Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:24])[C:5]([C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[N:17]=1)=[O:15])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1.CO>CCCCCC.C(OCC)(=O)C>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:5]2[C:4](=[O:24])[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:7][CH:6]=2)=[O:15])=[N:17][C:18]=1[CH3:23]
Reactant: CCOC(=O)C(=CNc1ccccc1)C(=O)c1ccc(C)c(C)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
Compound 3d was prepared following the procedure outlined in Step 2 of Example 1 using 575 mg (1.77 mmol) of 2-(5,6-dimethyl-pyridine-3-carbonyl)-3-phenylamino-acrylic acid ethyl ester 2e, 30 mL of diphenyl ether. The reaction time was 2 h. Flash chromatography using 50-100% ethyl acetate in hexane followed by 0-30% methanol in ethyl acetate yielded 100 mg of the product 3d as off-white solid: LC-MSD, m/z for C17H14N2O2 [M+H]+: 279.4, HPLC retention time: 0.4 min.
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[CH:8]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[Cl:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(PC2CCCCC2)CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClP(C1CCCCC1)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of 19 g (0.1 mol) dicyclohexylphosphine in 50 ml toluene was dropped into a suspension of 21 g (0.1 mol) PCl5 in 100 ml toluene. The reaction temperature was maintained at less than 30° C. After all had been dropped in, the whole was boiled for 1 hour under reflux. A slight precipitate was removed by means of a reverse frit and the reaction mixture was freed from all low boilers at 60° C. under 0.1 mbar. Yield: 23.3 g; 31P-NMR: δ P=126 ppm, (c-C6H11)2PCl, 96 mol %; δ P=54 ppm, (c-C6H11)2P(O)Cl, 3.7 mol %.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[Na+].OO>O1CCCC1>[C:19]([O:18][C:16]([NH:15][C@@H:10]1[CH2:11][CH2:12][CH:13]([OH:23])[CH2:14][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=CC[C@H]1NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC(O)CC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-N1,N2-Bis (tert-butoxycarbonyl)-4-cyclohexene-1,2-diamine (6.1 g) was dissolved in absolute tetrahydrofuran (40 ml), and borane-dimethyl sulfide complex (2.22 ml) was added by a syringe under ice cooling. The mixture was stirred for 16 hours while gradually heating the mixture to room temperature as it is. Ice was added to the reaction mixture, and a 1N aqueous solution of sodium hydroxide and 30% aqueous hydrogen peroxide (50 ml) were added to stir the mixture at room temperature for 2 hours as it is. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2→2:1) to obtain the title compound (6.1 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br>S1(CCCC1)(=O)=O>[O:31]1[CH:29]([CH3:27])[CH:30]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)[nH]c(=O)c2c1
Temperature: 25 °C

Procedure:
4.5 gm (16.7 mmols) of 2-(4-hydroxy-phenyl)-6-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 50 ml of sulfolane, and the solution was mixed, while stirring, with 2.55 gm (16.7 mmols+10%) of potassium carbonate. After a clear solution was formed, 4.5 ml of epibromohydrin were added, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was poured into ice water, and the resulting crystalline precipitate was suction-filtered off, washed well with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH2:28][OH:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:40]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH2:28][O:29][CH3:40])=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[CH:6][CH:7]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2CO)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of 7-(4-chlorophenyl)-2-((2-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (26 mg, 0.05 mmol) in anhydrous DMF (0.5 mL) cooled at 0° C. was added sodium hydride (60% in oil, 4.0 mg, 0.1 mmol). The resulting mixture was stirred at 0° C. for 30 min, then iodomethane (20 μL, 0.25 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min, then quenched by addition of water. The mixture was extracted with EtOAc (10 mL×2), and the combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluted with a gradient of ethyl acetate (50-100%) in hexanes to afford 12 mg of the title compound as a yellow foam. HPLC/MS: retention time=2.93 min, [M+H]+=526.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-benzyloxy-5-chlorobenzoic acid, as described above in Step B, (5.0 g, 19 mmol) in dry THF (150 mL) at 0° C., under argon, was added LiAlH4 (29 mL of a 1.0 M solution in THF, 29 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 hours, then EtOAc (1 mL) was added, followed by water (1 mL), then 15% aqueous NaOH (1 mL), then water (3 mL). The resulting mixture was filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica, eluting with hexane—20% EtOAc to yield the desired product as a colorless oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32](=[O:47])[CH2:33][CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36](O)=O)([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:36]([C@@H:35]([NH:39][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:34][CH2:33][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:47])[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CON=C1C[C@@H](c2noc([C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 75 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2S)-5-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid, the title compound was obtained in 75% yield (78.9% purity by HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Cl)c(F)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(Cl)c(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=399.4 (M+H+), was prepared in accordance with the general method of example 12b) from 6-chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C@H:8]([O:22][CH2:23][C:24](OCC)=[O:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1
Reactant: CCOC(=O)CO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)cc1[C@H](OCCO)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (8 g, 18.8 mmol) in MeOH (300 mL) was added NaBH4 (5.6 g, 0.15 mol) in portions while the temperature was lower than 40° C. After addition, the mixture was stirred overnight. The solvent was removed in vacuo to the residue, which was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give crude (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (7 g), which was used in the next step without purification.
Reaction SMILES: [C:1](Cl)(=O)C.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])=[O:12]>CO>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([O:13][CH3:1])=[O:12]
Reactant: O=C(O)c1cnccn1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cnccn1
Reaction time: 8 h

Procedure:
Acetyl chloride (50 ml) was added very slowly to methanol (500 ml), and the mixture was allowed to cool before pyrazine-2-carboxylic acid (15 g, 124 mmol) in methanol (15 ml) was added. The reaction mixture was left to stand at room temperature overnight. The methanol was removed in vacuo to give the required product (22 g). 1H NMR (250 MHz, DMSO) δ 3.95 (3H, s), 8.82 (1H, m), 8.90 (1H, d, J=2.5 Hz), 9.21 (1H, d, J=2.5 Hz); MS (ES+) m/e 153 [MH+].
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17]([SH:18])=[N:16][N:15]=[N:14]2)[CH2:6][CH2:5]1.CC(O[CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O.C(=O)(O)[O-].[Na+]>O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][S:18][C:17]3[N:13]([CH2:12][CH2:11][CH2:10][N:7]4[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]4)[N:14]=[N:15][N:16]=3)[CH2:33][S:32][C@H:27]12
Reactant: CN1CCN(CCCn2nnnc2S)CC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(CCCn2nnnc2SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)CC1
Temperature: 64 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of 1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazole-5-thiol.dihydrochloride (75.32 g) in water (6 l) was added 7-aminocephalosporanic acid (60.0 g) and the mixture was adjusted to pH 5.4 with a saturated aqueous solution of sodium bicarbonate and stirred for 2 hours at 64° C. The reaction mixture was cooled and adjusted to pH 6.84 with a saturated aqueous solution of sodium bicarbonate. The resulting mixture was subjected to column chromatography (CM-Cephadex, H-type: 3 l), eluting with water, 0.5% aqueous solution of sodium chloride and 2% aqueous solution of sodium chloride. The fiactions containing the object compound were collected. The resulting mixture (about 7 l) was adjusted to pH 4.5 with a saturated aqueous solution of sodium bicarbonate and then subjected to column chromatography (Non-ion adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries: 3 l) and eluting with water, 2% isopropyl alcohol and 15% isopropyl alcohol. The fractions containing the object compound were collected and then concentrated. The concentrate was lyophilized to give a powder of 7-amino-3-[1-[3-(4-methyl-1-piperazinyl) propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (34.6 g).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C:20]1[C:21]([OH:28])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[OH:28][C:21]1[C:20]([CH2:19][NH:18][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[CH:17][CH:16]=2)=[C:25]([CH3:26])[CH:24]=[C:23]([CH3:27])[N:22]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(S(=O)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.6 %

Procedure:
A mixture of 4-(phenylsulfinyl)benzoic acid (130 mg, 0.53 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.6 mmol), o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1.0 mmol) and triethylamine (0.1 mL) in dichloromethane (6 mL) was stirred at 25° C. for 12 hours. After the reaction, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(phenylsulfinyl)benzamide as a white solid (90 mg, 44%). LRMS (M+H+) m/z: calcd 380.12. found 380. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.47 (t, J=4.8 Hz, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.78-7.71 (m, 4H), 7.54-7.50 (m, 3H), 5.84 (s, 1H), 4.28 (d, J=4.8 Hz, 2H), 2.14 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:32]([F:35])([F:34])[F:33])=[CH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18]2([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[O:17][CH2:16]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N+:36]([CH3:39])([O-:38])=[O:37].C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:39][N+:36]([O-:38])=[O:37])([C:32]([F:33])([F:35])[F:34])[CH2:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18]2([CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]2)[O:17][CH2:16]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
To a stirred solution of tert-butyl 5′-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 10, 1 g, 1.89 mmol) in acetonitrile (10 mL) was added nitromethane (1.013 mL, 18.93 mmol) and DBU (0.275 mL, 1.84 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material; reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated under reduced pressure to get brown semi solid (1.41 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to get light yellow sticky liquid (1.02 g, 91.07%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.97 (d, J=18.64 Hz, 1H), 4.10-4.17 (m, 3H), 4.34 (d, J=9.8 Hz, 2H), 5.16 (s, 2H), 5.45 (d, J=12.32 Hz, 1H), 5.58 (d, J=12.36 Hz, 1H), 7.18 (s, 2H), 7.40-7.41 (m, 1H), 7.61 (d, J=7.92 Hz, 1H), 7.81 (s, 1H), 7.98-8.00 (m, 1H), LC-MS (m/z): 587.1 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].O>S(=O)(=O)(O)O>[F:1][C:2]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCN1C(=O)COc2cc(F)ccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 20.0 grams (0.096 mole) of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one in 100 ml of concentrated sulfuric acid was cooled to -10°C. A mixture of 10 ml of nitric acid (70% nitric acid by weight in water) and 10 ml of concentrated sulfuric acid was added dropwise during a 20 minute period. After complete addition the mixture was stirred at -5° C. for 10 minutes. The reaction mixture was poured into water which was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a tacky solid. This solid was triturated witha mixture of diethyl ether, petroleum ether, and ethyl acetate (1:1:1) to yield, after filtration, 7.2 grams of 7-fluoro-6-nitro-4-propyl-2H-1,4-benzoxazin-3(4H)-one.
Reaction SMILES: [F:1][C:2](=[CH2:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([N:15]([CH2:19][Si](C)(C)C)[CH2:16]OC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]([N:15]1[CH2:16][CH2:7][C:2]([F:1])([C:3]([O:5][CH3:6])=[O:4])[CH2:19]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(F)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(F)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
A 0.3 M solution of methyl 2-fluoroacrylate (4.37 g, 41.99 mmol) and DCM (140 mL) was stirred under nitrogen and cooled to 0° C. The reaction mixture was then treated with N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (10.47 g, 44.09 mmol) followed by TFA (1.56 mL, 20.99 mmol). The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was then concentrated in vacuo. The crude product was purified by SiO2 Biotage chromatography (hexanes/acetone) to afford 4.24 g (42.6%) of methyl 1-benzyl-3-fluoropyrrolidine-3-carboxylate (72a): 1H NMR (400 MHz, DMSO-d6) δ=7.35-7.23 (m, 5H), 3.72 (s, 3H), 3.63 (s, 2H), 2.97-2.80 (m, 3H), 2.54-2.48 (m, 1H), 2.43-2.30 (m, 1H), 2.18-2.04 (m, 1H).
Reaction SMILES: [C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([N:13]=[N+]=[N-])[C@@H:9]([OH:16])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2]>CCOC(C)=O.[Pd]>[C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([NH2:13])[C@@H:9]([OH:16])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2]
Reactant: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](N=[N+]=[N-])C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](N)C1=O
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A suspension of 5% Pd—C (0.175 g) in EtOAc (10 mL) was stirred for 1.5 hours under H2 atmosphere and a solution of the azido alcohol 12 (0.373 g, 1.621 mmol) in EtOAc (15 ml) was added portionwise. The reaction mixture was stirred for 17 hours under H2 and was evaporated to dryness. The residue was washed with dry ether (3×15 mL) and the product was extracted from the dried residue with hot (ca. 70° C.) water (30 mL). The aqueous solution was filtered through a paper filter and the black solid was washed with hot water (3×10 mL). Evaporation of the filtrate in vacuo provided 0.296 g (90%) of the product 13 as a white solid with mp 200-202° C. (decomp.). 1H NMR (400 MHz) in CD3OD+1 drop of CF3CO2H (J, Hz): δ 1.52 (3H, d, 3J=7.4, α-MeCH), 4.08 (1H, dd, 2J=−11.7, 3J=2.5, 6-HA), 4.18-4.16 (2H, m, 4-H, 5-H), 4.46-4.41 (1H, dd, 2J=−11.7, 3J=6.4, 6-HB), 4.98 (1H, q, 3J=7.4, α-CH). 13C (100 MHz) in D2O: δ 17.62, 59.62, 61.42, 73.69, 82.48, 169.06, 180.86. IR (KBr), cm−1: 3158, 1684, 1599, 1568, 1400. MS (CI, isobutane), m/Z: 205 (M++1). Anal. Calcd for C7H12N2O5+0.5 H2O: C, 39.4; H, 6.1; N, 13.1. Found: C, 39.3; H, 6.2; N, 13.2%.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23](CC5C=CC(OC)=CC=5)[N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][NH:23][N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: COc1ccc(Cn2cc3nccc(Nc4ccnc(-c5nc(C)ccc5F)c4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4c[nH]nc34)ccn2)n1
Temperature: 70 °C

Procedure:
N-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine (120 mg, 0.272 mmol) was dissolved in TFA (5 mL) and heated at 70° C. for 3 hours. The reaction mixture was then cooled and evaporated under vacuum to give a residue which was triturated with ether to give the title compound as a TFA salt (80 mg, 92% yield). MS [M+H] found 321.3.