Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Sc1ccc(Br)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSc1ccc(Br)cc1)OCC
Temperature: 55 °C
Yield: 96.5 %

Procedure:
1-Bromo-4-[(2,2-diethoxyethyl)thio]benzene (Chemical Abstracts number 96804-05-6) was prepared as described in Banfield et al.; J. Chem. Soc.; 1956; 2603-2607, and in Amin, et al.; J. Chem. Soc. Perkin Trans. 2; 1982; 1489-1492. 4-Bromothiophenol (20 g, 95%) in ethanol (80 mL) was treated with 21 wt % of sodium ethoxide in ethanol (36 g, 1.05 eq). The solution was heated at 55° C. for 30 minutes and bromoacetaldehyde diethylacetal (22.56 g, 1.05 eq) was added. The mixture was heated at reflux for 10 hours, ethanol was removed and the residue was diluted with 80 mL of water. The product was extracted with 2×120 mL of ethyl acetate. The combined ethyl acetate layer was washed with 2×40 mL of 15% NaCl and concentrated under vacuum to a brown oil (32.0 g, 92.5% potency, 96.5% yield). The product can be further purified by column chromatography (silica gel, 5:95 EtOAc:hexane).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9](O)[CH:8]2[OH:15].C(=O)([O-])[O-:17].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>S(=O)(=O)(O)O.O1CCCC1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:15][CH:8]1[CH2:9][CH:10]2[CH2:13][C:7]1([OH:17])[CH2:12][CH2:11]2
Reactant: OC1C2CCC(C2)C1O
Reactant: C1=COCCC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC12CCC(CC1OC1CCCCO1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
Into a 200 ml flask having four openings and equipped with a thermometer, a tube for introducing nitrogen gas into the flask, and a reflux tube were put 10.0 grams (0.11 mol) of 3,4-dihydro-2H-pyran, 12.8 grams (100 mmol) of norbornane-2,3-diol and 50 ml of dry tetrahydrofuran. Then, they were stirred. Then, five drops of thick sulfuric acid were added. Thereafter, the mixture was allowed to stand at a room temperature for 24 hours. After the mixture was cooled down to room temperature, 3 grams of solid sodium carbonate and 10 grams of anhydrous sodium sulfate were added to the mixture. Then, the mixture was stirred for 2 hours and filtrated. The gathered filtration was disposed with 0.2 grams of hydrogenated calcium. The residue obtained by removing excessive dihydropyran by means of a rotary evaporator under reduced pressure was refined through a silica gel column, in which ethyl acetate/n-hexane was used as an elution solvent, to thereby obtain 4.0 grams of (2-tetrahydropyranyl)oxynorbornyl alcohol. The yield was 19%. The obtained (2-tetrahydropyranyl)oxynorbornyl alcohol was oily.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:25])[F:26])=[O:19]
Reactant: [H][H]
Reactant: O=C(CC(F)(F)F)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(CC(F)(F)F)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 94.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-7-oxo-N′-(3,3,3-trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 229 (0.26 g, 0.65 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-7-oxo-N′-(3,3,3-trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 230 (0.19 g, 93.6%) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:9]/[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cccc(C)c1
Reactant: COC(OC)N(C)C
Product: Cc1cccc(C(=O)/C=C/N(C)C)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 1-(3-methylphenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.39 (3H, s), 2.79-3.11 (6H, m), 5.70 (1H, d, J=12.4 Hz), 7.24-7.31 (2H, m), 7.66-7.71 (2H, m), 7.78 (1H, d, J=12.4 Hz).
Reaction SMILES: [ClH:1].C(O)C.C([N:12]1[CH2:19][C:16]2([CH2:18][CH2:17]2)[N:15]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[ClH:1].[F:24][C:21]([F:22])([F:23])[C:20]([N:15]1[CH2:14][CH2:13][NH:12][CH2:19][C:16]21[CH2:18][CH2:17]2)=[O:25]
Reactant: O=C(N1CCN(Cc2ccccc2)CC12CC2)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(N1CCNCC12CC2)C(F)(F)F
Yield: 82.6 %

Procedure:
1 N Hydrochloric acid-ethanol (105 ml, 105 mmol) and 5% palladium carbon (3 g) were added to an ethanol (250 ml) solution of the compound (15.5 g, 51 mmol) obtained in Step 4 above and contact reduction was performed for 15 hours in a hydrogen atmosphere. The catalyst was filtrated through celite, then the filtrate was concentrated under reduced pressure, an ethanol-diethyl ether mixed solvent was added to the resulting residue, and the precipitated solid was collected by filtration to give the title compound (10.3 g, 83%) as a colorless solid.
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][CH2:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:20]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:27].[OH-].[Na+]>O.Cl.CC(O)=O>[ClH:27].[CH2:2]([O:9][CH2:10][CH2:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][NH2:20])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(F)c1CCOCc1ccccc1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NNc1cccc(F)c1CCOCc1ccccc1
Temperature: -10 °C
Reaction time: 1.25 h
Yield: 96.8 %

Procedure:
A mechanically stirred suspension of 2-(2-benzyloxyethyl)-3-fluoroaniline hydrochloride (53 g, 0.188 mole) in a mixture of water (30 mL), concentrated HCl (127 mL) and glacial HOAc (127 mL) was cooled to -10° C. (internal temperature). A solution of NaNO2 (14.27 g, 0.206 mole) in water (52 mL) was added dropwise while maintaining the internal temperature at -10° C. The resulting red solution was stirred an additional 75 minutes at -10° C. and then treated dropwise (over 30 minutes) with a solution of tin (II) chloride dihydrate (84.8 g, 0.376 mole) in concentrated HCl (97 mL) precooled to -40° C. The mixture was stirred an additional 75 minutes at -10° C. and then cooled at -15° C. and basified (to pH 14) with 50% NaOH (about 320 mL). The internal temperature was kept at - 8°/-10° C. during the addition of the base. The mixture was extracted with ether (3×). The combined extracts were washed with brine, dried (anhydrous K2CO3) and carefully acidified with ethereal HCl. Removal of the solvent provided the title compound as a tan solid (54 g, 96.9%). Trituration with light petroleum ether removed the less polar impurities and provided pure product (48.4 g, 86.8%).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[C:7]([NH:10][NH2:11])(=[O:9])[CH3:8]>C1C=CC=CC=1>[C:7]([NH:10][NH:11][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:9])[CH3:8]
Reactant: CC(=O)NN
Reactant: C=CCN=C=O
Solvent: c1ccccc1
Product: C=CCNC(=O)NNC(C)=O

Procedure:
Allyl isocyanate (25 g, 0.30 mol) was added slowly to a boiling solution of acethydrazide (22.2 g, 0.30 mol) in dry benzene (300 ml). The mixture was heated for 1 hour whereupon 2 layers formed. The benzene was then evaporated off and the residue triturated with ether to yield the title compound as a white solid. (m.p. 71°-74° C. ).
Reaction SMILES: [OH:1][C:2]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=1)([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[CH:13]=[C:12]([CH3:27])[CH:11]=2)=[CH:8][N:9]=1)[CH2:3][OH:4].CO.[OH-].[Na+].Cl>O>[OH:1][C:2]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=1)([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:20]=[CH:19][N:18]=3)[CH:13]=[C:12]([CH3:27])[CH:11]=2)=[CH:8][N:9]=1)[CH2:3][OH:4]
Reactant: COC(=O)c1ccc(C(O)(CO)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)(CO)c3ccc(C(=O)O)cc3)s2)c1
Yield: 69.1 %

Procedure:
A microwave vial was charged with the product of Step 2 (50 mg, 0.094 mmol), MeOH (666 μl) and then NaOH (700 μl, 0.700 mmol). The mixture was irradiated in the microwave for 20 minutes at 100° C. The pH was adjusted to 3-4 with 1M HCl, then diluted with water and extracted with 10% IPA/CHCl3. The combined organics were washed with water, dried (NaSO4), filtered and concentrated to afford racemic-4-{1,2-dihydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}benzoic acid (33.4 mg, 0.065 mmol, 68.6% yield). MS ESI: [M+H]+ m/z 517.1. 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.24 (s, 1H), 8.82 (d, J=4.8, 1H), 7.99 (s, 1H), 7.93-7.85 (m, 3H), 7.74 (d, J=8.3, 2H), 7.45 (s, 1H), 7.26 (d, J=4.8, 1H), 7.12 (s, 1H), 6.73 (s, 1H), 5.11 (t, J=5.8, 1H), 4.10 (dd, J=5.6, 11.2, 1H), 4.04-3.89 (m, 1H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].ClC1C=CC=CC=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCCC1
Temperature: 145 °C
Reaction time: 20 h
Yield: 285.5 %

Procedure:
2-fluoro-4-nitrophenol (36.73 g, 0.234 mol) was added to a dried chlorobenzene (5 v/w, 250 mL). The mixture was heated to 145° C. Intermediate VII (12.5 g, 0.039 mol) was added to the reaction solution. The reaction was conducted at this temperature for 20 h. After completion of the reaction, the solvent was evaporated off to produce a grey solid. This solid was dissolved in CH2Cl2, and washed with a satureated saturated K2CO3 solution several times. The organic layer was collected. The solvent was dried off to produce a solid, which is recrystallized with ethanol to produce a yellow solid (49.16 g) in a yield of 71.4%.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]([OH:31])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:16][C:15]1=[O:32])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][C:19](=[O:31])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:16][C:15]1=[O:32])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
Anhydrous CrO3 (2.274 g, 22.74 mmol) is added to a solution of anhydrous pyridine (3.597 g, 45.48 mmol) in anhydrous CH2Cl2 (60 ml). After stirring at room temperature (25° C.) for 15 mins, the reaction mixture is treated all at once with a solution of N-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one (1.432 g, 3.79 mmol) in anhydrous CH2Cl2 (25 ml). The resulting mixture is stirred at 25° C. for 5 mins. The CH2Cl2 layer is decanted from the dark, gummy residue which is triturated with more CH2Cl2. The combined CH2Cl2 phase is evaporated i.v. The residue is triturated with diethylether (Et2O) (100 ml) in several portions and the Et2O extracts are filtered to remove chromium salts. The etheral filtrate is washed with 5% NaHCO3, 1N HCl, 5% NaHCO3 and brine, dried with MgSO4, filtered, and evaporated i.v. to yield N-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (1.042 g) as a pale yellow oil:
Reaction SMILES: FC1C(O[C:9](=[O:31])[C:10]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[CH3:28])=[C:18]([F:29])[C:17]([F:30])=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[CH:11]=2)=C(F)C(F)=C(F)C=1F.Cl.C1(C[NH2:41])CC1.C(N(CC)C(C)C)(C)C.[CH2:51]1[CH2:55][O:54][CH2:53][CH2:52]1>>[CH:51]1([CH2:55][O:54][NH:41][C:9](=[O:31])[C:10]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[CH3:28])=[C:18]([F:29])[C:17]([F:30])=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[CH:11]=2)[CH2:52][CH2:53]1
Reactant: NCC1CC1
Reactant: CNC(=O)c1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2C)c(F)c1F
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(C(=O)NOCC2CC2)c(Nc2ccc(I)cc2C)c(F)c1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.8 %

Procedure:
To a suspension of 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid (0.13 g, 0.29 mmol) in N,N-dimethylformamide (5 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.055 mL, 0.32 mmol) and pyridine (0.03 mL, 0.32 mmol). After stirring for 17 hours the reaction mixture is diluted with ethyl acetate and transferred to a separatory funnel, washed twice with 1.0 M HCl, twice with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 4,5-difluoro-6-(4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid pentafluorophenyl ester (0.08g, 45.2%). To a suspension of 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid pentafluorophenyl ester (0.08 g, 0.13 mmol) in freshly distilled THF (3 mL) is added cyclopropylmethylamine hydrochloride (0.016 g, 0.13 mmol), and N,N-diisopropylethylamine (0.07 mL, 0.39 mmol). After stirring at room temperature for 17 hours the reaction mixture was partitioned between ethyl acetate and 1.0 M HCl solution. The organic layer was washed twice with water, twice with saturated brine solution, dried over MgSO4, filtered and concentrated in vacuo. Purification was performed by silica column chromatography in 2:1 ethyl acetate:hexanes affording N1-cyclopropylmethoxy-4,5-difluoro-6-(4-iodo-2-methyl-phenylamino)-N3-methyl-isophthalamide (0.033, 42.8%); mp 198–202° C.; 1H NMR (400 MHz; DMSO-d6) 8.59 (s, 1H), 8.01 (s, 1H), 7.44 (d, 1H, J=5.2), 7.32 (s, 1H), 7.18 (d, 1H, J=7.6), 6.36 (m,1H), 3.34 (d, 2H, J=6.8), 2.56 (d, 3H, J=4.0), 1.99 (s, 3H), 0.82 (m, 1H), 0.27 (d, 2H, J=8.4), 0.00 (m, 2H); MS(APCI)m+1=516;
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](=O)([O:21]C(C)(C)C)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.CN(C)C1C=CN=CC=1>[NH2:14][C:12]1[N:13]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][N:4]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:3][CH2:2]2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc(CN2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-(piperazin-1-ylmethyl)pyridin-2-amine 85 in THF was added di-tert-butyl carbonate (1 eq) and 4-(dimethyl)aminopyridine (catalytic). The reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. Pentane was added and the resulting solid was collected by filtration and dried to afford 86. The Boc protecting group could be removed after coupling with the appropriate carboxylic acid by treatment with TFA/CH2Cl2 for 12 h.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:12][O:13][C:14](=[O:29])[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])[C:16]([CH3:18])=O>>[CH3:12][O:13][C:14]([C:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]([CH3:11])[C:8]=2[NH:10][C:16]=1[CH3:18])=[O:29]
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Reactant: CCCCc1cc(N)n(C)n1
Product: CCCCc1nn(C)c2c1C(c1ccccc1[N+](=O)[O-])C(C(=O)OC)=C(C)N2

Procedure:
Starting from 3-butyl-1-methyl-5-pyrazolamine and methyl-2-(2-nitrobenzyliden)acetoacetate in equimolar proportions.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[C:12]([OH:15])=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].O[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1cccc2onc(O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)COc1cccc2onc(OCC3CCN(C(=O)OC(C)(C)C)CC3)c12

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using 4-isobutoxy-1,2-benzisoxazol-3-ol (EXAMPLE 8, Step 2) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([C@H:8]2[C@@:12]([F:14])([CH3:13])[C@H:11]([OH:15])[C@@:10]([F:18])([CH2:16][OH:17])[O:9]2)[CH:7]=1.C([Mg]Cl)(C)(C)C.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][P:39](=[N:41][C@@H:42]([CH3:49])[C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[O:40].CO>C1COCC1>[CH:46]([O:45][C:43](=[O:44])[C@@H:42]([N:41]=[P:39]([O:38][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[O:17][CH2:16][C@:10]1([F:18])[C@@H:11]([OH:15])[C@:12]([F:14])([CH3:13])[C@H:8]([N:6]2[CH:7]=[C:2]([Br:1])[C:3](=[O:20])[NH:4][C:5]2=[O:19])[O:9]1)=[O:40])[CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1Cl
Reactant: C[C@]1(F)[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Agent: CC(C)(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1OC[C@@]1(F)O[C@@H](n2cc(Br)c(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
To a solution of chiral 5-bromo-1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (92 mg, 0.26 mmol) prepared in Preparation 7 in THF (3 ml) at 0° C. was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (0.64 mL, 0.64 mmol) dropwise. The mixture was stirred at 0° C. for 15 min, followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate prepared in Example 3 Step B (1.29 mL, 0.64 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (5-10% MeOH in DCM) to give the title compound as a white solid (56 mg, 32%).
Reaction SMILES: [Li]CCCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[O:20].Cl>CCOCC.O.C1COCC1>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)[OH:20]
Reactant: Brc1ccccn1
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OC(c1ccccn1)c1ccccn1
Temperature: -10 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 80 mL n-BuLi in hexanes (2.5 M, 0.2 mol) was added 2-pyridylbromide (31.6 gram 0.2 mol) in 100 mL of ether at −80° C.-−60° C. The suspension was stirred for 1 h, and the temperature was allowed to rise to −45° C. Subsequently 2-pyridinecarboxaldehyde (21.42 gram 0.2 mol) in of ether (100 mL) was added during 30 min. To the thick slurry was added additional THF (200 mL) and the mixture was stirred for 1.5 h at −40° C.-−30° C. and then the mixture was allowed to warm up to −10° C. The mixture was poured into water (200 ml) and acidified with 2 M HCl to pH=1-2 and the layers were separated. The aqueous layer was extracted twice with ether (100 mL) and neutralized with saturated Na2CO3(aq) to pH=8. The aqueous layer was extracted CH2Cl2 (3×100 ml). Drying (Na2SO4) and evaporation of the solvent yielded a brown oil. Vacuum distillation (118° C., 0.2 mmHg) afforded di(2-pyridinyl)methanol (19.42 gram, 104.4 mmol, 52%) as a yellow oil. 1H-NMR (200 MHz. CDCl3) δ 5.88 (s, 2H), 7.11-7.19 (m, 2H), 7.47-7.67 (m, 4H). 8.50-8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 75.0 (d), 121.0 (d), 122.5 (d), 136.8 (d), 1448.1 (d), 160.7 (s).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)#[N:2].[OH-].[K+].N1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN(C([O:41]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCO.O.C(OCC)(=O)C>[CH:19]1([NH:18][C:16](=[O:17])[C:15]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[C:3]([C:1]([N:2]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:41])=[N:4][N:5]=[CH:6]4)[CH:14]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C1COCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C#N)nncc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C(=O)N3CCOCC3)nncc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-(1-Cyanophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (115 mg, 350 μmol) was dissolved in EtOH/water (1:1) (3.50 mL) with potassium hydroxide (39 mg, 700 μmol) and heated in a microwave oven for 15 min at 120° C. The reaction mixture was concentrated in vacuo and dissolved in DMF (700 μl) and morpholine (152 μl, 1751 μmol) to which HATU (399 mg, 1051 μmol) was added. The reaction was stirred at RT for 16 h, then diluted with ethyl acetate, filtered, diluted with 50 mL ethyl acetate, and partitioned with sodium bicarbonate (saturated, aqueous). The organic layers were washed 2×20 mL with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography to give the title compound. MS (ES+): 417 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5])(=[O:22])=[O:21]
Reactant: CC(C)(CO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-2-phenylpropan-1-ol (51) (8.5 g, 56.6 mmol, Eq: 1.00) was stirred in dichloromethane (90.4 ml) at 0° C., triethylamine (6.87 g, 9.46 ml, 67.9 mmol, Eq: 1.2) and then methanesulfonyl chloride (7.13 g, 4.82 ml, 62.2 mmol, Eq: 1.1) were added over 3 minutes. The reaction mixture was stirred at 0° C. for 30 minutes, removed from the ice bat h and allowed to warm to room temperature and stirred for 15 hours. The reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate, and brine, and dried with magnesium sulfate. The solvent was removed on a rotary evaporator to give 2-methyl-2-phenylpropyl methanesulfonate (52) as a clear oil, (12.0 g, 93%).