Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.Cl[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1.[CH3:13][S-:14].[Na+]>O>[CH3:13][S:14][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc([N+](=O)[O-])nc1
Reaction time: 13 h
Yield: 45.3 %

Procedure:
A methanol (40 mml) solution of 5-chloro-2-nitropyridine (2.0 g. 12.6 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (1.02 g, 13.9 mmol) while being cooled with ice, and after the mixture was stirred for 13 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexane to obtain 972 mg (yield 45%) of 5-methylthio-2-nitropyridine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(Cl)cc(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Concentrated sulfuric acid (2.8 ml) was added dropwise to 70% nitric acid (4.0 ml) in an ice-water bath. This mixture was added to a solution of 2,4,6-trichlorobenzoic acid (5.13 g) in concentrated sulfuric acid (23 ml) dropwise for 20 minutes in an ice-water bath. The mixture was stirred for 16 hours at ambient temperature and poured into ice-water (300 ml) slowly. This mixture was stirred for 1 hour at ambient temperature. The precipitate was collected by vacuum filtration and washed with water to give 2,4,6-trichloro-3-nitrobenzoic acid (5.26 g) as colorless fine crystals.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=O)=O.[I-:19].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:19][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(I)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate (0.54 g, 1.94 mmol) and sodium iodide (0.87 g, 5.8 mmol) were dissolved in acetone (10 ml) and the solution was refluxed under an inert gas for 6 h and then stirred at room temperature for 15 h. After thin layer chromatography control, the reaction mixture was heated in three portions in a microwave oven (CEM Discover): 10 min 100° C. 150 watt, 15 min 150° C. 200 watt, 20 min 100° C. 150 watt. After thin layer chromatography control, the three portions were combined, sodium thiosulfate solution (20 ml, 5 mmol/l) was added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (3:1). Yield: 0.14 g (23%)
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=O.[OH-].[Li+]>CO.O>[C:22]1([S:19]([N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([NH2:5])=[CH:11][CH:10]=3)[CH2:14][CH2:15]2)(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Reaction time: 48 h
Yield: 83.2 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.45 g) and lithium hydroxide (0.23 g) in methanol (10 mL) and water (1 mL) was stirred for about 48 hours. The reaction mixture was concentrated in vacuo, diluted with cold water, and extracted with dichloromethane. The organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was crystallized from ethyl acetate/hexanes to give 4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenylamine (0.29 g, 83%), m.p. 158° C.; Analysis for C18H22N2O2S: Calc.: C, 65.43; H, 6.71; N, 8.48; Found: C, 65.59; H, 6.61; N, 8.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:22][CH:21]=3)=[CH:19][C:14]=2[O:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:6][C:5]5[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:28][CH2:27]4)[CH2:22][CH:21]=3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC(N2CCNCC2)C1
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(CN2CCN(C3CC=C(c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from 3-methoxybenzyl chloride (0.13 g, 0.8 mmole), 1-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]piperazine (0.23 g, 0.8 mmole), and excess powdered K2CO3 as described in example 45 to give the product (45%, mp: 124-124.5° C.). Calc'd for C25H30N2O3 : C, 73.86%; H, 7.44%; N, 6.89%. Found: C, 73.88; H, 7.43%; N, 6.91%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[Cl-].[OH:31][NH3+:32].C([O-])(=O)C.[Na+]>O.CCO>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=[N:32][OH:31])=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NO)c3)cc21
Yield: 130 %

Procedure:
1.2 g (2.9 mmol) of the compound from Example 70, 0.4 g (6 mmol) of hydroxylammonium chloride and 0.48 g (6 mmol) of sodium acetate in 45 ml of H2O/EtOH (2:1) were refluxed for 30 minutes. The organic solvent was removed under reduced pressure, and the resulting aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield 1.6 g (70%) of the product. Melting point >250° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>O>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCNC(=O)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To a solution of 6-aminohexanoic acid (5.0 g, 38.7 mmol), Na2CO3 (4.1 g, 38.7 mmoL) in water (100 mL) was added drop-wise 4-bromobenzoyl chloride (8.5 g, 38.7 mmoL, dissolved in 80 mL THF) at 0° C. and stirred for 4 hours. The mixture was concentrated under reduced pressure. The pH value of the solution was adjusted to 1 by concentrated HCl. The resulting mixture was extracted by EtOAc (200 mL×3). The organic layers were combined and dried over Na2SO4, then concentrated to give the desired compound (7.5 g, yield 61.7%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[CH:9]1([NH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)CCCCCl
Reactant: NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCl)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 5-chlorovaleryl chloride (50.0 g, 0.322 mol) in dichloromethane (300 ml) at 0° C. was treated dropwise with a solution containing cyclohexylamine (31.68 g, 0.320 mol), triethylamine (32.32 g, 0.320 mol) and dimethylaminopyridine (0.02 g) in dichloromethane (300 ml). The resulting solution was stirred for 2 hours at 0° C. and then for an additional 16 hours at room temperature. The solution was diluted with dichloromethane (400 ml), washed with water (3×200 ml), saturated aqueous sodium hydrogen carbonate (3×100 ml), saturated aqueous ammonium chloride (3×100 ml), and brine (2×100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to yield a crude product. The crude product was recrystallized from ethyl acetate-hexane to yield N-cyclohexyl-5-chloropentanamide as a colorless crystalline solid, having a melting point of 70°-71° C. and the following physical characteristics:
Reaction SMILES: C(O)(=O)C.Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.O=[C:17]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18]1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:17]3[CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][C:21]=3[C:10]=2[CH:9]=1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To 250 ml of 80% acetic acid in water were added 4-methoxyphenylhydrazine hydrochloride (21 g, 0.12 mole) and 3-oxocyclopentane carboxylic acid (20 g, 0.15 mole). After stirring at ambient temperature for two hours, the mixture was stirred at 100° C. for three hours. After cooling, the mixture was filtered, and the tan precipitate washed with water, and dried to give 15 g of a solid, mp ~200° C. A sample of this material was recrystallized from ethanol/ether (1:2) to give a tan solid, mp 210° C. (dec.).
Reaction SMILES: [C:1](CC[NH-])#N.[CH3:6][NH:7][C:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)=[O:15])=[N:9][CH3:10]>>[NH:9]1[CH2:10][CH2:1][CH2:6][N:7]=[C:8]1[CH2:11][CH2:12][NH:13][C:14]([C:16]1[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)=[O:15]
Reactant: N#CCC[NH-]
Reactant: CN=C(CCNC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C)NC
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)NCCC1=NCCCN1

Procedure:
Compound 274 was synthesized from cyanoethylamide 242 as described above for compound 270 using 1,3-propylamine (6 ml). ES MS: 364.37 (M+H+).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3]OC1C=CC(C(OC)=O)=CC=1.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]>C1(C)C=CC=CC=1>[CH2:26]([N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:3][CH2:2][CH2:1][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)c1ccc(OCCCOc2ccc(C(=O)OC)cc2)cc1
Reactant: CCCCNCCCC
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)OC)cc1
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A solution of the mixture of methyl 4-(3-bromopropoxy)benzoate [17a] methyl 4,4′-[1,3-propanediylbis(oxy)]bisbenzoate [20] previous step (19.12 g) and dibutylamine (27.14 g, 35.7 mL, 210 mmol) in toluene (50.0 mL) was stirred under reflux conditions for 3 hours, cooled and extracted with 15% hydrochloric acid (3×40 mL). The combined aqueous layers were washed with of toluene (50 mL), basified to pH 8.5 with sodium bicarbonate and extracted with toluene (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure at 60° C. (water bath). The residue was dissolved in hexane and passed through thin layer of silica gel. The solvent was evaporated under reduced pressure at 50-60° C. (water bath) to give 14.71 g (61.1% yield from 2 steps) of methyl 4-(3-dibutylaminopropoxy)benzoate [18a] as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:8]([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:10])=[N:16][CH:17]=1
Reactant: CN1CCCC[C@H]1C(=O)O
Reactant: NNc1ccc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCC[C@H]1C(=O)NNc1ccc(F)cn1
Temperature: 45 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of (S)-1-methyl-piperidine-2-carboxylic acid (250 mg, 1.74 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (244 mg, 1.92 mmol) in DCM (20 mL) was added HATU (790 mg, 2.09 mmol) and DIPEA (606 μL, 3.48 mmol) and the reaction stirred for 18 h. The reaction was then heated to 45° C. for 1 h then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM to give the title compound (272 mg, 62%). LCMS (Method 4): Rt 0.87 min, m/z 253 [MH+].
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([CH2:36][CH:37]1[CH2:39][CH2:38]1)[CH2:33][CH2:34][CH3:35])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:50]>C(O)C>[Na+:50].[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([CH2:36][CH:37]1[CH2:39][CH2:38]1)[CH2:33][CH2:34][CH3:35])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (290 mg) is dissolved in ethanol (5 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (604 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (277 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (200 μl), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (278 mg). MS (m/z): 691 [M−Na]−
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([NH:24]C=O)/[CH:6]=[C:7](\[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH2:8][P:9]([O:14]CC)([O:11]CC)=[O:10])C>Cl>[NH2:24][CH:5](/[CH:6]=[C:7](\[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH2:8][P:9]([OH:14])([OH:11])=[O:10])[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(/C=C(\Cc1ccccc1)CP(=O)(OCC)OCC)NC=O
Agent: Cl
Product: NC(/C=C(\Cc1ccccc1)CP(=O)(O)O)C(=O)O

Procedure:
0.44 g of E-2-formylamino-4-benzyl-5-diethylphosphono-3-pentenoic acid ethyl ester are dissolved in ml of 4.5 N hydrochloric acid and heated at 85° for hours. After concentration in vacuo, the residue is dissolved in a small amount of ethanol and 1 ml of ethanol/propylene oxide (1:1) is added dropwise thereto. The resulting white precipitate is filtered off and, after recrystallisation from water, E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid is obtained in the form of colourless needles, m.p. 196°-198°.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:15]([NH:16][C:17](=[O:40])[CH2:18][CH:19]([NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:29])=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][S:13](=[O:42])(=[O:41])[N:12]([CH3:43])[C:11]=2[CH:44]=1)=O.CO>C1COCC1>[OH:4][CH2:5][C:7]1[CH:8]=[CH:9][C:10]2[CH:15]([NH:16][C:17](=[O:40])[CH2:18][CH:19]([NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:29])=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][S:13](=[O:41])(=[O:42])[N:12]([CH3:43])[C:11]=2[CH:44]=1
Reactant: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1c2cc(CO)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Lithium borohydride (10.0 mL, 20 mmol, 2.0 M in THF) was added to a THF (50 mL) solution of 4-(3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionylamino)-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazine-7-carboxylic acid methyl ester (Step C) (1.76 g, 2.9 mmol). Following addition of MeOH (0.3 mL, 8 mmol), the mixture was stirred for 20 h at 50° C. The reaction was quenched with acetone, MeOH and dilute HCl at 0° C. The mixture was diluted with CH2Cl2 (400 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica (0-5% MeOH in CH2Cl2) provided the title compound. MS (−APCI, m/z): 578 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:29]1[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)[CH:14]=2)[CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)OC(C)(C)C)C3)nn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of [6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid tert-butyl ester (1.12 g, 3 mmol), 3-chloro-6-methyl-pyridazine (501 mg, 3.9 mmol, 1.3 eq.), Pd(PPh3)4 (104 mg, 0.009 mmol, 0.03 eq.) under nitrogen, are added dioxane (30.0 ml) and sodium carbonate aqueous solution (2.0N, 3.0 ml). The resulting mixture is stirred at 90° C. for 16 hr. The reaction mixture is diluted with EtOAc (80 ml), washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel flash chromatography (hexane/EtOAc 1:1) to give the title compound. MS (+VE) m/z 340.20 (M++1).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7][C:8](OC)=[O:9])=[N+]=[N-].[H][H]>CO.[Pd]>[O:9]=[C:8]1[NH:1][CH2:4][C@@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7]1
Reactant: COC(=O)CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCC(=O)NC1
Yield: 99.3 %

Procedure:
Methyl (4S)-5-azido-4-[(tert-butoxy)carbonylamino]pentanoate (3.9 mmol, 1.07 g) was dissolved in methanol (10 mL), and 10% palladium on carbon (0.1 g) was added. The reaction was stirred overnight under 1 atm of hydrogen. The reaction was filtered and the solvent was removed in vacuo to yield the title compound (0.83 g, 99% yield). ES-MS: 215 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.CN(C)C=O.[CH2:27](OC(OCC)N(C)C)[CH3:28]>O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH2:27][CH3:28])[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1NCc2cccnc2N1c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 18.9 %

Procedure:
To a mixture of 2.9 g of 1-(m-trifluoromethylphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 25 ml of dimethylformamide and 4.4 g of dimethylformamide diethylacetal was reacted at 145° - 150° C for 5 hours. After the reaction was complete, the solvent was distilled off from the mixture under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether solution was applied on a column of alumina and then eluted with ether. The eluate was concentrated by evaporation to leave a residue, which was then recrystallized from a mixture of ether and petroleum ether to give 0.6 g of 1-(m-trifluoromethylphenyl)-3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 155° - 157° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[O:19]1[CH:7]2[CH2:6][C:5]3[C:10]([CH2:9][CH:8]12)=[CH:1][CH:2]=[CH:3][CH:4]=3
Reactant: C1=CCc2ccccc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CC1OC1C2

Procedure:
A solution of 1,4-dihydronaphthalene (32.5 g, 0.25 M) in 300 ml chloroform is cooled in an ice bath and, while stirring, is treated portionwise with 61 g (~20% excess) of 85% m-chloroperbenzoic acid. The mixture is stirred overnight at room temperature. After cooling in an ice bath, the solids are removed by filtration. The filtrate is washed twice with 5% K2CO3 solution, dried over MgSO4, filtered and the solvent is removed in vacuo leaving 37.7 g of yellow partially crystalline material. This is distilled from a small amount of solid K2CO3. After removal of some low boiling material, 16.0 g (44%) of the desired epoxide is collected, boiling point 95°-110° at 0.1 mm.