Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:26]([CH:32]4[CH2:34][CH2:33]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH:29]1([C:28]2[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:2]5[CH2:3][CH2:4][CH2:5][S:1]5(=[O:7])=[O:6])=[CH:14][N:13]=4)=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=[C:26]([CH:32]3[CH2:34][CH2:33]3)[CH:27]=2)[CH2:30][CH2:31]1
Reactant: O=S1(=O)CCCN1
Reactant: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 39.2 %

Procedure:
Using isothiazolidine 1,1-dioxide (105 mg) and (5-bromopyridin-2-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (338 mg) described in Preparation Example 142 and by the reaction and treatment in the same manner as in Example 1, the title compound (145 mg) was obtained.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[C:25]1[C:34]([F:35])=[C:32]([F:33])[C:30]([F:31])=[C:28]([F:29])[C:26]=1[F:27].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:2][CH2:3][C:4]([O:6][C:25]1[C:26]([F:27])=[C:28]([F:29])[C:30]([F:31])=[C:32]([F:33])[C:34]=1[F:35])=[O:5]
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CCNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 15 h
Yield: 89.9 %

Procedure:
To a solution of Fmoc-β-Ala-OH (311 mg, 1.0 mmol) and PfpOH(334 mg, 1.75 mmol) in DMF (2.5 mL) was added DCC (288 mg, 1.4 mmol) at 0° C. for 30 min and then room temperature for 15 h. The reaction mixture was filterd to remove DCUrea, the flitrate was evaporated in vacuo, and the residue was flush-chromatographed (CH2Cl2). The crude Fmoc-β-Ala-OPfp was recrystallized using hexane and CH2Cl2 to give the pure Fmoc-β-Ala-OPfp (429 mg 90%) as a white powder. To a solution of Fmoc-β-Ala-OPfp (100 mg, 0.21 mmol) and BocPNA-OH (41 mg, 0.19 mmol) in DMF (2 mL) was added diisoprppylethylamine (36 il, 0.21 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was evaporated in vacuo and the residue was flush-chromatographed (0-10% MeOH/CH2Cl2) to give Fmoc-Gly-BocPNA-OH (41 mg, 42%). 1H NMR (DMSO-d6) δ 7.88 (d, J=7.4 Hz, 2H), 7.68 (d, J=7.4 Hz, 2H), 7.41 (t, J=7.3 Hz, 2H), 7.33 (t, J=7.3 Hz, 2H), 7.18 (m, 2H), 6.83 (brt) and 6.72 (brt) (2H), 4.3-4.2 (m, 4H), 4.05-3.9 (m, 3H), 3.33 (brt) and 3.29 (brt) (2H), 3.19 (m, 2H), 3.07 (brq) and 3.02 (brq) (2H), 1.36 (brs, 9H) ; 13C NMR (DMSO-d6) δ 171.20 (d), 170.85 (d), 155.93, 155.56, 143.87, 140.69, 127.55, 127.01, 125.09, 120.05, 77.73 (d), 65.30 (d), 59.69, 47.35 (d), 46.68, 46.49 (d), 37.99 (d), 36.72 (d), 28.14 (d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:49]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[CH2:50]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:49]3[CH2:53][CH2:52][CH:51]([C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)[CH2:50]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1Cl
Yield: 65.1 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyrrolidin-3-ylpyridine (6 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z 384 (M+1); HRMS, calcd for C20H18ClN3O3: 383.1037, found 383.1033.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:19])=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH2:12][N:11]3[C:17]=2[CH3:18])[CH:5]=[CH:4][N:3]=1.N[C:21]1C=CC=CC=1>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:19])=[C:10]3[C:15](=[O:16])[N:14]([CH3:21])[CH2:13][CH2:12][N:11]3[C:17]=2[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1c(-c2ccnc(F)n2)c(C)n2c1C(=O)NCC2
Product: Cc1c(-c2ccnc(F)n2)c(C)n2c1C(=O)N(C)CC2

Procedure:
The following compounds were prepared by reaction of 7-(2-fluoropyrimidin-4-yl)-6,8-dimethyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one with an the appropriate aniline
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH:31]C1C=CC(N=C=O)=CC=1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][C:25]([OH:31])=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: O=C=Nc1ccc(O)cc1
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccc(O)cc1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 4-hydroxyphenyl isocyanate in Step 1 of the synthesis. The expected product melts at 190°-194° C.
Reaction SMILES: [C:1]([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)([CH3:9])([CH3:8])[CH3:7].CI>C1COCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[C:14]=1[CH3:1])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OC(C)(C)C)ccnc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
tert-Butyllithium (29 mL of 1.7M in pentane, 50 mmol) was added dropwise to a vigorously stirring solution of (2-chloropyridin-4-yl)carbamic acid tert-butyl ester (4.57 g, 20 mmol) in THF (150 mL) at −78° C. under nitrogen. The reaction mixture was kept at this temperature for 4 hours before adding a solution of methyl iodide (3.41 g, 24 mmol) in THF (20 mL). Warmed the reaction mixture to 0° C. over 2 hours, and quenched the reaction with saturated aqueous ammonium chloride solution (100 mL). Extracted into ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to dryness. Flash column chromatography on silica gel gave the product as a white solid (2.93 g, 12 mmol). 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.98 (d, 1H), 6.58 (br s, 1H), 2.30 (s, 3H), 1.52 (s, 9H). ESI MS (M+1)+: 243, 245 (Cl).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>O1CCOCC1.CCOCC>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)C(C)C)cnc12
Yield: 19.2 %

Procedure:
3-isobutyryl-4-chloro-8-methoxyquinoline (6.0 g, 0.022 mol) and o-toluidine (6 ml, 0.055 mol) were heated in 1,4-dioxan (100 ml) for 45 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and brine. The solution was dried and evaporated to an oil, which was chromatographed (silica gel, dichloromethane) to afford a yellow oil. Trituration in ether gave yellow crystals of 3-isobutyryl-4-(2-methylphenylamino)-8-methoxyquinoline (1.41 g, 18.3%), m.p. 116°-8°.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])([O-])=O.[N:14]([Si](C)(C)C)=[N+:15]=[N-].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C1COCC1>[NH:1]1[CH:4]=[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[N:15]=[N:14]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(/C=C/[N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2c[nH]nn2)c1

Procedure:
3-[(E)-2-Nitroethenyl]benzonitrile (2.79 g, 16.0 mmol) and azidotrimethylsilane (2.76 g, 24.0 mmol) was stirred in anhydrous DMF (100 mL) at 50° C. To this was added tetrabutylammonium fluoride (17.6 mL of a 1.0M solution in THF, 17.6 mmol) via syringe pump over 20 min. The resulting reaction was quenched with MeOH (25 mL) and concentrated in vacuo to a volume of ca. 30 mL. The resulting crude mixture was dissolved in EtOAc (300 mL) and washed with H2O (2×100 mL). The product was then extracted from the EtOAc layer with 1M aqueous NaOH (4×75 mL). The combined basic aqueous portions were treated with 4M HCl to obtain an endpoint of pH=4, and the product was extracted into EtOAc (4×100 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to obtain 3-(1H-1,2,3-triazol-4-yl)benzonitrile as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1)[CH3:2].[OH-].[Na+].[I:18]I>O>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[C:4]=1[I:18])[CH3:2]
Reactant: II
Reactant: CCc1cc(=O)[nH]c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(-c2ccccc2)[nH]c(=O)c1I
Temperature: 50 °C
Yield: 94.5 %

Procedure:
A mixture of 8.18 g (40.9 mmol) of 6-ethyl-2-phenyl-4(3H)-pyrimidinone, 1.68 g (42.0 mmol) of sodium hydroxide, 10.42 g (41.0 mmol) of iodine and 50 mL of water was heated at 50° C. for 4 h. The mixture was cooled and filtered. The white solid collected was dried in a vacuum oven to leave 12.60 g (75%) of 6-ethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone. 1 H-NMR (d6-DMSO) δ 1.25(3H,t), 2.85(2H,q), 7.50(3H,m), 8.15(2H,m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:1][O:2][C:3](=[O:8])[CH:4]([NH:5][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH2:6][OH:7]
Reactant: COC(=O)[C@@H](N)CO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
To a mixture of 5.0 g (32.14 mmol) of D, L-serine methyl ester and 15.7 mL (0.012 mol) of triethylamine in 100 mL of dichloromethane, cooled to 0° C., was added 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for two days. The mixture was diluted with 100 mL of dichloromethane and then washed with 60 mL each of water, 2N citric acid and brine and than dried over Na2SO4. The solvent was removed under vacuum to give a solid which was recrystallized from ethyl acetate to give 5.0 g (54%) of the product as white crystals, m.p. 92-94° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](N)C(=O)OCC(=O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
2-Oxo-2-phenyl-ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate (275 mg) was dissolved in methylene chloride (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was reacted with stirring for 30 minutes. After completing the reaction, the solvent was distilled off under reduced pressure. An appropriate amount (ca. 5 mL) of toluene was added and the mixture was concentrated in vacuo three times (azeotropic distillation) to obtain 290 mg of the target compound (LCMS m/z 352 (M+1) Rt 1.38 min.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41]O)=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1>C1(C)C=CC=CC=1.O>[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1
Reactant: OCc1cc2cc(Cl)cc(Br)c2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(Br)c2o1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of triphenylphoshine (1.44 g, 5.48 mmol) in toluene (50 mL) cooled to 0° C. was added the diisopropylazadicarboxylate (1.11 g, 5.48 mmol) followed by the phthalimide (0.81 g, 5.48 mmol) and the reaction mixture allowed to stir for 10 min. The (7-bromo-5-chloro-1-benzofuran-2-yl)methanol (1.37 g, 5.22 mmol) was then added and the reaction was allowed to stir at 0° C. an additional 1 h. The reaction mixture was then quenched with water (1 mL) and the solvent was removed in vacuo to provide a crude solid. The solid was suspended in water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL), the combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:5) provided 1.73 g (85%) of 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white solid. mp 194-198° C.; HRMS-ESI (m/z). [M+H]+ calcd for C17H9BrClNO3, 388.94545; found, 389.9553.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Yield: 51.4 %

Procedure:
To a 100 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (2.02 g, 7.5 mmol) followed by a addition of anhydrous THF (60 mL) under an atmosphere of nitrogen. Benzhydrazide (1.02 g, 7.5 mmol) was subsequently added and the mixture was cooled to −15° C. To this mixture was added HOBt (1.02 g, 7.5 mmol) followed by addition of EDC (2.88 g, 15.0 mmol) and lastly, TEA (3.2 mL, 23 mmol) was slowly added. The temperature of this reaction was maintained between −25° C. and −15° C. for a period of 1 h then allowed to warm to room temperature overnight. The solids were filtered off and washed with additional THF (20 mL) and EtOAc (20 mL). The mother liquor was then diluted with EtOAc (200 mL) and washed with 5% citric acid/water (2×50 mL), saturated sodium bicarbonate (1×25 mL), and brine (1×50 mL) then dried over sodium sulfate. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a white solid. This was purified via silica gel chromatography eluted with 85% EtOAc/hexane to provide title compound as a white solid (1.49 g, 51%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.64 (br s, 2H), 7.94 (m, 2H), 7.60 (m, 1H), 7.51 (m, 3H), 6.73 (d, J=8.7 Hz, 1H), 5.59 (d, J=7.2 Hz, 1H), 4.71 (br s, 1H), 4.24 (m, 1H), 4.12 (dd, J=5.1, 7.3 Hz, 1H), 2.35 (s, 3H), 1.39 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1.O>CN(C)C=O>[N:41]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:33][CH3:34])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCCl)c(OC)cc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCn3ccnc3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Propyl 3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (317 mg) and imidazole (78 mg) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (97 mg, yield 82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:26])[C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid XXI (1 g, 3 mmol) in dry THF (10 mL) was added sodium hydride (60% suspension in mineral oil) (0.72 g, 18 mmol; 6 eq. of pure NaH) in portions. Methyl iodide (1.12 mL, 18 mmol) was then added and the mixture was stirring at r.t. for 3 days. The mixture was then treated with water before removing the THF under reduced pressure. The aqueous phase was acidified and extracted 2× EtOAc. The combined EtOAc was washed with sodium thiosulfate, dried and evaporated under reduced pressure. The residue was crystallized to produce (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[4-(trifluoromethyl)phenyl]-propanoic acid XXII (0.73 g, 2 mmol, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH3:18][O-:19].[Na+]>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:19][CH3:18]
Reactant: C[O-]
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a stirred solution of 7-Chloro-6-fluoro-5-nitroquinoxaline-2(1H),3(4H)dione (0.100 g, 0.385 mmol, as prepared above) in DMSO (1.0 mL) at room temperature, sodium methoxide (0.125 g, 2.31 mmol, Mallinckrodt) was added in one port. The resulting dark red solution was stirred overnight at room temperate. It was then diluted with water (5.0 mL) and acidified with concentrated HCl (6 drops) to pH ˜2. The precipitated solid was filtered, washed with water (5.0 mL), and dried under vacuum to obtain 0.116 g (110%) of pure (1H NMR) title compound as a yellow powder; m. p. darkens at 316° C.; 1H NMR (DMSO-d6): δ 3.821 (s, 3H), 7.275 (s, 1H), 12.079 (s, 1H) 12.121 (s, 1H). The NMR also indicates the presence of DMSO (reaction solvent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](B(O)O)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cc2c(cc1-c1ccc(F)cc1)OCO2
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-c2cc3c(cc2-c2ccc(F)cc2)OCO3)cc1
Yield: 75.8 %

Procedure:
Under nitrogen, 500 mg of Pd(PPh3)4 was added to a stirred solution of 1.55 g (6.0 mmol) of [6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]boronic acid (Step 2) and 1.09 g (4.62 mmol) of 4-bromobenzenesulfonamide (Lancaster) in 30 mL of toluene, 20 mL of ethanol, and 15 mL of 2M Na2CO3. After vigorous stirring at reflux for 6 hours, the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The resulting solution was washed with water and dried over Na2SO4. Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 1.3 g (76%) of 4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide as a colorless solid: mp 191.0-192.5° C.; NMR (CDCl3) δ 4.80 (s, 2H), 6.06 (s, 2H), 6.83-6.92 (m, 4H), 6.97-7.06 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H). MS (FAB): m/e 372 (M+H). Anal. Calc'd for C19H14FNO4S: C, 61.45; H, 3.80; N, 3.77. Found: C, 61.48; H, 3.92; N, 3.68.