Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[CH:21]12[O:26][CH:22]1[CH2:23][CH2:24][CH2:25]2>C1COCC1>[CH2:1]([N:3]1[C:7]([C@H:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[OH:26])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cccn1
Reactant: C1CC2OC2C1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nccc1[C@H]1CCC[C@@H]1O
Yield: 16.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-ethylpyrazole (97%, 2.53 g, 25.5 mmol), N,N,N′,N′-tetramethylethylenediamine (3.83 mL, 25.5 mmol), butyl lithium (1.63 M solution in hexane; 18.3 mL, 29.8 mmol), cyclopentene oxide (2.66 g, 31.6 mmol) and THF (60 mL), to yield the title compound (750 mg, 16%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:11](I)=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])[CH:2]=[CH2:3]>CC#N.CCN(CC)CC>[F:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][O:4][CH2:1][C:2]2=[CH2:3]
Reactant: C=CCOCc1c(F)cccc1I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C1COCc2c(F)cccc21
Temperature: 80 °C

Procedure:
2-(Allyloxymethyl)-1-fluoro-3-iodobenzene (1 g) was dissolved in 20 mL of CH3CN and 2.4 mL of Et3N. The reaction solution was vacuum degassed three times, followed by the addition of Pd(OAc)2 (37.6 mg) and PPh3 (89.8 mg). The resulting mixture was heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with Et2O. The organic layer was washed with 1N HCl, 10% aqueous NaHCO3, brine, and then dried over Na2SO4. After filtration, the filtrate was concentrated to dryness to offer a brown oil, which was purified by flash chromatography to offer 200 mg of the title compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[NH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NC(C)(C)C
Agent: [Pd]
Product: COC(=O)c1c(N)cccc1S(=O)(=O)NC(C)(C)C
Yield: 86 %

Procedure:
A solution of 8.00 g (25.3 mmol) of methyl 2-[(tert-butylamino)sulfonyl]-6-nitrobenzoate is admixed with 3.2 g of palladium on activated carbon (5%) and hydrogenated at room temperature and under atmospheric pressure for 6 h. The reaction mixture is then filtered, the filtrate is concentrated to dryness and the residue is purified by silica gel chromatography [TLC (SiO2)ethyl acetate/n-heptane 1:1; Rf=0.38] using ethyl acetate/n-heptane (1:1). Evaporation gives 6.23 g (86% of theory) of methyl 2-amino-6-[(tert-butylamino)sulfonyl]benzoate as a beige solid of melting point 132-133° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[O:7]=[C:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH2:14][S:15][C@@H:16]3[C@H:27]([NH:28]C(=O)COC4C=CC=CC=4)[C:26](=[O:39])[N:17]3[C:18]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[O:9]1.CN1CCOCC1.CO>ClCCl.O>[NH2:28][C@@H:27]1[C:26](=[O:39])[N:17]2[C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:13]([C@H:10]3[O:9][C:8](=[O:7])[CH2:12][CH2:11]3)[CH2:14][S:15][C@H:16]12
Reactant: CC(C)(C)OC(=O)C1=C([C@@H]2CCC(=O)O2)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C([C@@H]2CCC(=O)O2)CS[C@@H]2[C@H](N)C(=O)N12
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 40.1 %

Procedure:
Phosphorus pentachloride (0.35 g,1.7 mmol) in dichloromethane (9 ml) was added to t-butyl (6R,7R)-3-[(5S)-2-oxotetrahydrofuran-5-yl]-7-phenoxyacetamido-ceph-3-em-4-carboxylate (0.526 g, 1.1 mmol) and N-methylmorpholine (0.24 ml, 2.2 mmol) in dichloromethane (15 ml) at <-20° C. The reaction was stirred at -15±5° C. for 0.75 h then methanol (3 ml) was added. Stirring was continued for 0.75 h without further cooling and then water (10 ml) was added and the mixture was stirred vigorously for 1 h. The dichloromethane was removed in vacuo, ethyl acetate (ca 10 ml) added, the mixture adjusted to pH5.5 with dilute ammonium hydroxide solution and extracted twice with ethyl acetate. The extracts were washed with brine, dried, concentrated and flash chromatographed, eluting with 40,50,75% ethyl acetate in hexane, to give the title compound as a foam (0.15 g,40%); (Found: M+, 340.1097. C15H20N2O5S requires M, 340.1093); νmax (CH2Cl2) 1770,1710,1362,1350,1235 and 1170 cm-1 ; δH (CDCl3) 1.54 (9H,s), 1.9-2.1 (1H,m), 2.5-2.8 (3H,m), 3.27 and 3.56 (2H,ABq,J18.5 Hz), 4.80 (1H,d,J5Hz), 4.96 (1H,d,J5 Hz), 5.6-5.7 (1H,m).
Reaction SMILES: [H-].[Na+].[Cl:3][CH:4](C(C)=O)[C:5]([O:7]CC)=[O:6].Br[CH2:14][C:15]1[O:19][C:18]([CH3:20])=[N:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>CN(C)C=O>[Cl:3][CH:4]([CH2:14][C:15]1[O:19][C:18]([CH3:20])=[N:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(Cl)cc2)c(CC(Cl)C(=O)O)o1
Temperature: 0 °C

Procedure:
60% Suspension of sodium hydride (1.08 g) in oil was added portionwise to a solution of ethyl 2-chloroacetoacetate (4.4 g) in N,N-dimethylformamide (70 ml) under stirring and ice-cooling. After stirring for 10 minutes, a solution of 5-bromomethyl-4-(4-chlorophenyl)-2-methyloxazole (7.0 g) in N,N-dimethylformamide (10 ml) was added dropwise under ice-cooling to the mixture. The mixture was stirred under ice-cooling for 30 minutes, and then diluted with ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was dissolved in ethanol (40 ml), added to an aqueous 2N sodium hydroxide solution (40 ml) under stirring and ice-cooling, and stirred for further 30 minutes. The solution was then diluted with water, washed with ethyl ether and the aqueous layer was adjusted to pH 2 with 2N hydrochloric acid to give crystals of 2-chloro-3-[4-(4-chlorophenyl)-2-methyl- 5-oxazolyl]propionic acid, yield 5.9 g (80.4 %). Recrystallization from methanol gave colorless prisms, m.p. 208°-209° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]2[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[CH2:2][O:1]2)=[CH:14][CH:15]=1
Reactant: CC(CO)(CO)C(=O)O
Reactant: COc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COc1ccc(C2OCC(C)(C(=O)O)CO2)cc1
Temperature: 22.5 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
2,2-bis(hydroxymethyl)propionic acid (10 g) and anisaldehyde dimethyl acetal (20.4 g) were added to acetone (50 ml) at 20-25° C. p-Toluenesulfonic acid (0.51 g) was added to the reaction mixture and stirred at 20-25° C. for 5 hours. The mixture was then cooled to 0-5° C. and stirred for 1 hour. The slurry was filtered and the solid was washed with chilled (0-5° C.) acetone (10 ml). The solid was dried under vacuum at 45-50° C. for 4 hour. The solid was added to toluene (150 ml) and the resulting mixture was heated at 65-70° C. for 2 hours. The mixture was then cooled to 5-10° C. and stirred for 30 minutes. The slurry was filtered and the solid was washed with toluene (10 ml) followed by drying under vacuum at 30-35° C. for 4 hours to obtain title compound (14.0 g, 74.4%).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]([CH2:21][C:22]([O:24]CC)=[O:23])[N:19]=[CH:18][CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]([CH2:21][C:22]([OH:24])=[O:23])[N:19]=[CH:18][CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nccc1-c1nc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1nccc1-c1nc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 5) from ethyl (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)acetate and aqueous NaOH. 1H NMR (500 MHz, acetone-d6): δ7.68 (d, 1H), 7.62 (dd, 1H), 7.14-7.08 (m, 2H), 6.76 (td, 1H), 5.49 (s, 2H), 4.93-4.89 (m, 1H), 3.81-3.74 (m, 2H), 3.66-3.55 (m, 2H), 2.16-2.10 (m, 2H), 1.98-1.88 (m, 2H). MS: m/z 466, 468 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]([NH2:18])=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH2:18])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: Nc1cc(OCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(OCCCN2CCCCC2)cc1N
Yield: 100.1 %

Procedure:
200 mg of 4-fluoro-2-nitro-5-(3-piperidin-1-ylpropoxy)-phenylamine in solution in 15 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 20 mg of palladium-on-charcoal at 25° C. for 10 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 180 mg of 4-fluoro-5-(3-piperidin-1-ylpropoxy)benzene-1,2-diamine are obtained in the form of a black oil. The product is used without any other purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:9]1[S:10][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:9]1[S:10][C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]([CH2:14][OH:15])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1CO
Reaction time: 15 h
Yield: 81.9 %

Procedure:
Ethyl 2-[bis(tert-butoxycarbonyl)amino]-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole-5-carboxylate obtained in Example (62b) (2.87 g, 5.55 mmol) was dissolved in THF (60 mL). TBAF (1 M solution in THF, 9.3 mL) and acetic acid (0.48 mL, 8.39 mmol) were added, followed by stirring for 15 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 70/30) to obtain 1.83 g of the title compound as a white solid (82%).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:6]([NH2:7])=[CH:5][C:4]=1F)#[N:2].[CH2:14]([N:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1)[CH3:15].C(N(C(C)C)CC)(C)C>>[CH2:14]([N:16]1[CH2:20][CH2:19][CH:18]([O:21][C:4]2[C:3]([C:1]#[N:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=2)[NH2:7])[CH2:17]1)[CH3:15]
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reactant: CCN1CCC(O)C1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(Oc2cc(N)c([N+](=O)[O-])cc2C#N)C1
Temperature: 140 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To 183 mg of 4-cyano-3-fluoro-6-nitroaniline (which was synthesized following J. Med. Chem. 1994, 37, 467) and 201 mg of 1-ethyl-3-pyrrolidinol, 0.5 ml of diisopropylethylamine was added and stirred for 3 hours at 140° C. The reaction liquid was cooled to room temperature, and concentrated after addition of chloroform-methanol (1/1). The residue was separated and purified on preparative thin-layer chromatography [Kieselgel™ 60F254, Art.5744 (Merck); chloroform/methanol=4/1] to provide 114 mg of the title compound as a yellow solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>ClCCl>[Cl:3][C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=[C:12]([CH3:17])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)cc[n+]1[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)(C)C)cc(Cl)n1
Temperature: 100 °C

Procedure:
Add phosphorus oxychloride (15 mL) to 4-tert-butyl-2-methyl-pyridine 1-oxide (2.00 g, 12.10 mmol) and heat to 100° C. for 36 hours. Evaporate off the excess phosphorus oxychloride. Treat the oil cautiously with ice and water with stirring and make basic by treatment with aqueous bicarbonate solution. Extract with dichloromethane (3×75 mL) and pool, desiccate, filter, and concentrated. Chromatograph the crude product on silica using a gradient of (0→5→8%) ethyl acetate in dichloromethane to afford the title compound (0.82 g, 4.46 mmol). MS (ESI), m/z 184 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)[F:20])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1>ClCCl>[F:20][C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc(Oc2ccccc2)cc1F
Yield: 14.3 %

Procedure:
To a 250 ml dichloromethane solution of 4-phenoxyphenol (2 g, 10.7 mmol) was added 3,5-dichloro-1-fluoro-pyridinium triflate (4.14 g, 13.1 mmol). After heating to reflux for 1 hr, the solvent was removed, the crude product was diluted with AcOEt and sat. bicarb. solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 10% methy t-butyl ether/hexanes gave 312 mg of the title compound as a pale yellow oil.
Reaction SMILES: C(OC([N:8]([CH:28]1[CH2:30][CH2:29]1)[C:9]1[N:14]2[N:15]=[CH:16][C:17]([CH:18]=[O:19])=[C:13]2[N:12]=[C:11]([C:20]2[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=2)[CH:10]=1)=O)(C)(C)C.Cl>O1CCOCC1>[CH:28]1([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([CH:18]=[O:19])=[C:13]3[N:12]=[C:11]([C:20]3[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=3)[CH:10]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2ccc(C(=O)O)s2)nc2c(C=O)cnn12)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(C(=O)O)s3)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To 5-(7-(tert-butoxycarbonyl(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (1 g, 2.33 mmol) was added 8 mL of 4M HCl in dioxane and another 5 mL of dioxane. The reaction mixture was stirred at 80° C. for 2 hours, cooled to room temperature and partitioned between CH2Cl2 and H2O. The emulsion that formed between the layers was filtered off and rinsed with H2O. The recovered solid was dried under vacuum to provide 627 mg of 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid as a red solid (82%). LCMS (M+1=329)
Reaction SMILES: Br[CH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[CH3:12][Li]>CCOCC>[CH3:12][C:6]1[C:5]([CH3:9])([CH3:8])[CH2:4][C:3]([CH3:11])([CH3:10])[CH2:2][N:7]=1
Reactant: [Li]C
Reactant: CC(C)(C#N)CC(C)(C)CBr
Solvent: CCOCC
Product: CC1=NCC(C)(C)CC1(C)C
Reaction time: 0.5 h

Procedure:
To 22 g of 5-bromo-2,2,4,4-tetramethyl pentane nitrile in 60 ml of anhydrous ether, 0.1 mol of methyl lithium in solution in 200 ml of anhydrous ether is added drop by drop in an inert atmosphere. The reaction medium is maintained between 0° and 5° C. during the addition and then for an additional 30 minutes and then kept at room temperature for 4 hours. After hydrolysis, the aqueous phase is extracted with ether. The 2,3,3,5,5-pentamethyl-3,4,5,6-tetrahydropyridine is then isolated by distillation. There is obtained a colorless liquid of B.P.10 -2 =43° C. in a yield of 70% of Δ1-piperideine.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)=[N:3][C:4]4[N:5]([N:17]=[CH:18][C:19]=4[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Reactant: CN1CCNCC1
Solvent: CCCCO
Product: CCOC(=O)c1cnn2c1nc(N1CCN(C)CC1)c1cnc3c(cnn3CC)c12
Reaction time: 12 h

Procedure:
3.5 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester (0.01 mol) are dissolved in 20 ml of butanol. 2 g of N-methylpiperazine are added and the solution is refluxed with stirring for 12 hours. After evaporation of the solvent, the residue is extracted three times with 50 ml portions of ethyl acetate. The ethyl acetate is distilled off until the volume is about 30 ml. The 8-ethyl-5-(4-methyl-1-piperazinyl)-8H-pyrazolo[1,5a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester crystallizes, yield 3.1 g (76%); m.p. 111°-113° (ethyl acetate).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[I-].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCNc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 49.7 %

Procedure:
Ethyl 6-bromohexanoate (8.44 mL, 49.7 mmol) and tert-butyl 4-aminobenzoate (6.41 g, 33.2 mmol) were dissolved in N,N-dimethylformamide (33 mL), N,N-diisopropylethylamine (8.64 mL, 49.7 mmol) was added, and the mixture was stirred at 50° C. for 3 days. Potassium iodide (8.25 g, 49.7 mmol) was added, and the mixture was further stirred at 50° C. for 4 days. A saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate (×2). The resulting organic layer was washed with water (×3) and saturated sodium chloride solution and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1, v/v). A mixed solvent of hexane and dichloromethane was added to the resulting white solid, and the mixture was filtered to give the title compound (5.54 g; yield, 50%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17]O)=[C:4]([S:8][CH2:9][C:10]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.O=S(Cl)[Cl:21].ClC1C=NC=C(Cl)C=1CCl>>[Cl:1][C:2]1[C:3]([CH2:17][Cl:21])=[C:4]([S:8][CH2:9][C:10]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)N(C)C(=O)CSc1cncc(Cl)c1CO
Reactant: O=S(Cl)Cl
Agent: ClCc1c(Cl)cncc1Cl
Product: CC(C)N(C)C(=O)CSc1cncc(Cl)c1CCl

Procedure:
2-(5-Chloro-4-hydroxymethyl-pyridin-3-ylsulfanyl)-N-isopropyl-N-methyl-acetamide (7.5 mg, 0.026 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine to give the title compound. MS (m/z): 307.0 [M+H+].
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:11]1([S:10][C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[NH2:1])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1Sc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1CCCC[C@H]1Sc1ccccc1

Procedure:
A room temperature solution of Example 7B (777 mg, 3.3 mmol), triphenylphosphine (2.62 g, 10.0 mmol), and water (180 mg, 10 mmol) in THF (5 mL) was stirred for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes followed by 10% methanol/dichloromethane to provide the desired product. MS (DCI) m/e 208 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C([N:25](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:16])[NH:17][NH2:25])=[N:6]1
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Reactant: CCN(CC)CC
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ncc2c(C(=N)NN)nn(Cc3cccc(F)c3F)c2n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Under an argon atmosphere, 440 mg (1.237 mmol, purity 85%) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 6 ml of ethanol and cooled to 0° C. 500 mg (4.49 mmol) of triethylamine and 85 mg (1.361 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 72 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 421 mg (purity 84%, 90% of theory) of the target compound were obtained.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]#[C:23][CH2:24][OH:25])[CH2:17][CH2:16]1.O.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[O:15]1[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][OH:25])[CH2:17][CH2:16]1
Reactant: OCC#CCN1CCOCC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC/C=C/CN1CCOCC1
Temperature: 4.5 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
Tetrahydrofuran (15 ml) was added to 70% solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (49.7 g) under an atmosphere of nitrogen and then cooled. A solution of 4-morpholino-2-butyn-1-ol (3.0 g) in tetrahydrofuran (15 ml) was added dropwise maintaining the reaction temperature 4-5° C. After being stirred for 10 minutes, the reaction mixture was allowed to warm room temperature. After 1 hour, water (6 ml) and 10% aqueous sodium hydroxide solution (4.5 ml) were added cautiously and then filtered. The filtrate was dried over potassium carbonate and concentrated under reduced pressure to give an oily product, which was purified by column chromatography on silica gel using ethyl acetate-methanol (5:1) to afford (E)-4-morpholino-2-buten-1-ol (1.08 g).