Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]1[CH2:29][CH2:28][CH2:27][C@H:22]1[C:23]([O:25]C)=[O:24].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:21]1[CH2:29][CH2:28][CH2:27][C@H:22]1[C:23]([OH:25])=[O:24])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 1.0 g (3.8 mmol) N-(tert-butoxycarbonyl)-3-pyridin-2-yl-L-alanine in 7 ml DMF was added 0.62 g (3.8 mmol) methyl L-prolinate hydrochloride, 0.52 mL (3.8 mmol) triethylamine, 0.51 g (0.38 mmol) HOAt, and 1.1 g (5.7 mmol) EDC. After 3 h at room temperature, the reaction mixture was diluted with 300 ml EtOAc, washed with 200 ml each of saturated NaHCO3 solution, water, and ml brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by automated flash chromatography (ISCO combiflash, 70 g silica gel, linear gradient 50–100% EtOAc:hexane 30 min then 2–10% MeOH/EtOAc at 60 mL/min) afforded 0.9 g N-(tert-butoxycarbonyl)-3-pyridin-2-yl-L-alanyl-L-proline of which 0.44 g (1.2 mmol) was dissolved in 7 mL MeOH. To this was added 1.2 mL (1.2 mmol, 1M aqueous solution) LiOH and the reaction mixture stirred 6 hours, then another 0.12 ml (0.12 mmol, 1M aqueous solution) portion of LiOH was added and the reaction mixture stirred an additional 16 hrs before addition of 0.12 mL conc. HCl (1.44 mmol, 12M aqueous solution) was added and the reaction concentrated to a foam. 1H NMR (CD3OD, 400 MHz) δ 8.47 (m, 1H); 7.78 (m, 1H); 7.34 (m, 2H,); 4.31 (dd, 1H, J=4.21, 8.8 Hz); 3.78 (br m, 1H); 3.54 (br m, 1H); 3.17 (dd, 1H, J=6.23 and 13.5 Hz); 3.02 (m, 2H); 2.3–1.8 (br m, 4H); 1.35 (s, 9H); electrospray mass spectrum 364.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][S:8][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:23][C:24]([F:33])([F:32])[C:25](C1NC=CN=1)=[O:26].Cl>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH:7]([C:25](=[O:26])[C:24]([F:33])([F:32])[F:23])[S:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CSCc2cc(Cl)ccc21
Reactant: O=C(c1ncc[nH]1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccc(Cl)cc2CSC1C(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
7-Chloroisothiochroman-4-one from Step 3 (0.3 g, 1.5 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to -78° C. A solution of sodium bistrimethylsilyl amide (1.5 mL of a 1.0M tetrahydrofuran solution) was added and the reaction stirred for 0.5 hours at -78° C. Trifluoroacetyl imidazole (0.21 mL, 1.8 mmol) was added and the reaction was warmed to room temperature and stirred under a nitrogen atmosphere for 16 hours. 1N Hydrochloric acid (100 mL) was added to the reaction followed by extraction with ether (150 mL). The organics were washed with brine (75 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:15][CH2:16][CH3:17])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][C:27]#[C:28][CH3:29]>CN(C=O)C>[CH2:16]([O:15][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=[C:9]2[N:12]([CH2:29][CH2:28][C:27]#[C:26][CH3:25])[N:13]=[CH:14][C:8]=12)[CH3:17]
Reactant: CC#CCCBr
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCCn1ncc2c(OCC)c(C(=O)OCC)cnc21
Reaction time: 4.5 h

Procedure:
A mixture of the ethyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate of Example 19c (8.13 g.), pulverized anhydrous potassium carbonate (14.3 g.) and 1-bromo-3-pentyne (10.7 g.) in dry DMF (58 ml.) was stirred at 55°-60° for 4.5 hours. Additional quantities of 1-bromo-3-pentyne (5.3 g.) and potassium carbonate (14.3 g.) were added after 1 hour. The mixture was cooled and filtered and the filtrate evaporated at 45°-50°. The residue was diluted with water and extracted with ether and EtOAc. The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel using EtOAc/hexane 1:1 v/v as eluant to give the title compound, m.p. 93°-95°, after recrystallization from toluene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([C:18]2[CH:17]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=2[F:12])=[CH:6][CH:7]=1
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Reactant: Nc1ccc(Br)nc1C(=O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(F)c(-c2ccc(N)c(C(=O)O)n2)c1
Yield: 75 %

Procedure:
Method 1 was followed using 3-amino-6-bromopicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 3-amino-6-(2-fluoro-5-propoxyphenyl)picolinic acid in 75% yield. LC/MS=291.0 (M+H), Rt=0.81 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH3:25][CH:26]([O:28][C:29]([O:31][CH:32](Cl)[CH:33]([CH3:35])[CH3:34])=[O:30])[CH3:27]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][CH:32]([O:31][C:29]([O:28][CH:26]([CH3:27])[CH3:25])=[O:30])[CH:33]([CH3:35])[CH3:34])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CC(C)OC(=O)OC(Cl)C(C)C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)OC(OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl)C(C)C
Yield: 66.6 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (0.4 g, 0.99 mmol) dissolved in 5 mL of anhydrous toluene was reacted with 0.57 g (3.0 mmol) of 1-chloro-(2-methylpropyl) (methylethoxy)formate in the presence of 0.33 g (1.1 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.37 g of a mixture of the title compound (47a) and (3R)-4,4-dimethyl-3-(1,1,2,2-tetramethyl-1-silapropoxy)-3,4,5-trihydrofuran-2-one (4a). MS (ESI) m/z 583.12 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(Br)cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromopyridin-2(1H)-one (4.4 g, 15.71 mmol) in DMF (50 mL) was added Cs2CO3 (6.65 g, 20.42 mmol) then iodomethane (1.2 mL, 19.19 mmol) at RT. After stirring overnight the mixture was concentrated. The residue was taken up in H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-100 g, 50% EtOAc/hexanes) gave the title compound (3.61 g, 78%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43-7.30 (m, 5 H); 7.05 (d, J=2.4 Hz, 1 H); 6.69 (d, J=2.4 Hz, 1 H); 5.24 (s, 0 H); 5.10 (s, 2 H); 3.55 (s, 3 H). LC/MS (M+H)+ 294/296.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16]CC)=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([OH:16])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of Example A7 (0.750 g, 2.87 mmol) in 3M NaOH (7.5 mL, 22.50 mmol) was heated at 100° C. for 1.5 h. The mixture was cooled to RT, acidified to pH 2 with 3M HCl and the resulting solid was collected via filtration and dried to afford 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (669 mg, 100%) as a white solid. MS (ESI) m/z: 234.1 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:28]([OH:29])=[CH:27][C:20]4[N:21]([CH3:26])[C:22](=[O:25])C[O:24][C:19]=4[CH:18]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCI>O1CCCC1>[C:1]1([CH:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:28]([OH:29])=[CH:27][C:20]4[N:21]([CH3:26])[C:22](=[O:25])[O:24][C:19]=4[CH:18]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C(=O)COc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Agent: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cn1c(=O)oc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 7-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one (3.4 g, 7.1 mmol) in anhydrous tetrahydrofuran (30 mL) was deoxygenated for 1 h with dry argon. Cesium carbonate (8.1 g, 25 mmol) and chloroiodomethane (1.5 mL, 21 mmol) were added and the heterogeneous reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (50 mL). The filtrate was concentrated in vacuo and the crude product was purified by column chromatography with ethyl acetate in hexanes (10% to 70% gradient) to afford 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one. To a solution containing 641-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one (1.0 g, 20 mmol), in trifluoroacetic acid (10 mL) was added triethylsilane (1.6 mL, 10 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography with ethyl acetate in hexanes (10% to 60% gradient) to afford 4-methyl-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione (0.52 g, 78%) as an off-white solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.63 (s, 1H), 7.28-7.23 (m, 1H), 7.10 (d, J=7.1 Hz, 1H), 6.99-6.90 (m, 2H), 6.87 (s, 1H), 6.36 (s, 1H), 4.81 (d, J=9.3 Hz, 1H), 4.70 (d, J=9.3 Hz, 1H), 4.51 (s, 2H), 3.26 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ178.0, 164.4, 156.0, 141.7, 139.2, 132.2, 130.7, 128.8, 123.7, 123.0, 122.2, 110.8, 109.8, 97.8, 79.7, 67.0, 57.6, 28.1; MS (ES−) m/z 321.2 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16][NH2:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:28]=O)[C:22]=2[CH:21]=[CH:20][N:19]=1.CC(O)=O>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16]/[N:17]=[CH:28]/[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][N:19]=[CH:18]3)=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Reactant: O=Cc1cccc2cnccc12
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C2CC2C(=O)N/N=C/c2cccc3cnccc23)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a room temperature solution of 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (200 mg, 0.86 mmol) in ethanol (10 mL) were added isoquinoline-5-carbaldehyde (162 mg, 1.0 mmol) and a catalytic amount of glacial AcOH (0.4 mL) under an inert atmosphere. The reaction mixture was then stirred at 90° C. for 4 h, concentrated in vacuo, and the residue was then dissolved in DCM (50 mL). The organic layer was washed with saturated NaHCO3 solution (15 mL) and brine (15 mL). The organic layer was then separated, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 1% MeOH in dichloromethane to afford (E)-2-(4-tert-butylphenyl)-N′-(isoquinolin-5-ylmethylene) cyclopropanecarbohydrazide (160 mg, 50%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 11.60 (s, 1H), 9.38 (s, 1H), 8.71-8.56 (m, 2H), 8.25-8.12 (m, 2H), 8.11-7.99 (m, 2H), 7.39-7.29 (m, 2H), 7.19-7.06 (m, 2H), 2.41-2.33 (m, 1H), 1.95-1.90 (m, 1H), 1.42-1.34 (m, 2H), 1.25 (s, 9H). MS: M m/z=372.2 HPLC: 96%, (Condition-A).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N:10]1[C:14]([C:15](Cl)=[O:16])=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:12]([CH3:28])=[N:11]1>O1CCOCC1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:15]([C:14]1[N:10]([CH3:9])[N:11]=[C:12]([CH3:28])[C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])=[O:16]
Reactant: CNc1ccccc1
Reactant: Cc1nn(C)c(C(=O)Cl)c1Nc1ccccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: Cc1nn(C)c(C(=O)N(C)c2ccccc2)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 84.8 %

Procedure:
2.7 g of N-methylaniline are added dropwise to a solution of 2.95 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxylic acid chloride in 10 ml of dioxane, and the resulting mixture is warmed at 90° C. for 1 hour. The solution is concentrated in vacuo, and water and a little dilute hydrochloric acid are added to yield 3.1 g of N,1,3-trimethyl-4-[(2-nitrophenyl)amino]-N-phenylpyrazole-5-carboxamide.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:34]=[C:35]([CH2:41][CH2:42][C:43](O)=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[N:53](C=O)C.[OH-].[NH4+]>C(Cl)Cl>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([C:28]([F:30])([F:31])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([NH2:53])=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CCC(=O)O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CCC(N)=O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.33 h

Procedure:
To a solution of 3-{3-[6-Azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}propanoic acid (EXAMPLE 60) (66 mg, 0.104 mmol) in DCM (4 ml) was added oxalyl chloride (2M in DCM) (0.259 ml, 0.518 mmol) and a drop of DMF. The solution was stirred for 20 minutes, concentrated, dissolved in THF (3 ml), added ammonium hydroxide (0.144 ml, 1.035 mmol) and stirred overnight. The crude was concentrated, dissolved in MeOH, filtered and purified by RP HPLC to afford 38 mg (0.060 mmol) of 3-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}propanamide. This was combined with N,N-dimethylformamide dimethyl acetal (1 ml, 7.50 mmol) and heated at 120° C. for 40 minutes. The reaction mixture was concentrated, added AcOH (1 ml), hydrazine hydrate (7.26 μl, 0.119 mmol) and heated at 90° C. for 1.5 hours. Added saturated aqueous sodium hydrogen carbonate to the reaction mixture and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by TLC and RP HPLC and lyophilized from MeCN/water to afford the title compound. Mass spectrum (ESI) 661.3 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.07 (br s, 1H); 7.97 (s, 1H); 7.89 (s, 2H); 7.25 (d, J=8.3 Hz, 1H); 7.14 (d, J=8.4 Hz, 1H); 6.94 (d, J=8.4 Hz, 1H); 6.89 (s, 1H); 6.34 (d, J=8.3 Hz, 1H); 5.76 (s, 1H); 4.57 (m, 1H); 4.24 (m, 1H); 4.05 (t, J=7.4 Hz, 4H); 3.92 (m, 1H); 3.73 (s, 3H); 3.03 (d, J=14.7 Hz, 4H); 2.45-2.37 (m, 2H); 0.60 (s, 3H).
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:66]([NH:68][CH3:69])=[O:67])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.Cl[C:115]1[C:120]([C:121]([F:124])([F:123])[F:122])=[CH:119][N:118]=[C:117]([NH:125][C:126]2[CH:140]=[CH:139][C:129]([CH2:130][P:131](=[O:138])([O:135][CH2:136][CH3:137])[O:132][CH2:133][CH3:134])=[CH:128][C:127]=2[F:141])[N:116]=1>>[F:141][C:127]1[CH:128]=[C:129]([CH:139]=[CH:140][C:126]=1[NH:125][C:117]1[N:116]=[C:115]([NH:50][C:51]2[C:52]([C:66](=[O:67])[NH:68][CH3:69])=[N:53][C:54]([C:57]3[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=3)=[CH:55][CH:56]=2)[C:120]([C:121]([F:124])([F:122])[F:123])=[CH:119][N:118]=1)[CH2:130][P:131](=[O:138])([O:135][CH2:136][CH3:137])[O:132][CH2:133][CH3:134]
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(F)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(F)c1)OCC
Yield: 22.8 %

Procedure:
Prepared analogously to Compound 1B replacing compound 1C with Compound 6C (278 mg, 1.01 mmol) and Compound 1 E with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-fluorobenzyl)phosphonate (Compound 22C, 446 mg, 1.01 mmol) to afford 157 mg of the title compound (23%). 1H NMR (400 MHz, CD3OD) δ=8.61-8.86 (m, 1H), 8.56 (s, 1H), 8.43 (br. s., 1H), 8.35 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.37 (dd, J=2.2, 11.0 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 4.12 (quin, J=7.3 Hz, 4H), 3.57 (t, J=6.1 Hz, 2H), 3.42 (d, J=21.0 Hz, 2H), 3.00 (s, 3H), 2.11 (quin, J=6.5 Hz, 2H), 1.17-1.34 (m, 6H). MS (ESI): m/z=681.74 [M+H]+. UPLC: tR=1.20 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:21])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N+:8]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccc(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1cccc(C)[n+]1[O-]
Temperature: 50 °C
Reaction time: 6 h
Yield: 44.3 %

Procedure:
A mixture of methyl 6-methylpyridine-2-carboxylate hydrochloride (5.8 g) and m-chloroperbenzoic acid (15.24 g) in dichloromethane (200 ml) was stirred at room temperature for 20 hours and 50° C. for 6 hours. After adding a small amount of sodium sulfite at 0° C., an aqueous solution of potassium carbonate was added to make the solution basic. The mixture was extracted with dichloromethane, and the organic phase was dried and concentrated. The resultant residue was purified by a column chromatography on a silica gel (ethyl acetate:hexane=5:1 to ethyl acetate:methanol=20:1) to obtain the title compound (2.29 g) as a tan oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([O:22][C:23]3[C:32]([N+:33]([O-])=O)=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[C:18]([O:20]C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[O:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][C:32]=4[NH:33][C:18]3=[O:20])[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(CCCN1CCN(c2ccc(F)cc2)CC1)Oc1cc2c(cc1[N+](=O)[O-])CCCC2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2cc3c(cc2OC1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
In a mixture of acetic acid (15 ml) and water (2.5 ml) was dissolved methyl 5-[4-(4-fluorophenyl)-1-piperazinyl]-2-(5,6,7,8-tetrahydro-3-nitro-2-naphthyloxy)valerate (4.1 g). To the solution was added little by little iron powder (1.9 g) whil stirring. The reaction was allowed to proceed for 30 minutes, followed by stirring at 80° C. for further 15 minutes. The resultant precipitate was filtered off, and the filtrate was concentrated. To the concentrate was added water, which was neutralized with an aqueous solution of sodium carbonate, followed by extraction with chloroform (then precipitated inorganic substances were filtered off). The chloroform layer was washed with water and dried (MgSO4). The concentrate was recrystallized from chloroform--ethyl acetate to give 1.54 g (43.1%) of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one as crystals, m.p. 164°-165° C. This product was in good agreement with the authentic sample obtained by Method A.