Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:23]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[CH:26]=[CH:25][C:24]=1[CH3:32])[CH2:9][C:10]([N:12]([N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.Cl.NO.[OH-].[Na+].CO[CH:45](OC)[N:46](C)C>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([CH2:9][C:10]([N:12]([N:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22]1)[CH3:13])=[O:11])[C:23]1[CH:28]=[C:27]([C:29]2[O:30][N:46]=[CH:45][N:31]=2)[CH:26]=[CH:25][C:24]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C(N)=O)cc1N(CC(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(-c2ncno2)cc1N(CC(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
The compound (400 mg, 0.88 mmol) of Example 81, step B, was dissolved in N,N-dimethylformamide dimethylacetal (2.5 ml), and the mixture was stirred at 110° C. for 1 hr. The reaction mixture was concentrated and the obtained residue was dissolved in 1,4-dioxane (1.5 ml). Then, acetic acid (1.5 ml), hydroxylamine hydrochloride (95 mg, 1.33 mmol) and 2N aqueous sodium hydroxide solution (0.7 ml, 1.4 mmol) were added, and the mixture was stirred at 90° C. for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-dichloromethane) to give the title compound (219 mg, yield 52%) as a pale-yellow amorphous solid
Reaction SMILES: ClC1C=CC([O:6][CH2:7][C:8]([OH:10])=[O:9])=CC=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Clc1ccc(CBr)cc1
Product: O=C(O)COCc1ccc(Cl)cc1

Procedure:
(4-Chlorobenzyloxy)acetic acid was prepared in analogy to (4-chlorophenoxy)-acetic acid using 4-chlorobenzyl bromide as precursor. The product with the molecular weight of 200.62 (C9H9ClO3) was obtained in this way; MS (ESI): 222.95 (M+Na—H).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15]C(=O)OC(C)(C)C)[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:35]=[N:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[C:32]([CH3:40])[C:31]=1[CH3:41].C(N(CC)C(C)C)(C)C>C(#N)CCC>[NH2:15][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:29]=[C:30]4[C:31]([CH3:41])=[C:32]([CH3:40])[C:33]([C:36]([O:38][CH3:39])=[O:37])=[N:34][N:35]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COC(=O)c1nnc(N)c(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: COC(=O)c1nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(C)c1C
Temperature: 125 °C
Yield: 16 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (630 mg, ˜90% purity, 1.28 mmol, 1.0 eq), methyl 6-amino-4,5-dimethylpyridazine-3-carboxylate [that was prepared in a manner analgous to that described for Intermediate Example Int-34] (257 mg, 1.28 mmol, 1.0 eq), N,N-diisopropylethylamine (220 μL, 1.28 mmol, 1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125° C. On cooling the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via preparative reversed phase HPLC to give 89 mg (16% yield) of the title compound directly as the free amine.
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11][Br:3])[N:10]=1
Reactant: Cc1sc(Br)nc1CO
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1sc(Br)nc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a stirred solution thionyl bromide (2.27 g, 10.94 mmol, 1.1 eq.) in 25 ml dry DCM, cooled to 5° C., was added dropwise a solution of (2-bromo-5-methyl-1,3-thiazol-4-yl)methanol (2.07 g, 9.94 mmol, 1 eq.) and pyridine (0.865 g, 10.94 mmol, 1.1 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 100 ml of water and 100 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give 2-bromo-4-(bromomethyl)-5-methyl-1,3-thiazole (1.94 g, 72% yield) as a white solid.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:5]=1[CH2:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:5]=1[CH2:6][C:7]1[N:12]([CH3:32])[C:11](=[O:13])[C:10]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:9]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:8]=1
Reactant: O=c1[nH]c(Cc2c(Cl)cccc2Cl)nc(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(Cc2c(Cl)cccc2Cl)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 2 h

Procedure:
Methyl iodide (41 ml, 0.65 mmol) was added to a stirring mixture of 2-(2,6-dichlorobenzyl)-5-(4-fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone (280 mg, 0.61 mmol) and potassium carbonate (181 mg, 1.30 mmol) in N,N-dimethylformamide (2 ml). Stirring was continued for 2 h, followed by evaporation and flash chromatography of the resulting product on a column of silica gel (hexane-acetone=3:1) to yield the title compound as a white solid. MS (m/z): 440.2 (M+H)+; C23H16Cl2FN3O requir. 440.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18]([CH2:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.[C:28](OCC)(OCC)(OCC)[CH3:29]>>[CH3:28][C:29]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH2:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:26][CH:27]=2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COCC(Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1)C(=O)OC
Product: COCC(Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1)C(=O)OC

Procedure:
A solution of 7 g of 10C in 25 ml of triethyl orthoacetate was refluxed for 4 hours. The resulting mixture was concentrated in a rotary evaporator and chromatographed over silica gel to give 10, as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][CH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(-c3ccccc3)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2sc(-c3ccccc3)nc12
Reaction time: 8 h

Procedure:
42.8 g (190 mmol) of 4-methyl-2-phenyl-benzothiazole [compare Perregaard, Lawesson, Acta Chem. Scand. Ser. B, 31, 203 (1977)] were dissolved in 1 l of carbon tetrachloride, and catalytic amounts of 2,2'-azoisobutyronitrile were added. 40.6 g (0.228 mol) of N-bromosuccinimide (NBS) were were added under reflux in portions and the mixture was boiled overnight. A further 40.6 g of NBS were added and the mixture was boiled for 2 h. After cooling, the mixture was diluted with methylene chloride, washed with water, dried and concentrated, and the residue was crystallized using petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH:25]1[CH2:27][O:26]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35])[CH3:30]>C(O)(C)C>[CH2:18]([O:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([F:16])[CH:13]=1)[CH2:9][C@H:8]([NH:7][C:6](=[O:28])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C@H:25]([OH:26])[CH2:27][NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[C:31]([CH2:29][CH3:30])[CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)NC(Cc1cc(F)cc(OCc2ccccc2)c1)C1CO1
Solvent: CC(C)O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(OCc3ccccc3)c2)NC(=O)OC(C)(C)C)c1
Yield: 96 %

Procedure:
[2-(3-Benzyloxy-5-fluoro-phenyl)-1-oxiranyl-ethyl]-carbamic acid tert-butyl ester (3.33 g, 8.59 mmol) and m-ethyl benzylamine (2.32 g, 17.19 mmol) were dissolved in isopropyl alcohol (80 ml) and brought to reflux for 2 h. Reaction mixture was then concentrated in vacuo to remove isopropyl alcohol. Dissolved yellow liquid in ethyl acetate (30 ml), then washed with 1N HCl (3×100 ml). Aqueous layers were combined then extracted with ethyl acetate (2×100 ml). Organic layers were washed with 10% sodium bicarbonate (aq., 3×100 ml), followed by a brine wash. Organic layer was dried over sodium sulfate, filtered, then concentrated in vacuo, yielding the product (4.31 g). (ES+: 523.9)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:27](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:45][S:46]([C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1)(=[O:48])=[O:47].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:23]([O:22][C:20](=[O:21])[NH:19][C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:27]([C:52]3[CH:53]=[CH:54][C:49]([S:46]([CH3:45])(=[O:48])=[O:47])=[CH:50][CH:51]=3)=[CH:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[C:14]2=[N:15][CH:16]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(NC(=O)OC(C)(C)C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 67.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-tert-butoxycarbonylamino-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (0.5 g, 0.78 mmol), 4-methylsulfonyl phenylboronic acid (468 mg, 2.34 mmol), dichlorobis(triphenylphosphine)palladium (II) (55 mg, 0.08 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.17 mL, 2.34 mmol). The resulting mixture was subjected to microwave irradiation for 3 h at 100° C. The mixture was diluted with ethyl acetate (80 mL), washed with a saturated aqueous sodium bicarbonate solution (2×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 33% ethyl acetate/hexanes) afforded {1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (326 mg, 67%) as a light yellow solid: LC/MS m/e calcd for C32H35N3O6S2 [M+H]+ 622.78, observed 622.1.
Reaction SMILES: COC(N[C@@H](C(C)C)C(O)=O)=O.[CH3:13][C@@H:14]1[CH2:19][CH:18]([C@H:20]([NH:24]C(OC)=O)[C:21]([OH:23])=[O:22])C[C@@H](C)O1>>[CH3:13][CH:14]1[NH:24][CH:20]([C:21]([OH:23])=[O:22])[CH2:18][CH2:19]1
Reactant: COC(=O)N[C@H](C(=O)O)C1C[C@@H](C)O[C@H](C)C1
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Product: CC1CCC(C(=O)O)N1

Procedure:
(2S,5S)-1-(S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)acetyl)-5-methylpyrrolidine-2-carboxylic acid was synthesized in a similar manner as Intermediate 4 substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid with (S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)acetic acid. 1H NMR (400 MHz, Chloroform-d) δ 5.33-5.16 (m, 1H), 4.70-4.59 (m, 1H), 4.54 (t, 1H), 4.34-4.19 (m, 2H), 4.12 (q, 1H), 3.78-3.70 (m, 1H), 3.67 (s, 3H), 2.37-2.17 (m, 3H), 2.15-2.07 (m, 1H), 2.04 (s, 1H), 1.84-1.73 (m, 1H), 1.82-1.43 (m, 3H), 1.32 (d, 3H), 1.26 (d, 4H), 1.11 (d, 3H), 0.96 (q, 1H). LCMS-ESI+ calc'd for C17H29N2O6: 357.19. Found: 357.08.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C@@H:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:20]([CH3:29])([CH3:28])[O:19][C:18]4=[O:30])=[CH:13][CH:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:37]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39][CH:38]=1>O1CCOCC1>[CH3:28][C:20]1([CH3:29])[O:19][C:18](=[O:30])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([C:41]5[CH:42]=[N:37][CH:38]=[N:39][CH:40]=5)=[CH:3][C:4]4=[N:10][N:9]=3)=[CH:12][CH:13]=2)[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(I)ccn34)cc2)[C@H]1c1ccccc1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(-c5cncnc5)ccn34)cc2)[C@H]1c1ccccc1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
(S)-3-(4-(7-Iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (70 mg, 0.137 mmol), sodium carbonate (2 M, 137 μL, 0.274 mmol), 5-pyrimidinylboronic acid (17.00 mg, 0.137 mmol) (commercially available from Sigma-Aldrich, Milwaukee, Wis.), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (11.20 mg, 0.014 mmol) (commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (457 μL) and stirred at 130° C. for 1 hour. LC-MS indicated that there was complete conversion to the desired product. The final reaction mixture was passed through a syringe filter, and the material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-5,5-dimethyl-4-phenyl-3-(4-(7-(pyrimidin-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)oxazolidin-2-one (15 mg, 0.032 mmol, 23.64% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 2H), 9.27 (s, 1H), 8.66-8.66 (m, 1H), 8.68 (dd, J=0.88, 6.36 Hz, 1H), 8.45 (dd, J=1.17, 1.86 Hz, 1H), 7.86-7.96 (m, 2H), 7.71-7.81 (m, 2H), 7.51 (dd, J=2.15, 7.43 Hz, 1H), 7.37-7.46 (m, 2H), 7.28-7.37 (m, 3H), 5.57 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 463.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19](OCC)=[O:20])[CH:15]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[OH:8].[NH3:24].CO>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]([NH2:24])=[O:20])[CH:15]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: N
Reactant: CCOC(=O)c1ccc2cncc(-c3ccc(O)c(F)c3)c2n1
Solvent: CO
Product: NC(=O)c1ccc2cncc(-c3ccc(O)c(F)c3)c2n1
Temperature: 80 °C
Yield: 56 %

Procedure:
Ethyl 8-(3-fluoro-4-hydroxyphenyl)-1,6-naphthyridine-2-carboxylate (100 mg, 0.32 mmol) synthesized in Example 1 (1a) was dissolved in a 7M ammonia-methanol solution (10 mL), followed by stirring while heating at 80° C. for three hours. After cooling the resulting reaction liquid to room temperature, a precipitated solid was collected by filtration to give the desired title compound (51 mg, yield 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:17](Cl)Cl.OS(O)(=O)=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1
Reactant: ClCCl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1CC(=O)N(c2ccc(F)cc2)C1

Procedure:
To 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid 51 was added 80 mL of CH2Cl2, 30 mL of MeOH, and 1.0 mL of concentrated H2SO4. After heating at reflux overnight, the mixture concentrated and triturated with water to give methyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate 52.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:14]#[N:15])[C:7]([CH3:9])([CH3:8])[CH:6]1[C:10]([O:12][CH3:13])=[O:11])=[O:4].[OH-].[K+]>CO.O>[CH3:8][C:7]1([CH3:9])[C:5]([C:14]#[N:15])([C:3]([OH:4])=[O:2])[CH:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1C(C)(C)C1(C#N)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1C(C)(C)C1(C#N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of 21.1 g (0.1 mol) of 3,3-dimethyl-1-cyano-cyclopropane-1,2-dicarboxylic acid dimethyl ester and 5.6 g of potassium hydroxide in a mixture of 50 ml of methanol and 25 ml of water was stirred at room temperature for 2 hours. The mixture was then filtered and the filtrate was acidified with dilute hydrochloric acid. An oil separated out and was taken up in methylene chloride. The methylene chloride phase was dried over sodium sulphate and then concentrated. 13 g (65% of theory) of 3,3-dimethyl-2-methoxycarbonyl-1-cyano-cyclopropane-1-carboxylic acid were obtained in the form of a partly crystalline mass, which could be further processed directly, without purification.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1O.C(Cl)Cl.[OH2:13]>FC(F)(F)C(O)=O>[OH:13][C@@H:7]1[C@@H:2]([OH:1])[CH2:3][C:4](=[O:8])[CH:5]=[CH:6]1
Reactant: O
Reactant: O=C1CCCC(O)=C1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=C[C@H](O)[C@@H](O)C1
Yield: 75 %

Procedure:
The α,β-unsaturated ketone 9 (FIG. 6) (0.344 g, 1.42 mmol) was stirred in a mixture of trifluroacetic acid (18 mL), CH2Cl2 (2 mL) and water (2 mL) for 30 minutes at 0° C. Solvents were removed in vacuo. The residue was azotroped with toluene (20 ml) and purified by flash chromatography to give compound 2 (FIG. 4) as a white solid (0.137 g, 75%). 1H NMR (D2O) δ 7.04 (dd, J=10.2, 2.4 Hz, 1H), 6.08 (dm, J=10.2 Hz, 1H), 4.45 (dm, J=8.4 Hz, 1H), 3.99-4.07 (m, 1H), 2.82 (ddd, J=16.4, 4.8, 1.2 Hz, 1H), 2.58 (dd, J=16.4, 11.9 Hz, 1H); 13C NMR (D2O) δ 204.8, 156.1, 131.4, 74.4, 74.3, 46.5.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]([CH3:7])[CH3:6].C([Li])CCC.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[C:2]#[C:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: CC(C)CC=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CCC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1,1-Dibromo-4-methyl-pent-1-ene 6 (40 g, 165.9 mmol) was dissolved in dry THF (120 mL) and cooled to −78° C. While stirring, n-butyllithium (1.6 M solution in hexane, 190.8 mL, 305 mmol) was added dropwise in a few minutes. After 1 hour, ethyl chloroformate (15 mL, 154.5 mmol) was added, and the reaction was stirred overnight during which it warmed to room temperature. It was poured onto water and extracted with ether (3×250 mL), dried on magnesium sulfate and evaporated. The light oil was flash chromatographed on a silica gel column, and the compound was eluted with 10% ether in pet ether to afford 5-methyl-hex-2-ynoic acid ethyl ester 7 (23.6 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:12]I>FC(F)(F)S([O-])(=O)=O.[Ag+].C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([I:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: II
Reactant: COc1ccc(C#N)c(Br)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)c(C#N)cc1I
Reaction time: 48 h
Yield: 57.1 %

Procedure:
A RBF was charged with 2-bromo-4-methoxybenzonitrile (891 mg, 4.20 mmol, Matrix Scientific) and DCM (1.68E+04 μl) to give a clear solution. silver trifluoromethanesulfonate (1188 mg, 4.62 mmol) and iodine (1173 mg, 4.62 mmol) were added in sequence. The resulting mixture was stirred for 2 d. Additional portions of silver trifluoromethanesulfonate (1188 mg, 4.62 mmol) and iodine (1173 mg, 4.62 mmol) were added, and the mixture was stirred for another 5 h. The reaction mixture was then filtered through celite with the aid of DCM. The filtrate was shaken with saturated aq. sodium thiosulfate until the color disappeared. The biphasic mixture was diluted with water then the layers were separated. The aq. layer was extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel column, 5-30% EtOAc/Heptane) give 2-bromo-5-iodo-4-methoxybenzonitrile (811 mg, 2.400 mmol, 57.1% yield) as an off-white solid. m/z (ESI) 337.8 (M+H)+.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OC(=O)C)(C)(C)C>C1COCC1.C(OCC)(=O)C.O>[C:12]([O:11][C:9](=[O:10])[CH2:8][O:6][CH2:1][CH2:2][C@H:3]([OH:5])[CH3:4])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@@H](O)CCO
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)CCOCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Put 1.0 g (11.1 mmol) (3R)-butane-1,3-diol in 20 ml THF at 0° C. Add dropwise 5.55 ml (11.1 mmol) of a 2 M solution of the phosphazene base P2-tert.-butyl in THF and stir for 30 min at 0° C. Then add 2.27 g (11.65 mmol) tert.-butyl bromoacetate. Stir for 30 min at 0° C., then leave to return to RT and stir for a further 1 h. Then dilute with ethyl acetate, add water and acidify with 10% citric acid solution. Extract once more with ethyl acetate, combine the organic phases, wash once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 8:2). 730 mg (32.2% of theor.) of the target compound is obtained, which according to 1H-NMR (doublet at 1.18 ppm) contains approx. 10% of the regioisomer [(1R)-3-hydroxy-1-methylpropyl]oxy}acetic acid tert.-butyl ester.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1)#[N:23]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C#N)cc3)nc2c1
Yield: 74.6 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, with methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.33 mmol, 1.00 equiv) and 4-cyanophenylboronic acid (74 mg, 0.50 mmol, 1.50 equiv) as reactants. Purification via silica gel column (ethyl acetate/petroleum ether (1:20 to 1:10)) afforded 90 mg (73%) of methyl 3-(4-cyanophenyl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.