Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](O)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:14][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Temperature: 47 °C

Procedure:
A 150 mL flask is charged with 2,4-dihydroxy-3-nitropyridine (Compound XII) (10.0 g, 0.064 mole), and toluene (30 mL). The mixture is stirred at moderate speed and warmed to 47° C. Phosphorus oxychloride (POCl3) (4.4 g, 0.0289 moles) is added over 10 minutes, via a syringe pump, giving an exotherm to 49° C. N,N-diisopropylethylamine (DIPEA) (2.22 g, 0.017 moles) is added over 10 minutes, giving an exotherm to 51° C. Another portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by another portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes. A third portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by a third portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes, followed by a final portion of POCl3 (4.4 g, 0.0289 moles) over 10 minutes (total POCl3 added is 17.7 g), then by a final portion of DIPEA (2.22 g, 0.017 moles) over 10 min. (total DIPEA added is 8.9 g). The reaction is then stirred at 50° C. for 5 hr until IPC indicates complete consumption of Compound XII. The reaction is allowed to cool to 20° C. over 30 minutes and 50 mL of water is added over 1.5 hr allowing the temperature to rise to 47° C. This mixture is stirred for four hours while cooling to 25° C. The batch is filtered washing twice with 15 mL of water, then twice with 15 mL of toluene. The product is dried to give Compound II.
Reaction SMILES: [C:1](ON1C(=O)CCC1=O)(=[O:3])[CH3:2].[NH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[N:29]=[N:30][C:31]([N:34]([CH3:45])[CH:35]4[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]4)=[CH:32][CH:33]=3)[C:23]([OH:27])=[CH:24]2)=[CH:19][CH:18]=1.CCOCC>CS(C)=O>[OH:27][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][NH:12][C:1](=[O:3])[CH3:2])=[CH:26]2)=[CH:21][C:22]=1[C:28]1[N:29]=[N:30][C:31]([N:34]([CH3:45])[CH:35]2[CH2:40][C:39]([CH3:41])([CH3:42])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]2)=[CH:32][CH:33]=1
Reactant: CC(=O)ON1C(=O)CCC1=O
Reactant: CN(c1ccc(-c2cc3ccc(OCCCN)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)NCCCOc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
N-Acetoxysuccinimide (98 mg, 0.624 mmol) was added to a solution of Example 20-5 (50 mg, 0.108 mmol) and TEA (0.747 ml, 5.39 mmol) in DMSO (2 ml) at RT. The reaction mixture was stirred at RT for 30 min then concentrated in vacuo to remove excess Et3N. The resulting residue was purified by preparative HPLC (eluting with 5-80% MeCN/H2O with 0.1% TFA modifier). The appropriate fractions containing product were combined then adsorbed onto a MeOH conditioned SCX column (5 g, BSA Varian brand). The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH. Evaporation of the solvent afforded a yellow oil. Et2O was added to the oil then concentrated to dryness affording the title compound as a yellowish orange solid (30 mg, 55% yield). LCMS Rt=0.52 min (LCMS method Q); MS (M+1)=506.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (br. s, 1H), 8.35 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.77 (d, J=9.09 Hz, 2H), 7.35 (d, J=9.60 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=2.02 Hz, 1H), 6.95 (dd, J=9.09, 2.53 Hz, 1H), 4.92-5.04 (m, 1H), 4.11 (t, J=6.32 Hz, 2H), 3.20-3.28 (m, 2H), 2.98 (s, 3H), 1.87-1.96 (m, 2H), 1.82 (s, 3H), 1.55-1.63 (m, 2H), 1.44-1.55 (m, 2H), 1.30 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>CCO.O>[N+:8]([C:7]1[C:2]([NH:17][C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@@H](Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Yield: 69.2 %

Procedure:
2-Chloro-3-nitropyridine (500 mg, 3.15 mmol) was dissolved in EtOH (12.5 ml), added potassium carbonate (435 mg, 3.15 mmol) and to this mixture (S)-2-aminopropanoic acid (561 mg, 6.3 mmol) in 2.5 ml water was added and refluxed for overnight. Reaction mixture cooled to 0° C. to obtain the solid. Then EtOH was removed on rotavapour and acidified with 2N HCl and solid filtered and dried on vacuum to obtain the title compound (460 mg) as an yellow solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH3:2].C(P(CCCC)CCCC)CCC.[I-:34].[K+].CN(C=O)C>C1(C)C=CC=CC=1.[Ni](Br)Br>[CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([I:34])=[CH:7][CH:8]=2)[CH3:2]
Reactant: [I-]
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Agent: Br[Ni]Br
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC1(CC)c2cc(I)ccc2-c2ccc(C=O)cc21
Yield: 75 %

Procedure:
A mixture of 9,9-diethyl-7-bromofluorene-2-carboxaldehyde, (28.8 g., 0.0875 mol.), nickel (II) bromide (2.1 g., 9.6 mmol.), tri-n-butyl phosphine (4m1, 16 mmol.), potassium iodide (52.0 g., 0.3132 mole, 3.6 equivalents), and DMF (125 ml), was held at reflux under an atmosphere of nitrogen for 15 hours, cooled, diluted with toluene (450 ml), and filtered. The filtrate was washed with water in several portions, dried, and concentrated. The residual solids were recrystallized from toluene-heptane (1:2, 150 ml); 24.79 g., m.p. 138-140° C., (75% yield). When the reaction was run longer, 24 and 34 hours, the yields fell to 61 and 59% respectively. Mass Spec (m/z): 376 (M+), not contaminated with the bromo aldehyde. Anal.Calcd. for C18H17Ol: C, 57.46; H, 4.55; and l, 33.73%. Found: C, 58.04 and 58.02; H, 4.72 and 4.66; and l, 32.62 and 32.89.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:19])=[C:16]([NH2:18])[N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:19])=[C:16]([NH:18][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])[N:17]=3)[CH:14]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(COc2ccc3nc(N)c(C)n3c2)cc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)c(C)n3c2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of 6-[(4-methoxybenzyl)oxy]-3-methylimidazo[1,2-a]pyridin-2-amine (1.0 g, 3.53 mmol) in N,N-dimethylacetamide (10 mL) was added cyclopropanecarbonyl chloride (352 μL, 3.88 mmol), and the mixture was stirred at 0° C. for 2 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (750 mg, 60%) as a slightly-yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:23]=[C:22]([OH:24])[C:21]([CH3:25])=[CH:20][CH:19]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[OH:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][N:14]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:19]=[CH:20][C:21]=1[CH3:25]
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: Cc1ccc(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A mixture of 0.15 g (0.66 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.1 g (0.78 mmol) of 5-amino-o-cresol and 0.075 g (0.66 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water, diethyl ether, methylene chloride, tetrahydrofuran and dried in vacuo to yield 0.17 g of 8-(3-hydroxy-4-methyl-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as white solid, mp 257-260° C. (dec).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:18])[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:18])[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nc(O)cc(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(Cl)cc(-c2cccnc2)n1
Temperature: 50 °C

Procedure:
Under inert atmosphere, 27 g 6-hydroxy-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine in 125 mL phosphorous oxychloride is suspended, and 11.5 g potassium carbonate is added portionwise. The mixture is heated to 50° C. for 6 hours under stirring. At the end of the reaction, the suspension is concentrated to residue, it is diluted with water, cooled, and the precipitate is filtrated. Upon drying, 26.6 g of product with HPLC purity of 80% (A %) is achieved, identified through LC-MS and 1H-NMR. Such raw product also contains a by-product, in an amount of about 15% (A %) which, during the following reduction reaction, still yields the desired product (4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine). The raw material, therefore, is employed as is in the example 13.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([NH2:19])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17](=[S:29])[NH2:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Yield: 64.7 %

Procedure:
A solution of the compound (4.00 g, 15.31 mmol) obtained in step 3 and Lawesson's reagent (6.19 g, 15.31 mmol) in THF (50 mL) was stirred at 50° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 2→65% ethyl acetate/hexane) to give 1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide (2.75 g, 9.91 mmol, 65%) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([O-])=O.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]([N:20]=[N+:21]=[N-:22])=[O:19])[N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-benzyl-3-(4-hydrazinocarbonyl-1,2,3-triazol -1-yl)pyrrolidine (3.6 g, 0.0125 mol) was dissolved in hot water (40 ml) and then cooled to 0° C. To the cooled suspension NaNO2 (950 mg, 0.0137 mol in 3 ml of water) was added dropwise and then glacial AcOH (7 ml) was added to the reaction mixture was stirred at 0° C. for 15 min. Reaction mixture was then neutralized by the addition of saturated NaHCO3. The separated white solid was filtered and washed with water, dried in vacuum oven. Yield: 3.73 g (100%), m.p. 160° C. 1H NMR (CDCl3) δ: 1.95-2.15 (m, 1H), 2.37-2.83 (m, 3H), 2.94-3.22 (m, 2H), 3.70 (d, 2H), 5.75-5.87 (m, 1H), 7.30 (s, 5H), 8.47 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Yield: 37.5 %

Procedure:
A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg, 3.0 mmol; 38% yield). MS (DCl/NH3): 266 (M+1)+, 283 (M+18)+.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:9]2[C:8]=1[N:7]=[C:12]([C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)[C:11]([CH:1]=[O:4])=[CH:10]2
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc2cc(C=O)c(-c3cccnc3)nc12
Yield: 281.9 %

Procedure:
Prepared according to the procedure described for Intermediate 1, utilising Intermediate 32 (10 g, 48.7 mmol), Na2CO3 (7.74 g, 73 mmol), 3-pyridylboronic acid (5.98 g, 48.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.81 g, 2.43 mmol) in DME (150 mL) and water (40 mL). The title compound (11.36 g, 94%) was obtained as a brown solid. δH (CDCl3) 10.20 (s, 1H), 9.02 (dd, J 2.3, 0.8 Hz, 1H), 8.86 (s, 1H), 8.80 (dd, J 4.9, 1.7 Hz, 1H), 8.10 (ddd, J 7.9, 2.3, 1.7 Hz, 1H), 7.90 (d, J 8.3 Hz, 1H), 7.78-7.75 (m, 1H), 7.58 (dd, J 8.1, 7.2 Hz, 1H), 7.53 (ddd, J 7.9, 4.9, 0.8 Hz, 1H), 2.88 (s, 3H). LCMS (ES+) 249 (M+H)+, RT 1.41 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11]O)[CH:5]=[C:6]([F:8])[CH:7]=1.P(Br)(Br)[Br:14].O>CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[CH2:11][Br:14])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OC/C=C/c1cc(F)cc(Br)c1
Solvent: CCOCC
Solvent: O
Product: Fc1cc(Br)cc(/C=C/CBr)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4.2 g (0.0182 mol) of (E)-3-(3-bromo-5-fluorophenyl)-2-propen-1-ol in 65 ml of anhydrous ether is cooled to 0° C. under a nitrogen atmosphere. 3.3 g (0.0121 mol) of phosphorus tribromide are added dropwise and then the mixture is stirred for 1 h at 0° C. and left to return to room temperature overnight. The mixture is poured into water and extraction with ether, washing with water, drying over sodium sulphate, filtration and concentration under vacuum are carried out.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[C:29]([O:32][CH2:33][C:34]([N:12]1[C:11]2=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]2[CH2:15][CH2:14][NH:13]1)=[O:35])(=[O:31])[CH3:30]
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(=O)OCC(=O)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (100 mg, 0.339 mmol) and pyridine (54 mg, 0.678 mmol) in N-methyl-2-pyrrolidone (1.5 ml) was added acetoxyacetyl chloride (60 mg, 0.441 mmol) in N-methyl-2-pyrrolidone (0.5 ml) under nitrogen atmosphere with ice cooling. After stirring for 30 minutes, the reaction mixture was diluted with an aqueous saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:dichloromethane/methanol; 100/1~20/1) and the obtained amorphous product was crystallized from diisopropyl ether to give 2-acetoxyacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo-[5,1-c][1,2,4]triazine (76 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@:11]1([C:31]2([OH:35])[CH2:34][CH2:33][CH2:32]2)[CH2:15][C@H:14]([N:16]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C@@H:17]2[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]2)[CH:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>CN(C1C=CN=CC=1)C.ClCCl>[C:45]([O:35][C:31]1([C@@:11]2([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:15][C@H:14]([N:16]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[C@@H:17]3[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]3)[CH:13]=[CH:12]2)[CH2:32][CH2:33][CH2:34]1)(=[O:47])[CH3:46]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(OC(C)=O)CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a stirred solution of 3.58 g (7.2 mmol) of 1,5-anhydro-3-{[(1S,4R)-4-[(benzyloxy)carbonyl]-4-(1-hydroxycyclobutyl)cyclopent-2-en-1-yl](trifluoroacetyl)amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol, 1.6 mL (9.2 mmol) of diisopropylethylamine, and 100 mg (0.82 mmol) of DMAP in 10 mL of dichloromethane was added dropwise 5.1 mL (72 mmol) of acetyl chloride. The solution was stirred at ambient temperature for 18 h, then cooled in ice and quenched with aqueous NaHCO3. The aqueous phase was extracted with additional dichloromethane, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 8-10% ethyl acetate in dichloromethane provided 2.63 g (68%) of the title compound as a viscous yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35-1.48 (m, 1H) 1.54-1.61 (m, 1H) 1.82-1.94 (m, 1H) 1.88 (s, 3) 2.17-2.26 (m, 1H) 2.34 (dd, J=14.7, 9.9 Hz, 1H) 2.43-2.64 (m, 5H) 3.32 (d, J=12.6 Hz, 1H) 3.37-3.43 (m, 1H) 3.43 (s, 3H) 3.46-3.55 (m, 1H) 3.84-3.94 (m, 1H) 4.09-4.15 (m, 1H) 4.19 (d, J=13.0 Hz, 1H) 4.98-5.05 (m, 1H) 5.08 (d, J=12.3 Hz, 1H) 5.23 (d, J=12.3 Hz, 1H) 5.75 (dd, J=5.8, 2.0 Hz, 1H) 6.16 (dd, J=5.8, 2.4 Hz, 1H) 7.28-7.43 (m, 5H). TLC Rf 0.39 (10% ethyl acetate-dichloromethane). LC-MS ES+ 540.2.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[Si](C(C)C)(C(C)C)C(C)C)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].B(O)(O)O>C1COCC1.O>[C:1]1([S:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(S(=O)(=O)c3ccccc3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OB(O)O
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc2cc[nH]c2c1
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 6-phenylsulfonyl-1-triisopropylsilanyl-1H-indole 0.365 g, 0.88 mmol) in THF (10 mL) was added a solution of TBAF in THF (1 M, 1 mL) followed by a solution of boric acid (0.062 g, 1 mmol) in water (1 mL) and stirring was carried out for 2 h. The mixture was partitioned between water (50 mL) and DCM (3×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% EtOAc in petrol) gave the title compound (0.21 g) as a colourless solid. MS: [M+H]+=258.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17]([O:19]C(C)(C)C)=O)[C:6]1=[O:24].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[CH2:8][C@H:7]([NH:16][C:17](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:24]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)NCc2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 164.4 %

Procedure:
A solution of 600a/103 (400 mg, 1.1 mmol) and benzylisocyanate (166 mg, 1.2mmol) in 10 ml of CH2Cl2 and 10 ml of DMF and heated at 80° C. for 3 days. The reaction was cooled to RT poured onto H2O and extracted with EtOAc (2×). The combined organic layers were washed with H2O (4×) and sat. aq. NaCl, dried over MgSO4 and concentrated in vacuo. Chromatography (flash, SiO2, 50% to 80% EtOAc/hexane) gave 440 mg (80%) of 602p as a white solid.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)=[CH:19][C:18]=1O.N1C=CC=CC=1>C(Cl)Cl>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:18]1[CH:19]=[C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)[CH:21]=[CH:22][C:17]=1[CH3:16])(=[O:4])=[O:3]
Reactant: Cc1ccc(C2(C)COC2)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C2(C)COC2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tf2O (3.07 mL, 18.2 mmol) was added dropwise to a solution of 2-methyl-5-(3-methyloxetan-3-yl)phenol (2.70 g, 15.2 mmol) and pyridine (1.71 mL, 21.2 mmol) in DCM (25 mL) at 0° C. The red/orange mixture was stirred at 0° C. for 1.5 h, then partitioned between DCM and water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/heptane) to provide 2-methyl-5-(3-methyloxetan-3-yl)phenyl trifluoromethanesulfonate. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.38 (d, J=8.08 Hz, 1 H) 7.26 (dd, J=7.96, 1.89 Hz, 1 H) 7.14 (d, J=1.77 Hz, 1 H) 4.89 (d, J=5.56 Hz, 2 H) 4.66 (d, J=5.81 Hz, 2 H) 2.41 (s, 3 H) 1.75 (s, 3 H).