)C(C)(C)C)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(N2CCC3(CCN(C(CO)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8-(1-((tert-butyldimethylsilyl)oxy)-3-(4-methyl-1-oxo-1,3-dihydro isobenzofuran-5-yl)propan-2-yl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (0.10 g, 0.18 mmol) in DCM (3 mL) was added trifluoroacetic acid (3 mL) at 0° C. After stirring at room temperature for 24 h, solvent was removed under reduced pressure and the residue was purified by preparative-HPLC to give the title compound, which was separated by SFC chiral chromatography into two single enantiomers Isomer A (faster elting) and Isomer B (slower eluting. Column: CHIRALPAK AD 250×30 mm I.D., 20 μm; Mobile phase: Supercritical CO2/EtOH (0.2% NH3H2O)=45/55; Flow rate: 80 ml/min. For both isomers: LC-MS (ESI, m/z): 455 [M+1].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)([Cl:15])=O>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:15])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)nc1Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)nc1Cl
Yield: 151.6 %

Procedure:
A mixture of 6-chloro-5-methoxypicolinic acid (1.5 g, 8.0 mmol), thionyl chloride (5 g, 8.0×5.25 mmol), a catalytic amount (35 mg) of N,N-dimethylformamide and 5 ml of benzene was refluxed for 1 hour. Then, thionyl chloride and benzene were distilled off, and the residue was distributed with water and dichloromethane. A dichloromethane layer was separated and dried with sodium sulfate. The solvent was then distilled off to obtain 1.64 g of 6-chloro-5-methoxypicolinic acid chloride. It was dissolved again in 5 ml of dichloromethane and the resultant solution was added dropwise to a solution of phenol (0.79 g, 8×1.05 mmol) and triethyl amine (0.89 g, 8×1.1 mmol) in 30 ml of dichloromethane under cooling with ice. After conclusion of the addition, the reaction solution was stirred at room temperature for 2 hours, followed by adding water to separate an organic layer. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with sodium sulfate. The organic solvent was distilled off to obtain a white solid.
Reaction SMILES: [CH:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)=[CH:2][CH2:3][CH3:4].[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].N1C=CN=C1>CN(C=O)C>[CH:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[C:8]([Cl:10])[N:9]=1)=[CH:2][CH2:3][CH3:4]
Reactant: CCC=Cc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC=Cc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 83.8 %

Procedure:
2-(But-1-en-1-yl)-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)-imidazole (1.4 g), t-butyldimethylsilyl chloride (0.55 g), and imidazole (0.5 g) were mixed and stirred in DMF (5 mL) for 18 hours at room temperature. Dilution with ethyl acetate and washing the organic phase with water followed by drying (MgSO4), evaporation of the solvent in vacuo, and flash chromatography in 3:1 hexane/ethyl acetate yielded 1.5 g of a clear oil. NMR (200 MHz, CDCl3) δ7.83 (d, 1H); 7.52 (t, 1H); 7.40 (t, 1H); 7.33-7.24 (m, 3H); 7.08 (d, 2H); 6.83 (d of t, 1H); 6.13 (d, 1H); 5.30 (s, 2H); 4.57 (s, 2H); 3.64 (s, 3H); 2.21 (quint., 2H); 1.04 (t, 3H); 0.86 (s, 9H); 0.05 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CCC(=O)OC(C)(C)C)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(CCC(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 5-(2-tert-butoxycarbonyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester (1.6 g, 5 mmol) in dichloromethane (12 mL) was added 8 mL of 40% trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. The reaction was concentrated, dissolved in toluene, concentrate, dissolved in dichloromethane and concentrated to give 1.3 g (99%) of 5-(2-carboxy-ethyl)-1H-indole-2-carboxylic acid ethyl ester.