Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O.C(OCC)(=O)C>[Pd].[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: O=C(Nc1ccc([N+](=O)[O-])c2ccncc12)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)C(F)(F)F)c2cnccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N-(5-nitroisoquinolin-8-yl)trifluoroacetamide (200 mg) were added ethyl acetate (15 ml) and 5% palladium-carbon (wet, 20 mg) and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hr. Tetrahydrofuran was added to the reaction mixture to dissolve the resultant crystals, and palladium catalyst was removed by celite filtration. The solvent was evaporated from the filtrate to give N-(5-aminoisoquinolin-8-yl)trifluoroacetamide as a crude product. Tetrahydrofuran (12 ml), pyridine (62 μl) and phenyl chloroformate (0.10 ml) were added to the obtained crude product, and the mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with dichloromethane, and washed twice with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with diethyl ether and dried under reduced pressure to give 8-(trifluoroacetylamino)isoquinolin-5-ylcarbamic acid phenyl ester (194 mg).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:21]1[CH:26]2[CH:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:28][CH:22]1[CH2:23][C:24](=O)[CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:21]1[CH:26]2[CH:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:28][CH:22]1[CH2:23]/[C:24](=[CH:5]\[C:3]#[N:4])/[CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CC(=O)CC1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CC2C/C(=C\C#N)CC1N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a suspension of NaH (6.98 g, 173 mmol) in tetrahydrofuran (460 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (18.5 mL, 103.8 mmol) in tetrahydrofuran (80 mL). The reaction was refluxed for 1 hour and then cooled at 0° C. again. To the reaction mixture was added a solution of compound 86a (26.0 g, 75 mol) in tetrahydrofuran (80 mL). The reaction was allowed to warm up to room temperature and stirred 2 hours. The reaction mixture was then quenched with saturated aqueous solution of NaHCO3, and most of the THF was removed under reduced pressure. Ethyl acetate (200 mL) was added, washed with water, brine, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product (2E)-2-[8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-ylidene]acetonitrile 86b (27 g, 98%). MS: calc'd (MH+) 369, measured (MH+) 369.
Reaction SMILES: C(O)C.O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:23]([O-])=O)[CH:9]=[C:10]([Cl:22])[C:11]=1[O:12][CH:13]([CH3:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16].Cl>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([Cl:22])[C:11]=1[O:12][CH:13]([CH3:21])[C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])[NH2:23]
Reactant: CC(Oc1c(Cl)cc([N+](=O)[O-])cc1Cl)C(F)(F)C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(Oc1c(Cl)cc(N)cc1Cl)C(F)(F)C(F)(F)F
Yield: 86.8 %

Procedure:
4.0 g iron filings, 240 mL of a 2/1 ethanol-water mixture, and 4.86 g 3,5-dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)nitrobenzene was stirred vigorously and heated under reflux while 1.0 mL conc. HCl in 2 mL ethanol was added dropwise. After one hour 2.0 mL conc. HCl in 2.0 mL ethanol was added and reflux was maintained overnight (about 15 hours). The mixture was filtered hot through Celite. The filtrate was concentrated under vacuum before being partitioned in saturated sodium bicarbonate and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give 3.86 g of 3,5-Dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)aniline as an amber oil. 1H NMR and GC/MS confirm pure product. Anal. calcd C10H8Cl2F5NO: C, 37.06; H, 2.49; N, 4.32. Found: C, 38.71; H, 2.51; N, 4.65.
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:28]=[C:29]=[O:30])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:28]1[C:20](=[O:21])[C@H:9]2[N:8]([C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:29]1=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Reactant: CCCCN=C=O
Product: CCCCN1C(=O)[C@@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C1=O

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and butyl isocyanate gave after recrystallisation from 2-propanol, the title compound as white crystals m.p.: 240-243° C. Analysis for C23H23N3O2: Calculated: C,73.97;H,6.21;N,11.25;
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH3:8])=[O:6]>CO.O>[F:17][C:16]([F:19])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:7]([C:5]2[O:6][CH2:2][CH2:3][N:4]=2)[CH3:8])=[CH:10][CH:11]=1)([OH:24])[C:20]([F:23])([F:22])[F:21]
Reactant: CN(C(=O)NCCCl)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CO
Solvent: O
Product: CN(C1=NCCO1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 86.3 %

Procedure:
Dissolve 10.0 g (26 m. mole) of N-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methyl-urea in a mixture of 50 ml of methanol and 100 ml of water. Heat for 1 hour on a steam bath. Concentrate, and partition between 1N aqueous sodium bicarbonate solution and ether (diethyl) and then extract with 200 ml of 1N hydrochloric acid. Add sodium bicarbonate and then extract with 200 ml of ether. Dry the ether extract and concentrate to obtain 7.8 g of the title compound as a white solid, m.p. 188°-190° C. The salts may be prepared by standrad techniques such as by treatment of a solution of the free base in a suitable organic solvent, e.g. ether, with the desired acid, e.g. hydrochloric, and then filtering off the precipitated salt. The hydrochloride salt melts at 147°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>ClCCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCCl
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
3-fluoro-4-methylphenol (3.66 g, 29.0 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. HNO3 70% (3.7 mL, 58 mmol) was diluted with H2O (33 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture, which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.83 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 6.85 (d, J=11.0 Hz, 1H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)[CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15](C(OCC3C=CC=CC=3)=O)[CH2:16]2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[CH:37][CH:36]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CN(C(=O)OCc3ccccc3)CC(C1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CNCC(C1)O2
Yield: 73.5 %

Procedure:
A solution of benzyl 7-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (ix) above; 2.55 g, 4.7 mmol) in 95% ethanol (50 mL) was hydrogenated over 5% Pd/C (0.8 g) at 30 kPa. When the quantity of hydrogen calculated for complete reaction had been consumed, the reaction was stopped. The mixture was filtered through Celite®, and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography on silica, eluting with CHCl3:ammoniacal methanol (95:5), to yield the title compound 1.39 g (75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][CH2:25][OH:26])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:60]([O:67][C:68]1[CH:78]=[CH:77][CH:76]=[C:75](O)[C:69]=1[C:70]([N:72]([CH3:74])[CH3:73])=[O:71])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][CH2:25][O:26][C:75]3[CH:76]=[CH:77][CH:78]=[C:68]([O:67][CH2:60][C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[C:69]=3[C:70](=[O:71])[N:72]([CH3:73])[CH3:74])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OCCO)ccc2cc1OCc1ccccc1
Reactant: CN(C)C(=O)c1c(O)cccc1OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OCCOc3cccc(OCc4ccccc4)c3C(=O)N(C)C)ccc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-benzyloxy-7-(2-hydroxyethoxy)-naphthalene-2-carboxylic acid methyl ester (239 mg, 0.68 mmol), triphenylphosphine (445 mg, 1.70 mmol) and DIAD (0.334 mL, 1.70 mmol) in THF (10 mL) is stirred at RT for 15 min. Then 2-benzyloxy-6-hydroxy-N,N-dimethylbenzamide (460 mg, 1.70 mmol) in THF (8 mL) is added drop wise and the mixture is stirred at RT for 18 h. The solvent is removed and the residue is purified to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13]C([C@@H]3CCCN3C(=O)[C@H](NC(=O)C)CC3C=CC(C4C=CC=CC=4)=CC=3)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:41]([NH:43][C:44](=[O:66])[NH:45][C@H:46]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)[C:47]([N:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[C:54](O)=[O:55])=[O:48])[CH3:42]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:54]([C@@H:50]3[CH2:51][CH2:52][CH2:53][N:49]3[C:47](=[O:48])[C@H:46]([NH:45][C:44]([NH:43][CH2:41][CH3:42])=[O:66])[CH2:57][C:58]3[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=3)=[O:55])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCNC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Product: CCNC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 69 %

Procedure:
Using the procedure described for example 97f 0.190 g of 1-[2-(R)-(3-ethyl-ureido)-3-(4-methoxyphenyl)-propionyl]-pyrrolidine-2-(S)-carboxylic acid was converted into 0.180 g (69%) of the title compound. (+)-APCI-MS: 519(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]([O:11][CH2:12][CH3:13])[C:9]#[N:10])=[O:6].C(N(CC)CC)C.[SH2:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]([O:11][CH2:12][CH3:13])[C:9]([NH2:10])=[S:24])=[O:6]
Reactant: S
Reactant: CCOC(C#N)NC(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(NC(=O)c1cccc(Cl)c1)C(N)=S

Procedure:
Into a solution of 3-chlorobenzoylamino(ethoxy) acetonitrile (1 g) in toluene (50 ml) containing triethylamine (1 g) was passed hydrogen sulphide gas. The precipitated product (0.72 g) was collected and crystallised from chloroform-light petroleum. m.p. 136°-137°.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:25]1([NH:24][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:20][CH2:19]2)=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)CC1
Yield: 79.2 %

Procedure:
Triethylamine (10.04 mL, 7.28 g, 72 mmol) was added to stirred, cooled (0° C.) mixture of 1-t-butoxycarbonylpiperidine-4-carboxylic acid (6.87 g, 30 mmol), aniline (2.73 mL, 2.79 g, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (9.16 g, 36 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, water (50 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 2×50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (40:60) to give the title compound as a colorless foam (7.23 g, 79%), δH (250 MHz, CDCl3) 7.51 (2H, d, J 7.6 Hz), 7.32 (2H, t, J 7.6 Hz), 7.26 (1H, br s), 7.11 (1H, t, J 7.6 Hz), 4.19 (2H, m), 2.78 (2H, m), 2.38 (1H, m), 1.90 (2H, m), 1.77 (2H, m), and 1.47 (9H, s). m/e (ES+) 305 (MH+).
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=3)[N:20]=2)[C@H:10]([CH3:28])[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[CH3:28][C@@H:10]1[CH2:9][NH:8][C@@H:13]([CH3:14])[CH2:12][N:11]1[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1c1ccc2nnc(C(F)(F)F)n2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[C@@H]1CN[C@@H](C)CN1c1ccc2nnc(C(F)(F)F)n2n1
Yield: 30.5 %

Procedure:
A solution of 6-[(2R,5S)-4-benzyl-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (6.1 g, 15.62 mmol) in ethanol (150 mL) and 5M hydrochloric acid (9.37 mL, 46.87 mmol) was hydrogenated over 10% palladium on charcoal (1 g, 9.40 mmol) under hydrogen at 1 atmosphere for 3 days. The catalyst was filtered off and the filtrate was evaporated. The residue was taken into DCM and washed with 2M aqueous K2CO3. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by MPLC silica chromatography, elution gradient 2 to 5% methanolic ammonia in DCM. Product fractions were evaporated to near dryness and crystallised from ether to afford 6-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.430 g, 30.5%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:50])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][CH:48]=[O:49])[CH2:15]2)=[CH:10][CH:9]=1.[CH3:51][Mg]Br>C1COCC1.S([O-])(O)(=O)=O.[K+]>[CH3:1][O:2][CH2:3][C@H:4]([CH3:50])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][CH:48]([OH:49])[CH3:51])[CH2:15]2)=[CH:12][CH:13]=1
Reactant: C[Mg]Br
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.0 mmol of [(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetaldehyde in 10 ml of THF are added 2.0 mmol of methyl magnesium bromide (3M in THF) at 0° C. The reaction mixture is allowed to warm to RT and stirred for 1 h, diluted with an aqueous solution of 1N potassium hydrogen sulfate and extracted with TBME. The organic phases are combined and dried over Na2SO4. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as colourless oil. Rf=0.38 (EtOAc/heptane 2:1); Rt=5.35 (gradient I).
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[N:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[H][H]>[Ni].C(O)C>[CH3:1][N:2]1[CH2:9][NH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: [H][H]
Reactant: Cn1cnc(=O)[nH]c1=O
Agent: [Ni]
Solvent: CCO
Product: CN1CNC(=O)NC1=O
Temperature: 90 °C
Yield: 59 %

Procedure:
A hydrogenation mixture consisting of 203.5 gm. (1.6 moles) of the 1-methyl-5-azauracil prepared in Part B, above, 7 teaspoons of Raney Nickel, and 8 liter ethanol in a five-gallon autoclave is subjected to 750 p.s.i. hydrogen pressure at 125° C. for an interval of 12 hours. The hydrogen is flushed out of the chamber with nitrogen gas and the reaction mixture is siphoned out of the chamber into a five-gallon carboy. The walls of the chamber are washed down with water and these washings are siphoned into the carboy. The carboy is then flushed with nitrogen (<20 p.s.i.) so as to force the medium through a filter stick onto a filter bed of Dicalite 4200 (diatomaceous earth). The solids are retained in the carboy substantially undisturbed. The medium is then sucked through the dicalite filter under reduced pressure until 1 inch of liquid remains. The solids retained in the bottom of the carboy are now mixed with two (2) liters water and 500 ml. Dicalite 4200 and this mixture is added to the filter cake. The filter cake is then washed with water. The filtrate and washings are combined and the water is removed to a volume of 1200 ml. by evaporation under reduced pressure, 20 mm mercury, and 50° C. temperature. The concentrate thus obtained is heated to 90° C., and 95% aqueous ethanol is added to a volume of two liters. Upon cooling, crystallization occurs. The crystals are collected on a filter and dried. There is thus obtained 120 gm. (59% yield) of 5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione having a melting point of 252° C. to 254° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23]O)[CH2:18][CH2:17]2)=[CH:8][CH:7]=1>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][Cl:3])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: ClCCl
Product: Fc1ccc(C(CCCN2CCC(CCCl)CC2)c2ccc(F)cc2)cc1

Procedure:
115 g of thionyl chloride were added dropwise to 23 g (61.6 mmol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxyethyl)piperidine in 100 ml of methylene chloride, while cooling with ice, and the mixture was then heated under reflux for 5.5 hours. The solvent and excess reagent were stripped off in vacuo, the residue (the hydrochloride of the product) was crystallized by addition of 450 ml of ether and the crystals were filtered off with suction, washed several times with ether and dried in vacuo.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[CH3:14]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspenson of 2,6-dichloro-3-nitropyridine (1.0 g, 0.00518 mole) and glycine ethyl ester hydrochloride (0.725 g, 0.00518 mole) in absolute ethanol (10 ml) was added triethylamine (1.05 g, 0.0104 mole). The resulting solution was stirred overnight at room temperature under nitrogen. An additional portion of absolute ethanol (10 ml) was added and the suspension was filtered and the solid was washed with 3-10 ml portions of absolute ethanol. The combined filtrate and washings were evaporated under reduced pressure at room temperature to give a yellow solid which was triturated in water (30 ml) collected by filtraton, and rinsed with additional water. The solid was recrystallized from isopropyl ether/light petroleum ether, and the resulting solid was purified by column chromatography (10 g of silica gel) with 1:1 isopropyl ether/light petroleum ether as the eluting solvent. The appropriate fraction was recrystallized from isopropyl ether and dried under high vacuum to give the title compound, mp 77.5°-80° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[CH2:16]([OH:19])[CH2:17][CH3:18]>CN(C=O)C>[CH3:15][C:5]1[C:4]([O:19][CH2:16][CH2:17][CH3:18])=[N:9][N:8]2[C:10]([NH2:13])=[N:11][N:12]=[C:7]2[C:6]=1[CH3:14]
Reactant: CCCO
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nn2c(N)nnc2c(C)c1C

Procedure:
1-Propanol (28 ml) was deprotonated analogously to W1.056 with sodium hydride (1.3 g) and reacted with 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 1 g), dissolved in 1-propanol (10 ml) and DMF (10 ml), and worked up. 647 mg of the title compound were isolated in sufficient purity.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH:5]=[C:6]2[C:10]([OH:12])=[O:11].[C:14]1([C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N+]=[N-])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:14]1([CH:20]([O:11][C:10]([C:6]2[CH:7]3[CH:3]([CH2:4][CH:5]=2)[C:2]([Cl:13])([Cl:1])[C:8]3=[O:9])=[O:12])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1=CCC2C1C(=O)C2(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2C1C(=O)C2(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
The crude 6,6-dichloro-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid (61 g) from Example 3 was stirred as a suspension in 300 mL of ethyl acetate and treated portionwise with 57 g of diphenyldiazomethane over a 45 min period. The resulting solution was stirred at room temperature for 1 hr. Evaporation of the solvent and trituration with ether afforded 76.9 g (71.9%) of 6,6-dichloro-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid diphenylmethyl ester. Material prepared by essentially the same procedure had the following characteristics: IR (Nujol mull): 1625, 1730, 1800 cm-1 ; NMR (CDCl3): δ 3.07 (1H, dddd, J=20, 8, 2, 2), 3.20 (1H, broad d, J=20), 3.64 (1H, ddd, J=8, 8, 2), 4.89 (1H, ddd, J=8, 4, 2), 6.86 (1H, s), 6.95 (1H, dd, J=4, 2), and 7.2-7.5 (10H, m). HRMS: Calcd for C21H16O3Cl2, 386.0475; found, 386.0495.