Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.Cl>CCOCC>[ClH:1].[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OCc1cnc2ccc(Cl)nn12
Reactant: NCc1ccccn1
Agent: Cl
Solvent: CCOCC
Product: OCc1cnc2ccc(NCc3ccccn3)nn12
Yield: 20 %

Procedure:
Prepared from (6-chloroimidazo[1,2-b]pyridazin-3-yl)methanol (7) and 2-(aminomethyl)pyridine according to general procedure 4 (StepB). The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (48 mg, 20%) as a yellow solid; 1H NMR (300 MHz, CD3OD) δ 8.49 (d, J=4.2 Hz, 1H), 7.77 (dt, J=1.7, 9.4 Hz, 1H), 7.61-7.52 (m, 2H), 7.35 (s, 1H), 7.31-7.26 (m, 1H), 6.77 (d, J=9.7 Hz, 1H), 4.74 (s, 2H), 4.67 (s, 2H); 13C NMR (75 MHz, CD3OD) δ 160.2, 154.9, 149.6, 138.8, 137.8, 129.8, 129.5, 125.9, 123.7, 123.6, 114.2, 53.8, 47.6; HPLC tR=7.0 min (Synergi), 96.1%; ES-MS: (M+H)=256 m/z.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][O:10][C:9](=[O:12])[C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[CH3:31][NH2:32]>CO>[OH:10][CH2:11]/[C:7](/[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[C:8](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:15][CH:14]=1)\[C:9]([NH:32][CH3:31])=[O:12]
Reactant: CN
Reactant: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CO
Product: CNC(=O)/C(=C(\CO)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 86 %

Procedure:
A solution of 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (1.0 g, 0.002 mol) and MeNH2 in MeOH (25 mL) was refluxed for 1 h. The reaction mixture was concentrated in vacuo to afford (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)-phenyl) but-2-enamide (920 mg, 86%) as a solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[CH3:24])=O)(C)(C)C>ClCCl>[CH3:23][O:22][C:18]1[C:17]([CH3:24])=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH2:15]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(N)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (40.7 mL, 548 mmol) was added to a solution of N-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline, in dichloromethane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z=138 (M+H)+. The TFA salt was transformed to the free aniline by treatment with NaHCO3.
Reaction SMILES: [C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=[O:2].O.O[N:22]1C2C=CC=CC=2N=N1.N>O1CCCC1>[C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:2])[NH2:22]
Reactant: CCOC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=Cc2cccc(C(N)=O)c2OCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 31.9 %

Procedure:
A solution of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) in tetrahydrofuran (10 ml) was cooled in an ice bath. To this solution was added 1-hydroxybenzotriazole hydrate (0.57 g) and 1-(3-dimethylaminopropyl)-3-ethylcarboxiimide hydrochloride (0.80 g). Thereto aqueous ammonia (0.28 ml) was added dropwise at 5° C. The reaction mixture was stirred for 7 hours at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) to give ethyl 2,3-dihydro-9-carbamoyl-1-benzoxepin-4-carboxylate (0.31 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>ClCCCl>[ClH:14].[N:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][C:5]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccncc2)cc1
Solvent: ClCCCl
Product: Cl
Product: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-phenoxypyridine (6.84 9) in 20 mL of 1,2-dichloroethane at 0° C. was added 8.0 mL of chlorosulfonic acid in a dropwise manner. After 10 minutes, the ice bath was removed and the solution was allowed to warm to 25° C. After an additional 1 hour, the solution was heated to 40° C. for 3 hours, and then cooled to 25° C., and oxalyl chloride (4.4 mL) was added. The solution was heated to 50° C. for 16 hours, and then an additional 2.2 mL of oxalyl chloride was added. After 5 hours more at 5° C., the solution was cooled to 25° C., and poured with rapid stirring into 250 mL of diethyl ether. After 1 minute, the solids were allowed to settle and the supernatant was decanted. The residue was suspended in 3:1 toluene:dichloromethane (250 mL) at about 5° C. and 50 mL of 1.6 M aqueous K3PO4 was added with stirring. After about 30 seconds, the mixture was transferred to a separatory funnel and the layers were separated. The organic layer was washed with 25 mL of 1 N pH 7 phosphate buffer and with 10 mL of brine, and the combined aqueous layers were extracted with 50 mL of toluene. The combined organic layers were dried over sodium sulfate then filtered through a glass-fiber filter. To the filtrate was immediately added 11 mL of 4 M HCl in dioxane and the solution was then concentrated. Partial concentration from dichloromethane:t-butyl methyl ether and filtration gave 2.11 g of 4-((pyrid-4-yl)oxy)benzenesulfonyl chloride hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25](C4CCCCO4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][NH:25][N:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([O:10][CH2:35][C:36]3[CH:41]=[N:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=3)[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn2ccc(OCc3ccc(C(F)(F)F)nc3)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A mixture of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (100 mg, 0.22 mmol) obtained in Example 31-B(i), 5-(chloromethyl)-2-(trifluoromethyl)pyridine (64 mg, 0.33 mmol), potassium carbonate (60 mg, 0.44 mmol) and DMF (4 mL) was stirred at 60° C. for 2 h. Water (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and THF (30 mL), 6 N hydrochloric acid (3 mL) was added, and the mixture was stirred at 70° C. for 3 h. The reaction mixture was allowed to cool to rt, and the mixture was concentrated under reduced pressure. To the residue were added EtOAc (50 mL), THF (50 mL), 8 N aqueous sodium hydroxide solution (3 mL) and water (30 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was crystallized from EtOAc to give the title compound (107 mg, 92%) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16]CO)[CH:10]=[CH:9][N:8]=1.O.C(=O)(O)[O-].[Na+].Cl[CH2:26][Cl:27]>>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][CH2:26][Cl:27])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(OCCCO)ccnc1CO
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(OCCCCl)ccnc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.3 ml (31.7 mmol) of thionyl chloride in 5 ml of dichloromethane is added dropwise at 0° C. to a solution of 2.5 g (12.6 mmol) of 3-(2-hydroxymethyl-3-methylpyridin-4-yloxy)propan-1-ol in 20 ml of dichloromethane and the mixture is subsequently stirred at room temperature for a further 16 h. Water (20 ml) is then added, and the mixture is adjusted to pH 8 using sodium bicarbonate solution and extracted with 3×20 ml of dichloromethane. The organic extracts are washed with water, dried over magnesium sulfate and concentrated. The residual oil (2.8 g) is employed in stage b) without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl>C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][O:24][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ncnc2ncccc12
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CCOc2ncnc3ncccc23)cc1
Temperature: 25 °C

Procedure:
A mixture consisting of 1.86 g (0.011 mole) of 4-chloropyrido-[2,3-d]pyrimidine, 2.0 g (0.011 mole) of 2-[4-(t-butyl)phenyl]ethanol, and 40 mL of toluene containing a little HCl gas was stirred at room temperature. The mixture was then cooled, and a yellow solid was collected. This was washed with hexane, then partitioned between 1N NaOH and CH2Cl2. The CH2Cl2 layer was dried over MgSO4, then the solvent was removed under vacuum to leave a yellow solid, which was recrystallized from hexane. Yield 2.5 g. M.P. 77°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[Cl:15].C1COCC1.CO>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[Cl:15]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(OCc2ccccc2Cl)c(Cl)c1

Procedure:
To a three-neck flask (500 ml) was added 1-(2-chlorobenzyloxy)-2-chloro-4-nitrobenzene (8.567 g). To the flask were added THF (100 ml) and methanol (50 ml). The solution was mechanically stirred and heated under reflux. Glacial acetic acid (17 ml) and reduced iron powders (16.8 g) were added into the solution. The mixture reacted for 1 hr. After the reaction finished, the resultant substance was filtered in vacuo and the filtrate was rotary-evaporated to dryness. To the resultant crude product was added HCl (4N, 200 ml). The mixture was sufficiently vibrated and then filtered in vacuo. To the resultant filter cake was added water (100 ml). The pH of the mixture was adjusted to 12 with 5% sodium hydroxide. Ethyl acetate (700 ml) was added. The solution was sufficiently vibrated and separated. The ethyl acetate layer was washed with saturated sodium carbonate (200 ml), water (200 ml) and staturated saline solution (200 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was rotary-evaporated to dryness. The resultant substance was recrystallized with ethyl acetate to give the target compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7](C2N=C(N)N=C(N)C=2F)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([NH:34]C3C=CC=C(O)C=3)[C:31]([F:42])=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.[C:43](Cl)(=[O:45])[CH3:44].N1C=CC=CC=1>C(Cl)Cl>[C:43]([O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([NH:34][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[C:31]([F:42])=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Oc1cccc(-c2nc(N)nc(N)c2F)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(Nc2ncc(F)c(Nc3cccc(OC(C)=O)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-acetoxyaniline were reacted to yield N2,N4-bis[(3-acetoxyphenyl]-5-fluoro-2,4-pyrimidinediamine. Alternatively, N2,N4-bis[(3-acetoxyphenyl]-5-fluoro-2,4-pyrimidinediamine can be prepared by acetylation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with acetyl chloride in the presence of pyridine in CH2Cl2. 1H NMR (CDCl3): δ 8.00 (bs, 1H), 7.51-7.25 (m, 8H), 2.32 (s, 3H), 2.28 (s, 3H); LCMS: ret. time: 22.14 min; purity: 100%; MS (m/e): 397 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCOCC>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1OCc1ccccc1

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (2.00 g), benzyl bromide (1.54 mL), and cesium carbonate (4.60 g) in N,N-dimethylformamide (50 mL) were stirred for 24 hours. The reaction was taken up in ether and washed with 3×1M NaOH solution, and brine, then concentrated to give the pure product.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6])=[CH:19][CH:20]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of 2.32 g t-butyl N-{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate in tetrahydrofuran was added dropwise under ice-cooling to a tetrahydrofuran solution of Grignard reagent prepared from 5.2 g of 1-bromo-4-fluorobenzene and 1 g magnesium. The mixture was stirred at 5° C. for 2 hours, then poured into an aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The extract was purified by silica gel column, to give 2.6 g of t-butyl N-{(1S)-2-(4-fluorophenyl)-1-methyl-2-oxoethyl]carbamate as colorless oil. This product was treated with 4 N hydrochloric acid/ethyl acetate, to give 1.73 g of the title compound as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:29])/[CH:7]=[CH:8]/[C:9]1[CH:28]=[N:27][C:12]2[NH:13][C:14](=[O:26])[CH2:15][N:16]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:38]>>[ClH:38].[N:20]1([CH2:19][CH2:18][N:16]2[CH2:17][C:11]3[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:29])=[O:5])[CH:28]=[N:27][C:12]=3[NH:13][C:14](=[O:26])[CH2:15]2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)CC(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of (E)-3-[4-(2-morpholin-4-yl-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid tert-butyl ester (92 mg, 0.23 mmol) in CH2Cl2 (2 mL) was treated with TFA (2 mL). After stirring at room temperature for 30 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl (4 mL of a 4.0 M solution in dioxane, 16 mmol) and then sonicated for 15 min. The mixture was diluted with Et2O and sonicated for 10 min. The solid was isolated by filtration, washed with Et2O and dried under vacuum at 50° C. for 4.5 hr to give the title compound (0.10 g, 96%) as an off-white solid: MS (ESI) m/e 347 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: C=CC(=O)OC
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCP(=O)(O)CCCCc1ccccc1
Yield: 88.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (1 g, 0.005 mole) in chloroform (40 ml) was added triethylamine (1.55 ml, 0.0111 mole), trimethyl silylchloride (1.41 ml, 0.0111 mole) and methyl acrylate (0.50 ml, 0.0055 mole). The reaction mixture was stirred at reflux for 18 hours. CHCl3 was removed in vacuo. The residue was diluted with ether and extracted with 5% aqueous NaHCO3 solution. Aqueous layers were acidified with concentrated HCl and extracted with ether. Organic layers were extracted with brine and dried over Na2SO4. Solvent was removed in vacuo to give 1.26 g of an oil. T-60 1H NMR appeared to characterize product from Michael addition.
Reaction SMILES: [K].[OH:2][C:3]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][S:5](=[O:14])[N:4]=1.CN(C=O)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:4]2[C:3](=[O:2])[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][S:5]2=[O:14])=[O:26])=[CH:23][CH:22]=1
Reactant: O=S1N=C(O)C(N2CCOCC2)=N1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C(N2CCOCC2)=NS(=O)N1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 2.3 grams of the potassium salt (C) from Example III(a) in 10 ml methylene chloride and 5 ml DMF is added 1.5 ml p-chlorobenzoylchloride. This mixture is allowed to stir for 1 hour at room temperature. After this, saturated sodium bicarbonate solution is added and the product is extracted into methylene chloride. The organic layer is dried and concentrated in vacuo. The crude product (E) is crystallized from ether and hexane to yield 2 grams of the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:15][C:16]([F:34])([F:33])[C:17]([N:19]([CH2:26][P:27]([O:31]Cl)([O:29]Cl)=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18].[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CCOCC>[F:15][C:16]([F:34])([F:33])[C:17]([N:19]([CH:26]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[P:27]([OH:31])([O:29][NH:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18]
Reactant: NN1CCCCC1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(Oc1ccccc1)P(=O)(O)ONN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phenol (2.3 g, 0.025 mole) and triethylamine (3.49 ml, 0.025 mole) in 50 ml. of ether was added to a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (8.25 g, 0.025 mole) in 150 ml. of ether at 0° C. After two hours, the solution was filtered and the filtrate was added to a cooled (0° C.) solution of N-aminopiperidine (5.2 ml, 0.05 mole) in 100 ml. of ether. The resulting solution was stirred at 25° C. for 16 hours, then filtered. The filtrate was washed with 0.3% hydrochloric acid, dried over sodium sulfate and concentrated in vacuo to afford ethyl N-trifluoroacetyl-N-(phenoxy(N-piperidinoamino)phosphonomethyl)glycinate which could not be further purified by any means.
Reaction SMILES: [CH3:1][SH:2].[Na].O.[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][S:2][CH3:1])=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]
Reactant: COc1cc(C(=O)CBr)ccc1OC(C)=O
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C(=O)CSC)ccc1OC(C)=O
Reaction time: 20 h
Yield: 83 %

Procedure:
As shown in the above-described reaction formula, the mixture of 600 ml of sodium methyl mercaptan (8.56 ml) and three drops of aliquat/5 ml of water solution was added to the solution containing 2.46 g of 4-(2-bromoacetyl)-2-methoxyphenyl acetate (8.56 mM) dissolved in 10 ml of benzene. The mixture solution was stirred for 20 hours. The resulting product was extracted with ethylacetate, dried with anhydrous magnesium sulfate and the remaining solvent was removed. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 2-methoxy-4-[-2-(methylthio)acetyl]phenyl acetate (3; 2.18 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.Cl.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(CNc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-chloro-3-nitrobenzotrifluoride (5.05 g, 22.4 mmol), 4-(dimethylamino)benzylamine dihydrochloride (5.0 g, 22.4 mmol), potassium carbonate (9.29 g, 76.2 mmol) and dimethylformamide (60 ml) was stirred at room temperature for 3 days. Water (60 ml) was added and the mixture was stirred for 0.5 h followed by filtration. The crystalline product was triturated with petroleum ether. Yield 6.08 g, 80%. M.p. 158-160° C.