Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:26][O:27][CH3:28])=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][CH:11]=[C:10]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[N:9]=2)=[O:4].O=P(Cl)(Cl)[Cl:31]>N1C(C)=CC=CC=1C.C(Cl)(Cl)Cl>[Cl:31][C:14]1[C:13]2[C:8](=[N:9][C:10]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:12]=2)[N:7]=[C:6]([CH2:26][O:27][CH3:28])[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(O)c1C(=O)OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Cl)c1C(=O)OC

Procedure:
Dissolve 4-hydroxy-2-methoxymethyl-7-(3-trifluoromethylpyridin-2-yl)-[1,8]naphthyridine-3-carboxylic acid methyl ester (500 mg, 1.27 mmol) in a solution of POCl3 (0.4 mL), 2,6-lutidine (0.43 mL) and CHCl3 (25 mL). Heat the mixture at reflux overnight. Remove the solvent under reduced pressure. Partition the residue between CH2Cl2 and saturated NaHCO3 (aq). Extract the aqueous layer twice with CH2Cl2 (2×100 mL). Dry the combined organic extracts over Na2SO4. Remove the solvent under reduced pressure. Purify the crude product by preparatory TLC eluting with EtOAc\Hexanes (1:1) to yield the title compound.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][CH:28]=[N:27][CH:26]=1)[CH:20]([NH:30]C(OC(C)(C)C)=O)[C:19]2=[O:38])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:30][CH:20]1[C:19](=[O:38])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([C:25]1[S:29][CH:28]=[N:27][CH:26]=1)=[C:17]2[C:15]([OH:16])=[O:14]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cncs3)CSC12
Solvent: O=C(O)C(F)(F)F
Product: NC1C(=O)N2C(C(=O)O)=C(c3cncs3)CSC12

Procedure:
Following the working method described in Example 6, 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.2 g) is treated with trifluoroacetic acid (80 cc). 7-Amino-2-carboxy-8-oxo-3-(thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]-oct-2-ene trifluoroacetate (4 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:8]([C:9](OCC)=[O:10])[C@H:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@@H:6]([O:21][C@@H:22]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH3:23])[CH2:5][CH2:4]1.[C:38]1(=O)[CH2:42][CH2:41][C:40](=[O:43])[CH2:39]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[C:28]1[CH:29]=[C:24]([C@H:22]([O:21][C@H:6]2[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:38]3[CH2:42][CH2:41][C:40](=[O:43])[CH:39]=3)[C@@H:8]([CH2:9][OH:10])[C@@H:7]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:23])[CH:25]=[C:26]([C:34]([F:36])([F:37])[F:35])[CH:27]=1
Reactant: O=C1CCC(=O)C1
Reactant: CCOC(=O)[C@@H]1[C@@H](CN)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H](CNC2=CC(=O)CC2)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 16 h
Yield: 10.7 %

Procedure:
To a solution of ethyl (1R,2R,3S,6S)-6-(aminomethyl)-3-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(4-fluorophenyl)cyclohexanecarboxylate (0.07 g, 0.13 mmol, intermediate from Step E) in 30 mL dry toluene was added cyclopentane-1,3-dione (0.064 g, 0.65 mmol) and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 1 hr. The solvent was removed under vacuum. The residue was dissolved in 10 mL toluene and was cooled to −78° C. under nitrogen. Dibal-H (2 mL, 1.0 M) was added. The reaction mixture was stirred for 16 hr at −78° C., quenched with water and diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (10 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was purified by preparative TLC (silica gel eluting with 9:1 ethyl acetate: methanol) to give 8 mg of the title compound. MS: (MH)+ 574.2. The rest of the material was still unreacted ester.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Br:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[Br:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(Br)c1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(Br)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 35 %

Procedure:
3-[(3-Bromo-4-fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 57-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (35% yield); mp 154–157° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.81 (2H, s, NCH2), 7.1 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.54 (1H, m, aromatic). Anal. calcd for C14H14BrFN2O4: C, 45.06; H, 3.78; N, 7.50. Found: C, 44.80; H, 3.81; N, 7.33.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(C3CCN(CCc4ccccc4)CC3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.3 %

Procedure:
A mixture of 5.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 4.6 g of (2-bromoethyl)benzene, 4.2 g of sodium bicarbonate and 50 ml of dimethylformamide was stirred at 60° for 3 hr and at ambient temperature for 14 hr. The reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized twice from 2-propanol (one charcoal treatment) to yield 2.6 g (35%) of product, mp 163°-165° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:37]([CH3:40])([CH3:39])[CH3:38])[O:3][C@@H:4]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:6]([C@@H:7]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][C@@H:9]3[C@@H:23]2[CH2:22]C[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)C=CC=O)[CH2:5]1.O1[CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH3:36][Si:30]([CH3:35])([C:31]([CH3:33])([CH3:34])[CH3:32])[O:29][C@@H:7]1[CH2:8][CH2:9][C@@:23]2([CH3:22])[C@H:5]([C@@H:4]([O:3][Si:2]([CH3:41])([CH3:1])[C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:26][C@@H:25]3[C@@H:24]2[CH2:27][CH2:25][C@@:26]2([CH3:4])[C@H:43]3[CH2:44][CH2:45][C@@H:46]2[C@H:23]([CH3:22])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:24])[CH3:5])[CH2:6]1
Reactant: C[C@H](C=CC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CCOC1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1.4 g of 3α,6α-bis(dimethyl-t-butylsilyloxy)-5β-cholen-24-al (prepared as described in my U.S. patent application Ser. No. 236,160) was dissolved in 5 ml of tetrahydrofuran and added dropwise to the ylid solution (as described in Example I). The reaction mixture was stirred, refluxed and processed in the manner of Example I. The product remaining after the evaporation of the petroleum ether extract was identified by IR and NMR data as the 3α,6α-bis (dimethyl-t-butylsilyloxy)-5β-cholest-24-ene.
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][N:9]1[C:14](=[O:15])[C:13]2[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][C:12]=2[N:11]=[C:10]1[CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>>[NH2:8][N:9]1[C:14](=[O:15])[C:13]2[CH2:16][NH:17][CH2:18][CH2:19][C:12]=2[N:11]=[C:10]1[CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(CCCCN3CCN(c4ccc5ccccc5n4)CC3)n(N)c(=O)c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To 10 ml of 4N-hydrochloric acid-dioxane solution, 53 mg of 3-amino-6-tert-butoxycarbonyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one as synthesized in above Step 4-44-A was added and stirred for 18 hours at room temperature. The solution was neutralized with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=9:1) to provide 39 mg (90%) of 3-amino-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:28])([F:27])[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[F:28][C:13]([F:27])([F:12])[S:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:9]
Reactant: FC(F)(F)Sc1ccccc1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccccc1-c1ccccc1)C(F)(F)F
Yield: 97.8 %

Procedure:
Under ice cooling, 7.77g (31.5 mmol) of m-chloroperbenzoic acid was added little by little to a solution of 7.63 g (30 mmol) of 2-(trifluoromethylthio)biphenyl in 20 ml of methylene chloride with stirring. The mixture was stirred overnight at room temperature. The precipitate in the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to give 7.93 g (97.8%) of 2-(trifluoromethylsulfinyl)biphenyl. The properties of the product were as shown below.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3](O)=[O:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[C:25]1([C@H:31]2[C@@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33](=[O:42])[NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([N:32]1[C@@H:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:34][C:33]1=[O:42])=[O:4]
Reactant: CC/C=C(\C)C(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC/C=C(\C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of (E)-2-methyl-2-pentenoic acid (5.3 g, 47 mmol) in 250 mL of THF at 0° C. was added 16.3 mL (117 mmol) of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride resulting in a thick suspension. The mixture was stirred for 1 hour at 0° C. at which time 2.0 g (47 mmol) of lithium chloride was added in one portion, followed by 10 g (42 mmol) of (4S,5R)-4,5-diphenyl-2-oxazolidinone in four batches. Stirring was maintained throughout the solid additions. The reaction mixture was stirred for 1 hour at 0° C., and for 1 hour at ambient temperature, and was vacuum filtered through a coarse frit and concentrated. The residue was partitioned between EtOAc/water, and the organics were dried over MgSO4 and concentrated. To the residue was added 200 mL of MTBE and the mixture was warmed cautiously with swirling. The warm slurry was filtered to provide 13.0 g (83% yield) of the titled compound as a colorless solid: 1H NMR (CDCl3) δ 7.12 (m, 3H), 7.08 (m, 3H), 6.93 (m, 2H), 6.86 (m, 2H), 6.14 (m, 1H), 5.90 (d, J=7.8 Hz, 1H), 5.69 (d, J=7.8 Hz, 1H), 2.23 (pent, J=7.6 Hz, 2H), 1.92 (s, 3H), 1.07 (t, J=7.6 Hz, 3H). The titled acylated oxazolidinone may be used in the next step instead of (S)-3-((E)-2-Methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+].Cl>[Cl-].[Zn+2].[Cl-].CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[NH:13][N:12]=[N:11][N:6]=1
Reactant: COc1ccccc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nnn[nH]1
Yield: 36 %

Procedure:
The title compound is prepared by the procedure of Example 1 using 2-methoxybenzonitrile, zinc chloride, sodium azide and N,N-dimethylformamide. The reaction is heated at reflux temperature for 5 hours, acidified with 10% hydrochloric acid, extracted with ethyl acetate, dried and concentrated in vacuo. The residue is chromatographed (silica gel: 50% ethyl acetate/methylene chloride) to give 2.57 g (yield=36% of theory).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH2:22]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]>[Pd].CO>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH2:22]3)=[O:20])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)N1CCC(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (50 mg, 0.128 mmol) and methanol (10 ml) were added to 5% Pd—C, wet (10.00 mg, 0.094 mmol) in a 50 ml pressure bottle and stirred for 16 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated. Chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.60 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.35 (s, 1H), 7.49-7.40 (m, 3H), 7.13 (m, 2H), 4.79 (m, 4H), 4.56 (m, 1H), 4.05 (m, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 2.71 (m, 1H), 2.57 (m, 1H), 1.79 (m, 2H), 1.55-1.30 (m, 2H), 1.02 (m, 6H); MS (ESI(+)) m/e 393 (M+H)+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=O)[CH3:26]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:31][C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1cc(C=O)ccc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1cc(C=C(Br)Br)ccc1OC
Yield: 90.4 %

Procedure:
According to the General Procedure F, carbon tetrabromide (3.70 g, 11.10 mmol), triphenylphosphine (5.82 g, 22.20 mmol) and 3-Ethoxy-4-methoxybenzaldehyde (2.00 g, 11.10 mmol) are converted to give after workup and chromatography (SiO2, CH2Cl2, Rf=0.55) the title compound (3.37 g, 10.03 mmol) as a pale yellow solid. M.p. 41-42° C.;
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:33][CH2:34][F:35])[C:15]3[CH:32]=[CH:31][C:18]([C:19]([NH:21][C@H:22]([C:28]([O-:30])=[O:29])[CH2:23][CH2:24][C:25]([O-:27])=[O:26])=[O:20])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:33][CH2:34][F:35])[C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][C@H:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])=[CH:31][CH:32]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(O)c2cc(CN(CCF)c3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(O)c2cc(CN(CCF)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)ccc2n1
Reaction time: 2 h
Yield: 60.1 %

Procedure:
N-(4-(N-((2-amino-4-hydroxy-6-quinazolinyl)methyl)2-fluoroethylamino)benzoyl)-L-glutamate (0.206 g) was suspended in a mixture of water (4.5 ml) and ethanol (1 ml) and treated with 1 N NaOH aq. (5 mol eq.). Vigorous shaking gave a solution within 5 min. After 2 hr. the solution was clarified by filtration and the pH brought to 4.0 using 1 N HCl aq. A gelatinous precipitate of the product resulted. It was freed from inorganic ions by three cycles of suspension-centrifugation-decantation. The amorphous white solid was dried at 70° C. in vacuo, (m.p.>350° C. with some darkening and slow decomposition from 245° C.) giving N-(4-(N-((2-amino-4-hydroxy-6-quinazolinyl)methyl)2-fluoroethylamino)benzoyl)-L-glutamic acid (CB 3731). Yield 60.1%. The structure was confirmed by elemental analysis (C,H,N and F) and by uv spectroscopy (spectrum determined in 0.1 N NaOH aq.). uv λ(nm) (ε) maxima: 307 (29,200), 275 (19,500), 227.5 (49,700 ); minima: 279 (19,200), 250 (9,100).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[NH2:12][NH2:13]>ClCCl>[F:1][C:2]1[C:3]([F:11])=[C:4]([NH:12][NH2:13])[C:5]([F:9])=[C:6]([F:8])[N:7]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: NN
Solvent: ClCCl
Product: NNc1c(F)c(F)nc(F)c1F
Reaction time: 8 h

Procedure:
Pentafluoropyridine (3.4 g; 20 mmol) was dissolved in dichloromethane (50 mL) and chilled in an ice bath. To the solution was added hydrazine (640 mg; 22 mmol) and it was stirred overnight. The solvent was evaporated, and the residue was dissolved in dichloromethane (50 mL) and washed with a 10% sodium carbonate solution (5 mL). It was dried over magnesium sulfate, and evaporated, to give crude 2,3,5,6-tetrafluoro-pyridin-4-yl-hydrazine. The crude product was then dissolved in ethanol. To the solution was added one drop of acetic acid, and m-tolylaldehyde (1.45 g; 12 mmol) and it was heated at 60° C. overnight. The resulting precipitate was filtered and dried to give N-(3-methyl-benzylidene)-N′-(2,3,5,6-tetrafluoro-pyridin-4-yl)-hydrazine (2.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][NH:13]C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O1CCOCC1.[ClH:27]>>[ClH:27].[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][NH2:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@@H](NN)CC1

Procedure:
A solution of cis-4-(N′-tert-butoxycarbonyl-hydrazino)-cyclohexanecarboxylic acid ethyl ester (1.03 g, 3.60 mmol) in 4 M hydrogen chloride solution in 1,4-dioxane (9.0 ml, 36 mmol) was stirred at room temperature for 3 days. The precipitate was collected by filtration, washed with tert-butyl methyl ether and dried in vacuo to give the title compound as white solid in quantitative yield. MS m/e: 187 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCCCO2)=[C:18]([F:28])[C:17]=1[O:29][CH3:30].[F-].[K+].C(#N)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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:29][CH3:30])[C:18]=2[F:28])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 70 °C
Yield: 76 %

Procedure:
A 250 mL three-neck flask with a reflux condenser, a nitrogen inlet and a thermocouple was charged with methyl 4-amino-3,6-dichloro-5-fluoropicolinate (9.965 g, 41.7 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (12.74 g, 52.1 mmol) and KF (4.84 g, 83 mmol). Acetonitrile (78 mL) and water (26 mL) were added. The reaction mixture was purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2; 1.477 g, 2.10 mmol, 5 mol %) was added, and the solution was heated to 70° C. under nitrogen for 2 h. Upon cooling to room temperature, a precipitate formed which was filtered and washed with water. The precipitate was dissolved in EtOAc (ca 500 mL) and washed with water and then brine. The organic layer was dried (MgSO4) and the solvent was removed using a rotary evaporator to give an orange solid, which was dried in vacuum oven at 50° C. (11.46 g, 76% yield): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 164.85 (s), 153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s), 142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2 Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz), 113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364 ([M+H]+). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.I[CH3:22].CO>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N:14]([CH3:22])[C:15]1[CH:20]=[N:19][CH:18]=[N:17][CH:16]=1
Reactant: CI
Reactant: COC(=O)c1ccc(F)c(Nc2cncnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(N(C)c2cncnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium hydride (110 mg, 4.58 mmol, 1.10 eq) was dissolved in THF (10 mL), added to dry, argon purged flask, and cooled to 0° C. Compound 19 (1.0 g, 4.0 mmol, 1.0 eq) was dissolved in THF (10 mL) and added to sodium hydride solution. The reaction stirred at 0° C. for 30 minutes. Iodomethane (630 mg, 4.44 mmol, 1.10 eq) was added. The reaction warmed to rt and stirred overnight. Methanol was added and the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel afforded 600 mg (57%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.26 (s, 2H), 7.99 (dd, J=7.8, 2.0 Hz, 1H), 7.93 (ddd, J=8.5, 4.8, 2.2 Hz, 1H), 7.51 (dd, J=10.8, 8.7 Hz, 1H), 3.86 (s, 3H), 3.35 (s, 3H); ES-MS [M+1]+:262.1.
Reaction SMILES: [C:1]([CH:6]=[C:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)([O:3][CH2:4][CH3:5])=[O:2].[I-].[CH3:32][S+](C)(C)=O.CC(C)([O-])C.[K+]>CS(C)=O>[C:1]([CH:6]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]4=[O:29])=[CH:15][C:14]=3[F:30])[CH2:11][CH2:12]2)[CH2:32]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C=C1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC12CCN(c1ccc(N3C[C@H](CNC(C)=O)OC3=O)cc1F)CC2
Yield: 61 %

Procedure:
The title compound was prepared by reacting (S)-N-[3-{4-[4-carboethoxymethylidenepiperidin-1-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-ylmethyl]-acetamide (1.0 mmol, Example E), trimethyloxosulphonium iodide (1.3 mmol), potassium tert-butoxide (1.3 mmol) in dimethylsulfoxide (10 ml) at a temperature 25° C. for 14 hours in 61% yield.