Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19]([O:20]CC)=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:17]=[N:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:28][CH2:29][CH2:30]Cl>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:16]([CH2:30][CH2:29][Cl:28])[C:14]=3[N:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: ClCCCl
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C(C)=O)CC3)ncc2c1OCC
Product: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O

Procedure:
A solution of 1.0 g of ethyl 2-(4-acetyl-1-piperazinyl)-5-ethoxypyrido[2,3-d]pyrimidine-6-carboxylate in 10 ml of 1,2-dichloroethane was heated to reflux for 15 hours. After removal of an excess of the reagent by distillation, the resulting solid was taken up in chloroform and the chloroform solution washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to leave a solid which was recrystallized from ethyl acetate to give 0.65 g of the product, m.p. 205° - 206°C.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1B1OC(C)(C)C(C)(C)O1)[C:18]([NH:20][CH3:21])=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:46])[CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43](Br)[CH:44]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:46])[CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([C:24]2[CH:23]=[CH:22][C:17]([C:18](=[O:19])[NH:20][CH3:21])=[CH:16][C:15]=2[CH2:14][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(=O)NC)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-N-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 3, Step 6 to provide (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-methylcarbamoyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[CH:17]=[N:18][NH:19][CH:20]=1.O[CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:17]=[N:18][N:19]([CH:26]2[CH2:27][CH2:22][CH2:23][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[CH:20]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2cc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
DIAD (1.18 ml, 6.0 ml) was added dropwise to a solution of 4-bromopyrazole (0.74 g, 5.0 mmol), 3-hydroxy-1-tert-butoxycarbonylpiperidine (1.00 g, 5.0 mmol) and triphenylphosphine (1.57 g, 6.0 mmol) in THF (50 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and ethyl acetate. The organic fractions were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc/Petrol) to give the product (1.46 g). MS: [M+H]+=332.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:47]([CH2:50]C)CC)C.[OH2:52]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:27][C:50](=[O:52])[NH:47][CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: CCN(CC)CC
Reactant: O=C(O)C(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2cccc(Oc3ccccc3)c2)C(c2ccc(F)cc2)O1
Yield: 77 %

Procedure:
To a solution of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionic acid (2.2 g, 6.00 mmol) in tetrahydrofuran (60 ml) were added diphenylphosphoryl azide (1.42 ml, 6.60 mmol) and triethylamine (1.26 ml, 9.00 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was allowed to stand at room temperature, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give (4RS,5SR)-5-(4-fluorophenyl)-4-((3-(phenyloxy)phenyl)methyl)-1,3-oxazolidin-2-one (1.69 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])CO)[CH2:9][CH2:10][CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC(CO)CCCC
Reactant: COc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC(CCCC)COc1ccsc1
Reaction time: 15 h
Yield: 83 %

Procedure:
Under a nitrogen atmosphere, 3-methoxythiophene (5.0 g, 44.8 mmol), 2-butyloctanol (16.7 g, 89.6 mmol), and p-toluenesulfonic acid (850 mg, 4.48 mmol) were dissolved in toluene (40 ml), and refluxing was performed for 15 hours. Then, water was added to the reaction solution. The reaction solution was then extracted with methylene chloride, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solution was distilled off under reduced pressure. By separating and purifying the obtained reaction solution by silica gel column chromatography in which hexane was used as a mobile phase, a target substance was obtained as clear oil (83% yield). 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.17 (dd, J=5.2 Hz, 1.6 Hz, 1 H), 6.76 (d, J=5.2 Hz, 1 H), 6.21 (d, J=1.6 Hz, 1 H), 3.81 (d, J=5.8 Hz, 2 H), 1.25 (m, 17 H), 0.88 (m, 6 H)
Reaction SMILES: C([C@@H](N[C@H](C(N1CCC[C@H]1C(O)=O)=O)CCCCN)CCC1C=CC=CC=1)(O)=O.C(=O)(O)[O-].[Na+].[C:35]([C@@H:38]([NH:47][C@H:48]([C:65]([N:67]1[CH2:74][CH2:73][CH2:72][C@H:68]1[C:69]([OH:71])=[O:70])=[O:66])[CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:64])[CH2:55][NH:56]C(OC(C)(C)C)=O)[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([OH:37])=[O:36]>O.C(#N)C.FC(F)(F)C(O)=O>[C:35]([C@@H:38]([NH:47][C@H:48]([C:65]([N:67]1[CH2:74][CH2:73][CH2:72][C@H:68]1[C:69]([OH:71])=[O:70])=[O:66])[CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:64])[CH2:55][NH2:56])[CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.5 %

Procedure:
A solution of 405 mg (1.0 mmol) of N-[N2 -(1(S)-carboxy-3-phenylpropyl)-L-lysyl]-L-proline and 252 gm (3.0 mmol) of sodium bicarbonate in 3 ml of water was treated with a solution of 272 mg (1.0 mmol) of N-t-butoxycarbonyl-glycine N-hydroxysuccinimide ester in 2 ml acetonitrile. The resulting clear solution was stirred at room temperature for 11/2 hours, concentrated in vacuo to 3/4 volume and acidified by dropwise addition of 2.5 N HCl. The resulting mixture was shaken with a small amount of ethyl acetate and the ethyl acetate/water layer decanted off a white, insoluble gum. The insoluble gum was flushed in vacuo with methanol and pumped out on an oil pump to provide 395 mg of crude product contaminated with a small amount of starting material. LH-20 Chromatograph (2.5×240 cm, methanol system) yield 305.6 mg of N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -(N-tert-butoxycarbonylglycyl)-L-lysyl]-L-proline. 305 mg (0.54 mmol) of the above intermediate was then dissolved in 8 ml trifluoroacetic acid (drying tube) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated in vacuo, flushed 2x with ethyl ether and pumped out on an oil pump. The residual dry, white foam was dissolved in 8 ml of water and put on a column of 8 ml of Dowex 50W-X2(H+) resin. After aqueous washes, the product was eluted with water containing 2% pyridine, which after freeze-drying, provided 265 mg of N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -glycyl-L-lysyl]-L-proline that was single spot by tlc (ethyl acetate/pryridine/acetic acid/water (10:5:1:3) system) and had an excellent nmr in deuteromethanol (aromatic singlet at 7.2 ppm and the glycyl methylene at 3.7 ppm).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:45])([CH3:44])[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])[N:36]=2)[N:33]=1.CN(C)[CH:48]=[O:49]>>[C:48]([OH:49])(=[O:8])/[CH:35]=[CH:37]/[C:38]([OH:40])=[O:39].[C:48]([OH:49])(=[O:8])/[CH:35]=[CH:37]/[C:38]([OH:40])=[O:39].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:45])[C:38]([O:40][CH:41]([CH3:42])[CH3:43])=[O:39])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)C(C)(C)c1cn2nc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.10 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 60 ml of N,N-dimethylformamide; 1.11 g of 60% sodium hydride in oil was added, followed by stirring at room temperature under reduced pressure for 1 hour. While the solution was ice cooled, 7.79 g of isopropyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was added, followed by stirring at constant temperature for 4 hours. Ice water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure. The residue was dissolved in 10 ml of ethanol; 476 mg of fumaric acid was added, followed by concentration again. The residue was crystallized by the addition of ethyl acetate, collected by filtration, washed with ethyl acetate and dried to yield 1.05 g of the title compound.
Reaction SMILES: C(NC1CCC([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])CC1)(C)C.[N:20]1([CH:29]=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2N=N1.[CH2:31]1[CH2:35]OC[CH2:32]1>>[CH:31]([C:29]([NH:20][CH:24]1[CH2:25][CH2:26][CH:27]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:28][CH2:23]1)=[O:30])([CH3:35])[CH3:32]
Reactant: CC(C)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: C1CCOC1
Reactant: O=Cn1nnc2ccccc21
Product: CC(C)C(=O)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of a tert-butyl N-[4-(isopropylamino)cyclohexyl]methylcarbamate (7.89 mmol, 1 equivalent) in THF (5 ml) was added dropwise to a solution of 1H-benzotriazole-1-carboxaldehyde (8.68 mmol, 1.2 equivalent) in THF (10 ml) at room temperature, stirred overnight and heated at reflux temperature for two hours. 1H-Benzotriazole-1-carboxaldehyde (1 equivalent) was added and stirred overnight. The solvent was removed and dichloromethane was added to the residue. The organic extract was washed with 2N NaOH solution, washed with saturated NaCl solution, and dried over Na2SO. The solvent was then removed and the product chromatographed to give tert-butyl N-[4-(isopropylformylamino)cyclohexyl]methylcarbamate: 100% yield, 299 (ESMS, MH+); 1H NMR (CD3OD) δ 6.22 & 8.18 (two s, 1H), 4.63 (broad, 1H), 4.30 & 3.60 (two m, 1H), 3.76 (m, 1H), 2.99 (m, 2H), 1.44 (s, 9H), 1.27 (d, 3H, J=6.5 Hz), 1.21 (d, 3H, J=6.5 Hz), 1.91-0.82 (m, 9H).
Reaction SMILES: [CH2:1]([S:4][CH2:5][C@@H:6]([C:8]([OH:10])=O)[NH2:7])[CH:2]=[CH2:3].[OH-].[Na+].[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:19]2[C:8](=[O:10])[CH:6]([CH2:5][S:4][CH2:1][CH:2]=[CH2:3])[NH:7][C:20]2=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCSC[C@H](N)C(=O)O
Reactant: S=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCSCC1NC(=S)N(c2ccccc2)C1=O

Procedure:
When 5 g of S-allylcysteine (0.031 mole), 1.24 g of sodium hydroxide (0.31 mole) and 4.19 g of phenylisothiocyanate (0.031 mole) were reacted according to the procedure for the preparation of the compound of Example 2, 8.59 g of crude product was obtained which did not require purification by chromatography. Crystallization of the crude product from isopropyl alcohol gave pure title compound: RF on silica gel=0.44 [ethyl acetate-hexane (2:3)].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][C:32]=2[CH3:38])=[C:28]([CH:39]([CH3:41])[CH3:40])[NH:27][N:26]=1)(=[O:3])[CH3:2].[C:42]([OH:46])(=[O:45])[CH:43]=[CH2:44].C(O)(=O)CC=C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:44]=[CH:43]/[C:42]([OH:46])=[O:45])=[CH:33][C:32]=2[CH3:38])=[C:28]([CH:39]([CH3:41])[CH3:40])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CC(=O)O
Agent: C=CCC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 4 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and acrylic acid instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole and 3-butenoic acid, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.OC1C=NC=CC=1.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[C:30](=[O:33])[CH2:31]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH2:31][C:30]([C:29]2[CH:34]=[C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:26]=[CH:27][C:28]=2[O:35][CH3:36])=[O:33])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)CBr
Reactant: COc1cccc(O)c1
Agent: Oc1cccnc1
Product: COc1cccc(OCC(=O)c2cc(OCc3ccccc3)ccc2OC)c1

Procedure:
By the method of Example 1, substituting a molar equivalent of 3-methoxyphenol for 3-hydroxypyridine, 5-benzyloxy-2-methoxyphenacyl bromide was converted to present title product; mp 76°-77° C.; IR (KBr) 1680 cm-1 ; MS 378 (M+); Anal. C 73.05, H 5.74, calcd. C 73.00, H 5.86.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[F:42][C:43]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:44]=1[O:45][CH2:46][CH2:47][OH:48].[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:42][C:43]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:44]=1[O:45][CH2:46][CH2:47][O:48][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Reactant: OCCOc1cc(F)ccc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COCCOc4cc(F)ccc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The stirred solution of 0.150 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate, 0.035 g of 2-(2,5-difluorophenoxy)ethanol and 2.0 ml of N,N-dimethylformamide is admixed at 0° C. with 0.0094 g of sodium hydride dispersion (55%). The reaction mixture is stirred at room temperature over a further 1 hour and subsequently poured onto 1M sodium hydrogencarbonate solution (30 ml). The mixture is extracted with tert-butyl methyl ether (2×30 ml). The organic phases are washed successively with water (30 ml) and brine (30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:1 EtOAc-heptane); Rt=5.78.
Reaction SMILES: C([N:3]1[CH2:8]COCC1)C.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[N:16][N:17]=[C:18]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32](C(O)=O)=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[CH:13][CH:12]=1.[Cl:46]C(OCC)=[O:48].N>O1CCCC1>[ClH:46].[ClH:46].[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)=[N:16][N:17]=[C:18]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([NH:3][CH:8]=[O:48])=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[CH:13][CH:12]=1
Reactant: CCN1CCOCC1
Reactant: COc1ccc(-c2nnc(NC3CCN(Cc4ccc(C(=O)O)cc4)CC3)c3cc(OC)ccc23)cc1
Reactant: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(NC3CCN(Cc4ccc(NC=O)cc4)CC3)c3cc(OC)ccc23)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
0.29 mL (2.3 mmol) of N-ethylmorpholine is added to a stirred suspension of 400 mg (0.7 mmol) of {4-[(4-{[7-methoxy-4-(4-methoxyphenyl)phthalazin-1-yl]amino}piperidin-1-yl)methyl]phenyl}carboxylic acid (dihydrochloride) in 10 mL of tetrahydrofuran at 0° C., followed by dropwise addition of 0.074 mL (0.77 mmol) of ethyl chloroformate. The mixture is stirred for 1 hour at 0° C., and 0.6 mL (3.5 mmol) of a 20% aqueous ammonia solution is then added slowly. The reaction medium is stirred for 20 hours at room temperature and is then concentrated under reduced pressure. 1N sodium hydroxide is added to the residue and the mixture is then extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified on a column of silica (eluent: 85/15 (v/v) dichloromethane/methanol). 150 mg of a colourless oil are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[NH:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([C:14](O)=[O:15])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:14](=[O:15])[C@@H:12]([NH:11][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:13]
Reactant: Nc1cc(F)c(F)cc1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)c(F)cc1N
Reaction time: 3 h

Procedure:
To the mixture of 1,2-diamino-4,5-difluorobenzene (2.00 g, 13.9 mmol) and Boc-L-Ala-OH (2.63 g, 13.9 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.85 g, 30.5 mmol) in DCM (139 mL) was added triethylamine (6.00 mL, 43.0 mmol) at rt and stirred for 3 h. The mixture was then concentrated in vacuo and absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (S)-tert-butyl 1-(2-amino-4,5-difluorophenylamino)-1-oxopropan-2-ylcarbamate as orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (1H, s), 7.21 (1H, dd, J=11.9, 8.8 Hz), 7.11 (1H, d, J=6.7 Hz), 6.65 (1H, dd, J=12.9, 8.0 Hz), 5.04 (2H, br. s.), 4.04-4.14 (1H, m), 1.39 (9H, s), 1.25 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 338.0 [M+Na]+ and m/z 314.0 [M−H]−.
Reaction SMILES: ClC1S[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[N:6]=1.C(OCC)(=O)[CH2:20][C:21](C)=[O:22].C([O-])(=O)C.[Na+].FC(F)(F)C(F)(F)C#N>O.CO>[C:21]([C:4](=[C:5]([NH2:6])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:22])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: N#CC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Yield: 37 %

Procedure:
Preparation of Ethyl 2-Chloro-4-Pentafluoroethyl-5-Thiazolecarboxylate To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil; dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo -4-pentafluoroethyl-5-thiazole-carboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoro-ethyl-5-thiazolecarboxylate, nD25 =1 4460.