Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].[P:4]([OH:7])([OH:6])[OH:5]>O>[NH2:3][C:1]([P:4]([OH:7])([OH:6])=[O:5])([P:4]([OH:7])([OH:6])=[O:5])[CH3:2]
Reactant: CC#N
Reactant: OP(O)O
Solvent: O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 150 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A 1 liter autoclave was charged with a mixture of acetonitrile (61.5 g, 1.5 moles), ISOPAR-M (300 g), and the wetting agents (7.5 g each). The mixture was pressurized with nitrogen and heated to 150° C. Melted phosphorous acid (246 g, 3.0 moles) was pumped into the reactor through 15 minutes. The reaction was continued for 3 hours, maintaining the temperature at 150° C. Water (300 g) was pumped in and the product was collected after cooling. Colorless crystals of 1-amino-1,1-diphosphono ethane was obtained as fine grains, 76% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn2ccc(-c3ccccc3F)nc12
Temperature: 100 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (150 mg, 0.83 mmol) in 4 mL DMF/water (0.05%) was added 2-fluorophenylboronic acid (174 mg, 1.245 mmol) and cesium carbonate (812 mg, 2.49 mmol). The mixture was degassed under nitrogen during 10 minutes. PdCl2(dppf)2 (30.3 mg, 0.041 mmol) was then added. The mixture was heated in the microwave at 100° C. for 10 minutes. Water was added, the precipitate was isolated by filtration and air dried to give 5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1)=241
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[N:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:38][CH2:37][CH2:36][C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)=[O:24])=[CH:25][CH:26]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: NCCc1ccncc1
Reactant: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)NCCc4ccncc4)cc3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (47 mg, 0.12 mmol), 2-(pyridin-4-yl)ethanamine (16 mg, 0.132 mmol), HATU (50 mg, 0.132 mmol), DIPEA (18 mg, 0.144 mmol), DMAP (18 mg, 0.144 mmol) and EDCI (28 mg, 0.144 mmol) in DMF (3 mL) was stirred at room temperature for 16 h. Ethyl acetate (50 mL) was added then the mixture was washed with water (2×2 mL) and brine (2×2 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with ether and filtered to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (43 mg, 72%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.96 (s, 1H), 8.71 (t, 1H, J=5.4 Hz), 8.53-8.46 (m, 3H), 8.21 (s, 1H), 8.03-7.94 (m, 4 h), 7.67 (s, 1H), 7.42 (d, 1H, J=8.4 Hz), 7.29-7.27 (m, 2H), 7.11 (d, 1H, J=8.4 Hz), 4.01 (s, 3H), 3.78 (s, 3H), 3.60-3.54 (m, 2H), 2.90 (t, 2H, J=7.2 Hz). LC-MS: [M+H]+, 496, tR=1.226 min, HPLC: 98.86% at 214 nm, 98.46% at 254 nm, tR=3.144 min.
Reaction SMILES: [CH3:1][C@:2]12[C:11]3=[CH:12][CH2:13][C@@:14]([CH:17]=[CH2:18])([CH3:16])[CH2:15][CH:10]3[CH2:9][CH2:8][CH:7]1[C@@:6]([C:20](O)=[O:21])([CH3:19])[CH2:5][CH2:4][CH2:3]2.C(Cl)(=O)C(Cl)=O.[CH2:29]([N:31](CC)[CH2:32][CH3:33])[CH3:30].N1CCCC1>C(Cl)Cl.CN(C=O)C>[CH3:19][C@@:6]1([C:20]([N:31]2[CH2:32][CH2:33][CH2:30][CH2:29]2)=[O:21])[CH:7]2[C@@:2]([CH3:1])([C:11]3[CH:10]([CH2:9][CH2:8]2)[CH2:15][C@:14]([CH3:16])([CH:17]=[CH2:18])[CH2:13][CH:12]=3)[CH2:3][CH2:4][CH2:5]1
Reactant: C=C[C@@]1(C)CC=C2C(CCC3[C@](C)(C(=O)O)CCC[C@@]23C)C1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C[C@]1(C)CC=C2C(CCC3[C@@](C)(C(=O)N4CCCC4)CCC[C@]23C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of acanthoic acid 1 (30 mg, 0.10 mmol) in CH2Cl2 (3.0 ml) was treated with oxalyl chloride (0.013 ml, 0.15 mmol) in the presence of a catalytic amount of DMF at room temperature. The reaction mixture was stirred for 3 h at room temperature, distilled under reduced pressure, and then 3 ml of CH2Cl2 was added. Triethylamine (0.03 ml, 0.20 mmol) and pyrrolidine (0.02 ml, 0.20 mmol) were added to the reaction mixture. The reaction mixture was stirred for 30 min., quenched with water and extracted with 5 ml of CH2Cl2. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to afford 25 mg of the analog 2 (71%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]1[C:24]2([CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:23][CH2:22][NH:21]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:21]3[CH2:22][CH2:23][C:24]4([CH2:28][CH2:27][NH:26][CH2:25]4)[CH2:20]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: C1CC2(CCNC2)CN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCNC4)C3)c(F)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.3 %

Procedure:
A suspension of 0.81 g (3.0 mmol) 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 40 ml acetonitrile was treated with 0.80 g (6.3 mmol) 2,7-diazaspiro[4.4]nonane [J. Org. Chem. 46, 2757 (1981)] and the mixture stirred two days at room temperature, refluxed 1.5 hours, cooled, and filtered to afford 1.17 g of the title compound, mp 234°-240° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N-:13]=[N+]=[N-].[Na+].OS(O)(=O)=O>CC(O)=O>[CH3:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][C:7](=[O:12])[NH:13][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1SCCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc2c1SCCC(=O)N2
Temperature: 50 °C

Procedure:
To a solution of 8-methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2.24 g, 12.6 mmol) and NaN3 (1.64 g, 25.2 mmol) in AcOH (7.6 mL) was added dropwise at 50° C. conc. H2SO4 (1.9 mL). The reaction was maintained at 50° C. for 2 h and poured onto ice chips. The solid was collected by vacuum filtration and dried under vacuum at 23° C. This crude sample was a mixture of starting material, desired product and regioisomeric product with a ratio of 1:11:7 (by 1H NMR). Purification of the crude solid by column silica gel chromatography eluting with 20:1 CHCl3-MeOH provided a mixture 9-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and its regioisomer (500 mg, 4:1, by 1H NMR). This sample was used without further purification. 1H NMR (CHCl3, 300 MHz) δ7.22 (t, 1H, J=7.7 Hz), 7.15 (d, 1H, J=7.3 Hz), 6.94 (d, 1H, J=7.4 Hz), 3.39 (t, 2H, J=7.3 Hz), 2.59 (t, 2H, J=7.0 Hz), 2.54 (s, 3H) ppm.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[CH:6][CH:5]=1.O[N:31]=[C:32]([O:34][CH2:35][CH3:36])[NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:26]3[O:27][N:33]=[C:32]([O:34][CH2:35][CH3:36])[N:31]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
226 mg (0.52 mmol) of the compound from Example 40A and 109 mg (1.05 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 2.0 ml of DMF and reacted with 298 mg (0.8 mmol) of HATU and 0.27 ml (203 mg, 1.6 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 5.0 ml of dioxane and admixed with about 1 g of 4 Å molecular sieve. The mixture was heated to reflux for 16 h, and the reaction mixture was purified by means of preparative HPLC. Yield: 86 mg (30% of theory)
Reaction SMILES: [S:1]([O-:5])([O:3]O)=[O:2].[Al+3:6].[OH:7][O:8][S:9]([O-:11])=[O:10].[OH:12][O:13][S:14]([O-:16])=[O:15].OO.O=O.S(=O)=[O:22]>O.[Fe]>[S:1]([O-:5])([O-:7])(=[O:3])=[O:2].[Al+3:6].[S:9]([O-:11])([O-:12])(=[O:10])=[O:8].[S:14]([O-:16])([O-:22])(=[O:15])=[O:13].[Al+3:6]
Reactant: O=S([O-])OO
Reactant: O=S=O
Agent: [Fe]
Agent: O=O
Agent: OO
Solvent: O
Product: O=S(=O)([O-])[O-]
Reaction time: 0.3 h

Procedure:
The aluminum hydroxy sulfite precipitate is then transported by suitable means indicated by the numeral 5 to an oxidizer indicated by the numeral 6. The precipitate is reslurried in water and preferably heated between 60° C. and 90° C. Hydrogen peroxide, oxygen and air can be used as oxidizing agents, with air being preferred for economy reasons. A catalyst, such as a soluble iron compound may be needed to improve the yield. Among the satisfactory iron catalysts are ferric sulfite, ferric sulfate, ferrous sulfite and ferrous sulfate. The reaction time can be reduced to approximately 16 to 20 minutes by vigorously contacting the slurry with air. Conducting the reaction in a closed vessel reduces the escape of sulfur dioxide into the air. The reaction time may be further reduced by operating at pressures greater than atmospheric. The oxidation produces aluminum sulfate which can then be separated by conventional means from the slurry. A small amount of Al2O3 will also be produced which can be recycled through the entire process by adding it to the scrubber indicated by the numeral 2 or reacting it with sulfuric acid to form aluminum sulfate. The soluble aluminum sulfate can then be used in many commercial processes.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][SH:6].[CH2:7](Cl)/[CH:8]=[C:9](/[CH2:11][CH2:12][CH2:13][C@@H:14]([CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15])\[CH3:10].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:10][C:9]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:8][CH2:7][S:6][CH2:5][CH2:4][NH2:3]
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: NCCS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=CCSCCN)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Under an atmosphere of argon, sodium hydride (9.60 g, 240 mmol, 60% dispersion in mineral oil) was added to a solution of 2-aminoethanethiol (15.3 g, 200 mmol) in 200 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 30 minutes. To the reaction mixture, 18-crown-6 (50 mg, 0.190 mmol) was added and then a solution of phytyl chloride (1-chloro-3,7,11,15-tetramethyl-2-hexadecaene) [55.0 g, 175 mmol, prepared as described in Item a) given above] in 200 ml of tetrahydrofuran was added in dropwise for an hour at below 10° C. After stirring at 20°-30° C. for 24 hours, water was added to the reaction mixture until forming did not occur. The solvent was evaporated in vacuo to dryness and the remaining residue was extracted with ethyl ether. The ether layer was washed twice with water and an aqueous solution saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (10:1) to afford 50.9 g (81.8%) of the desired compound, as a pale brown oil.
Reaction SMILES: [CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>C(#N)C.C(Cl)Cl>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](/[N:7]=[C:5]1\[S:6][C:2]([CH3:1])=[CH:3][N:4]\1[C:8]1[CH:21]=[CH:20][C:11]2[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=2[CH:9]=1)=[O:36]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=N)S1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)C(C)(C)C)s1
Temperature: 65 °C

Procedure:
To a solution of 5-methylene-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazolidin-2-imine (Example 22C, 0.14 g, 0.44 mmol) in acetonitrile (3 mL) was added Hunig's base (0.062 g, 0.48 mmol) followed by pivaloyl chloride (0.064 g, 0.54 mmol). The mixture was heated for 12 hours at 65° C. The mixture was cooled down and more pivaloyl chloride (0.064 g, 0.54 mmol) was added. The mixture was heated again at 65° C. for 12 hours. After cooling, the reaction mixture was diluted with CH2Cl2 (50 mL) and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and dried. After evaporation under reduced pressure, the residue was chromatographed over silica using CH2Cl2-5%MeOH/CH2Cl2 to supply the titled compound. 1H NMR (CDCl3) δ ppm 1.05 (9H), 2.30 (3H), 6.80 (1H), 7.20 (1H), 7.40 (1H), 7.50 (1H); MS (ESI) m/z 405 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]([C:13]1[C:18]([F:19])=[C:17]([Cl:20])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=C)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.CCN(C(C)C)C(C)C.[O:32](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>O1CCOCC1.CO>[Cl:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C@@H:9]([N:7]([CH3:8])[C:6](=[O:21])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH:11]=[O:32])[C:18]=1[F:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CC[C@@H](c1nccc(Cl)c1F)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC=O)c1nccc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
(S)-tert-Butyl(1-(4-chloro-3-fluoropyridin-2-yl)but-3-en-1-yl)(methyl)carbamate: A solution of Intermediate 30A (0.11 g, 0.345 mmol), 4 N HCl in dioxane (3 mL), and MeOH (3.00 mL) was stirred at rt for 1 h. The reaction mixture was concentrated. The residue was re-dissolved in acetonitrile (3.00 mL) and added DIEA (0.241 mL, 1.380 mmol) followed by BOC2O (0.104 mL, 0.449 mmol). The reaction was stirred at rt for 2 h and concentrated. The residue was purified by silica gel chromatography to yield the desired product (0.11 g, 101%). MS (ESI) m/z: 314.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[F:12][C@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1N1C=C(C)C(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>[K]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:14]2[O:15][C@H:16]([CH2:19][OH:20])[C@@H:17]([OH:18])[C@@H:13]2[F:12])=[C:4]([NH2:11])[N:3]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: Nc1nc(N)c2[nH]cnc2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [K+]
Agent: [K]
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3F)c2n1
Temperature: 37 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
2,6-Diaminopurine (Pacific Chemical Laboratories, 1.0 g, 6.4 mmoles) and 1-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)thymine (C. H. Tann et al., J. Org. Chem. 50:3647, 1985; 0.3 g, 1.2 mmoles) was suspended in 100 ml of 5 mM potassium phsophate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (160,000 I.U.) and purine nucleoside phosphorylase (290,000 I.U.) (T. A. Krenitsky et al., Biochemistry, 20:3615, 1981 and U.S. Pat. No. 4,381,444) absorbed onto 69 ml of DEAE-cellulose were added and the suspension shaken at 37° C. for 1 day. The suspension was then shaken at 50° C. for 1 day at which time 2.0 g of 2,6-diaminopurine was added. After shaking for 4 additional days at 50° C., the reaction was filtered. The filter cake was washed with water and the filtrates combined and the solvent removed under vacuum. The residue was dissolved in water and applied to a 2.5×17 cm AG1X2-hydroxide (Bio-Rad) column. After washing the column with water, the product was eluted with methanol/water (9/1). The product was further purified by chromatography on silica gel with acetonitrile/water (9/1) as the solvent followed by chromatography on silica gel with chloroform/methanol/water (80/20/2) as the solvent. After the solvent was removed under vacuum, the residue was dissolved in water and lyophilization yielded 0.2 g of title compound that analysed as a 1.4 hydrate.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S([O-])([O-])=O.[Na+].[Na+].[C:27](=O)(O)[O-].[Na+].IC>O>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([CH3:27])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Temperature: 70 °C

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (18 g, 0.056 m) was added in portions to a mixture of sodium sulfite (8.8 g, 0.069 m) and sodium bicarbonate (10.8 g, 0.115 m) in water (36 ml) stirred at 70° C. There was a vigorous evolution of gas after each addition. The mixture was stirred for fifteen minutes, treated with iodomethane (8.5 ml, 0.136 m) and refluxed for forty-five minutes. The mixture was partitioned between methylene chloride and water. The methylene chloride phase was washed with water, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 159°-162° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=1)[C:14]([NH:16][CH2:17][C:18]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH2:38])=[O:37]>CS(C)=O.O>[C:36]([CH2:35][N:7]1[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=2)[C:14]([NH:16][CH2:17][C:18]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])[C:2]1=[O:1])(=[O:37])[NH2:38]
Reactant: NC(=O)CBr
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-n2ncc(=O)n(CC(N)=O)c2=O)cc1C(=O)NCC1(O)CCCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (200.0 mg, 0.537 mmol) and Cs2CO3 (290.3 mg, 0.891 mmol) were stirred in DMSO (1.79 mL, 0.3 M) at ambient temperature for 15 minutes. 2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at ambient temperature for 14 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo to a tan oil. The crude was triterated from IPE/Et2O/CH2Cl2 to give the title compound as a tan solid (105 mg). LCMS (m/z) 430.5 M+1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ccnc(-c2ccccc2)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccccc3)c2)cc1
Yield: 31.8 %

Procedure:
4-Chloro-2-phenylpyridine 1.0 g (5.5 mM), paranitrophenol (1.68 g, 12 mM), Hunig's base (diisopropylethylamine, 5 ml) and 1-methylpyrrolidone (10 ml) were stirred at 160° C. for 20 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed 5 times with water. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain 490 mg of 4-(4-nitrophenoxy)-2-phenylpyridine as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])(CC)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[B:16]([OH:19])[OH:17]
Reactant: COB(OC)OC
Reactant: Cn1ccc2ccccc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cn1c(B(O)O)cc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
1-Methylindole (0.38 mL, 3 mmol) was dissolved in THF (10 mL), and the solution was cooled to -78° C. To this solution was added sec-butyllithium (1.9 mL, 2.5 mmol), and the reaction mixture was stirred for 20 minutes. Trimethyl borate (0.34 mnL, 3 mmol) was added at -78° C., and the mixture was stirred and allowed to warm to room temperature. The reaction was quenched with water, and the solvents were removed under vacuum. The residue was taken directly to the next step.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3]1>CO.C(Cl)(Cl)Cl.C(O)(=O)C.[Pd]>[O:5]1[C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCc2ccccc2O1
Reaction time: 24 h
Yield: 83.3 %

Procedure:
A solution of ethyl 4-oxo-4H-1-benzopyran-2-carboxylate (2.0 g, 9.17 mmol) in methanol (60 ml), chloroform (25 ml) and glacial acetic acid (20 ml) was added with 10% palladium-on-charcoal and the mixture was left under stirring at room pressure and temperature for 24 h. under hydrogen atmosphere. After that, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was redissolved in ethyl ether and washed successively with a 5% sodium bicarbonate solution and a sodium chloride saturated solution. The mixture was dried and the solvent was evaporated off under reduced pressure, to obtain 1.575 g of the title product (84% yield).