Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]N)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.C=O.[C:30]([BH3-])#[N:31].[Na+].[C:34](O)(=O)C>C(#N)C>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:31]([CH3:30])[CH3:34])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: NCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 23, a solution of 8-trifluoromethyl-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and acetic acid to give 8-trifluoromethyl-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:32][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:30])([CH3:31])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(C(C)C)cc3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 6-chloro-2-(4′-isopropyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 0.9 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-2-(4′-isopropyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (351 mg, 90%) as a white solid: LC/MS m/e calcd for C27H28ClNO2 (M+H)+: 434.98, observed: 434.0.
Reaction SMILES: [K+].[Br-].[CH:3]1[C:16]2[CH:15]([CH2:17][OH:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O.[ClH:27]>O.C1COCC1>[Cl:27][C:12]1[CH:11]=[CH:10][C:9]2[O:8][C:7]3[C:16](=[CH:3][C:4]([Cl:19])=[CH:5][CH:6]=3)[CH:15]([CH2:17][OH:18])[C:14]=2[CH:13]=1
Reactant: Cl
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCC1c2ccccc2Oc2ccccc21
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1c2cc(Cl)ccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A. From 2,7-Dichloroxanthene-9-carboxylic Acid: To a suspension of 0.75 g of LiAlH4 in 90 mL of anhydrous ether was added dropwise a solution of 3.0 g of 2,7-dichloroxanthene-9-carboxylic acid in 45 mL of freshly distilled THF over a period of 25 minutes. The mixture was stirred at room temperature until the color had changed from grey to light brown (ca. 6hr). The excess LiAlH4 was decomposed by the slow addition of 10 mL of methanol and 2 mL of water while stirring. The suspended precipitate was filtered, rinsed with ether (2×30 mL) and discarded. The combined filtrate was washed with water (2×40 mL), dried over MgSO4, and evaporated under reduced pressure to give 1.53 g (53.6%) of the alcohol as a white solid. Recrystallization from Skelly B--EtOAc (4:1) gave 1.21 g (42.36%) of the 2,7-dichloro-9-xanthenemethanol as a white fluffy solid, m.p. 134.5°-136° C.; IR (KBr): 3250 (b, OH) cm-1 ; 1H NMR (CDCl3): δ 1.65 (b, 1H, OH), 3.75 (d, 2H, CH2O), 4.01 (t, 1H, CH), 6.94-7.40 (m, 6H, aryl). Anal. Calcd for C14H10O2Cl2 : C, 59.81; H, 3.59. Found: C, 60.73; H, 3.91. B. From 9-Xanthenemethanol: To a suspension of 3.0 g of 9-xanthenemethanol and 4.2 g of N-chlorosuccinimide in 25 mL of freshly distilled THF and 12.5 mL of water was added dropwise 2.0 mL of conc. HCl over a period of 5 minutes. The mixture was stirred at room temperature for 6 hours and poured into 200 mL of water with stirring. The precipitated solid was filtered, rinsed with water (2×30 mL), and dried in air to afford 3.95 g (100%) of the crude alcohol. Recrystallization from Skelly B--EtOAc (4:1) gave 1.35 g (34%) of 2,7-dichloro-9-xanthenemethanol as a fluffy solid, m.p. 134.5°-136° C., identified by the mixture melting point, IR and NMR spectral comparison with an authentic sample obtained by the reduction of 2,7-dichloroxanthene-9-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:25])([F:24])[CH2:11][CH2:12]N1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl.C(NN)(=O)C1C(=CC=CC=1)C([NH:35]N)=O>C(O)C>[CH2:1]([O:8][CH:9]([NH2:35])[C:10]([F:25])([F:24])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC(F)(F)COCc1ccccc1
Reactant: NNC(=O)c1ccccc1C(=O)NN
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCC(F)(F)C(N)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
The compound N-(4-benzyloxy-3,3-difluorobutyl)phthalimide (68.5 g, 198.6 mmoles) and hydrazine hydrate (10 g, 200 mmoles) are stirred and heated overnight in ethanol (200 mL) at 90°-100° C. A mixture of concentrated HCl (94 mL) and ethanol (1130 mL) is added, and heating (90°-100° C.) is continued for 1.5 hours. After cooling (ice bath), phthalhydrazide is removed by filtration, and the filtrate is evaporated. The residue is taken up in water and extracted with ether (2×500 mL). After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals. These dissolved in ethanol, the solution is filtered (Millipore organic) and the filtrate is evaporated to yield a residue which crystallizes on addition of ether: 34 g (68%). Evaporation of the ether extracts yields a partially crystalline material (20 g) consisting of starting material. Repetition of the hydrazine cleavage upon this mixture yields a second crop of 4-benzyloxy-3,3-difluorobutylamine (9.1 g). Total: 43.2 g (86.5%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=[O:3].[FH:13]>>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[F:13].[F:13][C:2]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=[O:3]
Reactant: F
Reactant: Cc1cccc(C)c1OC(=O)Cl
Product: Cc1cccc(C)c1F
Product: Cc1cccc(C)c1OC(=O)F
Temperature: 110 °C

Procedure:
500 ml of anhydrous hydrogen fluoride were placed at 0° C. in a stainless steel laboratory autoclave and 1000 g of 2,6-dimethylphenyl chloroformate were added dropwise. The autoclave was then sealed and heated at a maximum temperature of 110° C. for 2 hours, the pressure of the gases formed being released at 30 bar. The reaction mixture was worked up as described in Example 9. Distillation gave 2,6-dimethylfluorobenzene in a yield of 11% and 2,6-dimethylphenyl fluoroformate in a yield of 68%. The latter can be added to a new batch for the preparation of 2,6-dimethylfluorobenzene (see Example 15).
Reaction SMILES: [N:1]([CH:4]1[C@@:16]2([CH2:17][CH2:18][CH3:19])[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]2)[C:10]2[C:5]1=[CH:6][C:7]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:8]([Cl:22])[C:9]=2[Cl:21])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[ClH:21].[NH2:1][CH:4]1[C@@:16]2([CH2:17][CH2:18][CH3:19])[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]2)[C:10]2[C:5]1=[CH:6][C:7]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:8]([Cl:22])[C:9]=2[Cl:21]
Reactant: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2N
Product: Cl
Reaction time: 4 h

Procedure:
A solution of ethyl [(9-azido-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetate (2.229 g, 0.00517 mole) and triphenylphosphine (1.493 g, 0.00569 mole) in tetrahydrofuran (30 ml) was refluxed with stirring for 4 hours. Then, water (0.4 ml) was added and refluxing was continued for another 16 hours. After cooling and evaporating the solvents in vacuo, the residue was dissolved in ether, dried over sodium sulfate, filtered and the filtrate acidified with ethanolic hydrogen chloride. The solid that separated was removed by filtration, washed with hot ethanol and dried. The ethyl [(9-amino-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetate hydrochloride weighed 940 mg; m.p. 261° C.(d).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]2[CH2:40][CH2:39][CH2:38][C@H:37]2[CH2:41]O)=[O:35])=[CH:30][CH:29]=1>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]2[CH2:40][CH2:39][CH2:38][C@H:37]2[CH2:41][I:25])=[O:35])=[CH:30][CH:29]=1
Reactant: II
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CI
Reaction time: 3 h
Yield: 61.8 %

Procedure:
A solution of imidazole (310 mg, 4.5 mmol), 1.75 g (6.5 mmol) of triphenylphosphine, and 568 mg (2.2 mmol) of iodine in tetrahydrofuran (12 ml) was added under ice cooling to a solution of 504 mg (1.8 mmol) of (S)-(4-bromophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone synthesized in step (i) of Reference Example 8 in methylene chloride (40 ml), and the mixture was stirred under ice cooling for 3 hr and then at room temperature for 4 hr. The reaction solution was diluted with 60 ml of ethyl acetate and was washed with an 8% aqueous sodium hydrogencarbonate solution. The aqueous layer was washed twice with 8 ml of ethyl acetate. The organic layers were combined and were washed with 25% brine. The organic layer was dried over anhydrous sodium sulfate and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give 438 mg (yield 63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:37]([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH:26]([CH3:37])[CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 120 °C
Yield: 73.9 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.250 g, 0.485 mmol, see: Example 1) and K2CO3 (0.250 g, 1.809 mmol) in isopropanol (10 mL) was heated at 120° C. for 40 min with microwave irradiation. The reaction mixture was concentrated to dryness, was stirred in water (10 mL), filtered, washed, and dried in vacuo to provide N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (190 mg, 74.0% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 8.31 (m, 2H), 7.87 (d, J=7.8 Hz, 1H), 7.51-7.48 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 7.17 (d, J=2.3 Hz, 1H), 7.04 (dd, J=5.8, 2.3 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 4.85 (m, 1H), 1.31 (d, J=6.0 Hz, 6H); MS (ESI) m/z: 530.1 (M+H+).
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#C.[Mg].[CH2:7](Br)C#C.[CH3:11][O:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16]>CCOCC>[OH:17][C:15]([CH3:7])([CH2:14][CH2:13][O:12][CH3:11])[CH2:16][C:1]#[CH:2]
Reactant: C#CC[Mg]Br
Reactant: COCCC(C)=O
Reactant: C#CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(C)(O)CCOC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of propargylmagnesium bromide in 35 ml. of ether, prepared from 7.65 g. (0.3 moles) of magnesium, 170 mg. of mercuric chloride and 33.6 g. (0.28 moles) of propargyl bromide, is added dropwise under argon atmosphere a solution of 25 g. (0.245 moles) of 4-methoxy-2-butanone [L. R. Fedor, J. Am. Chem. Soc., 91:4, 908 (1969)] in 20 ml. of ether at a rate to maintain gentle refluxing. The resulting mixture is stirred at ambient temperature for an additional 30 minutes then quenched at 5° C. by the addition of 140 ml. of saturated ammonium chloride solution. After filtration the ether phase is separated; the aqueous phase is extracted twice with additional ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness in vacuo. Distillation of the residual oil provided 13.7 g. (40%) of product; b.p. 84°-85° C. (13 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:23][N:24]([CH2:26]N(C)C)[CH3:25]>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1)[CH3:25]
Reactant: CN(C)CN(C)C
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Solvent: CC(=O)O
Product: COC(=O)c1nc(CN(C)C)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 55 °C

Procedure:
A flask was charged with 1a (29.5 g) and acetic acid (44.3 g±5%), and then stirred. Bis-dimethylaminomethane (12.8 g±2%) was slowly added. The mixture was heated to 55±5° C. and maintained until reaction completion. The reaction product was evaluated by MS, HPLC and 1H NMR. 1H NMR (200 MHz, DMSO-d6) δ 11.7 (s, 1 H), 8.38 (d, J=9.0 Hz, 1 H), 7.61 (dd, J=9.0, 2.7 Hz, 1 H), 7.49 (m, 3 H), 7.21 (m, 3 H), 5.34 (s, 2 H), 3.97 (s, 3 H), 1.98 (s, 3 H); MS-(+)-ion M+1=368.12.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[BH4-].[Na+]>O1CCOCC1.C(O)C.O>[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[O:18][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)N=C1c1ccccc1
Reactant: Nc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)N=C(c2ccccc2)C(c2ccc(N)cc2)O1

Procedure:
48 g of 2,2-dimethyl-3-phenyl-2H-azirine and 18.5 g of p-aminobenzaldehyde were exposed to light for 2 hours in 6 liters of 1,4-dioxane in the manner described in Example 1. The solvent was then removed in a water-jet vacuum and the oily residue was chromatographed on silica gel, the elution was carried out with dichloromethane. The thus-obtained crude product (60 g) was stirred in ethanol for 2 hours at room temperature together with 1.8 g of sodium borohydride. The mixture was then diluted with water and extracted with dichloromethane. The crude product obtained after drying and evaporation of the organic phase was purified by pressure chromatography (6 bar) on silica gel with dichloromethane/ether (3:1), whereby there was obtained a product which, after 2-fold recrystallization from ethanol, yielded 5-(p-aminophenyl)-2,2-dimethyl-4-phenyl-3-oxazoline having a melting point of 162°-163° C. after drying for 4 hours 90° C. and 13 Torr.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[C:5]([N:9]=[N:10][C:11]1([N:17]=[C:18]=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([N:9]=[N:10][C:11]1([NH:17][C:18]([O:2][CH3:1])=[S:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CO
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 50 ml of methanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred 24 hours at room temperature, poured into 300 ml water and the product extracted with 100 ml pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and the pentane evaporated under reduced pressure to leave 9.2 grams of a mushy semi-solid. The semi-solid was slurried in cold pentane and filtered. The solids were dried and weighed 5.6 grams (43.5% crude yield) and melted at 79°-82° C. The infrared spectrum of the product had a strong broad band at 1530 cm-1 and a sharp NH band at 3250 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2CO3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcoEt/hexane gave a white powder (78 mg, 8.2%). mp 143-144° C.; 1H NMR (CD3OD, 400 MHz) δ1.65 (dq, J1=3.16 Hz, J2=11.9 Hz, 2H), 1.90-2.00 (m, 4H), 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[P:30]([O:42][CH2:43][C@H:44]1[O:48][C@@H:47]([N:49]2[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]2=[O:51])[C@H:46]([OH:57])[C@@H:45]1[OH:58])([O:33][P:34]([O:37][P:38]([OH:41])([OH:40])=[O:39])([OH:36])=[O:35])(=[O:32])[OH:31].C([NH+](CCCC)CCCC)CCC>CN(C=O)C.C(N(CCCC)CCCC)CCC>[OH:40][P:38]([O:37][P:34]([O:33][P:30]([O:42][P:30]([OH:33])([OH:32])=[O:31])([OH:31])=[O:32])([OH:36])=[O:35])(=[O:39])[OH:41].[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C@@H:47]1([N:49]2[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:44]([CH2:43][OH:42])[C@@H:45]([OH:58])[C@H:46]1[OH:57]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O
Temperature: 50 °C
Reaction time: 72 h

Procedure:
Uridine 5′-monrophosphate (Sigma, Milwaukee, 3.0 g, 9.26 mmol) was dissolved in dry DMF (10 mL) and tributylamine (Aldrich, 2 mL). The solution was evaporated in vacuo at 40° C. to an oil. The residue was dissolved in dry DMF (Aldrich, 8 mL) to form a solution. Carbonyldiimidazole (Aldrich, 1.65 g, 10.18 mmol) was added to this solution. The reaction was heated at 50° C. for one hour. Uridine 5′-triphosphate (Yamasa, 5.60 g, 10.18 mmol) prepared as the anhydrous tributylammonium salt in DMF (5 mL) and tributylamine (2 mL), as described in Example 3 below, was added to the reaction solution. The mixture was allowed to stir at 50° C. for three days when the solution was evaporated in vacuo to an oil, redissolved in water (5 mL) and purified by column (300×50 mm) chromatography (Sephadex DEAE-A25, 40-120μ, Aldrich, pre-swollen in 1.0 M NaHCO3 and washed with 2 column volumes of deionized H2O) (H2O→0.3 M NH4HCO3 gradient). The pure fractions were concentrated in vacuo at 35° C., and H2O added and reevaporated 5 times to obtain diuridine tetraphosphate tetrammonium salt as a white solid (2.37 g, 30% yield): 92.11% pure by HPLC with the same retention time as the standard. In addition, the tetrammonium salt was analyzed by FABMS to give a mass of [C18H25N4O23P4 (M—H+)−: calculated 788.9860] 788.9857, confirming a parent formula of C18H26N4O23P4 for the free acid].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=1[Cl:24])=[O:28]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 45.6 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (89.5 mg, 0.25 mmol), 2-chloro-6-methylbenzoic acid (47 mg, 0.28 mmol), DIEA (175 μL, 1.0 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 3:1 ethyl acetate:hexane to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (54 mg). LR(+)LSIMS : m/z 962 (2M+NH4), 945 (2M+H), 490 (M+NH4), 473 (M+H (2 Cl)).