Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[N:7]([CH3:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1cnc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
400 mg 7-Bromoquinazolin-4(3H)-one was dissolved in DMF and 720 mg of CsCO3 and 130 μL of methyliodide were added and the mixture stirred for 3 h at 25° C. Additional 50 μL methyliodide were added and stirred overnight at 25° C. The mixture was filtered off and the mother liquor diluted with DCM and extracted with water. The solvent was removed to yield 490 mg of 7-bromo-3-methylquinazolin-4(3H)-one as solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.00 g (17.7 mmol/1 eq) of L-threonine methyl ester hydrochloride are suspended in 50 ml of methanol, and 7.4 ml (53 mmol/3 eq) of triethylamine are added thereto. After 10 minutes, the mixture is cooled to 0° C. and the benzoyl chloride (2.74 g/190.5 mmol/1.1 eq) is added. Stirring is carried out at 0° C. for a further two hours. The solvent is then removed using a rotary evaporator. The solid that remains behind is taken up with ethyl acetate/H2O (50/20 ml). The aqueous phase is separated off and extracted by shaking twice more with ethyl acetate (30 ml each time). The combined organic phases are washed with 15 ml each of H2O and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 4.07 g (97% of theory) of a white solid are obtained.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:9]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1.C(Cl)Cl.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[F:3][C:4]1[C:9]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:26](=[O:28])[CH3:27])[CH2:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ncccc1C1CCCNC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(c2cccnc2F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To an ice cooled solution of 2-fluoro-3-(piperidin-3-yl)pyridine dihydrochloride (612 mg, 2.418 mmol), DCM (20 mL) and triethylamine (2022 μL, 14.51 mmol) was added acetic anhydride (229 μL, 2.418 mmol) dropwise. After 1 hour, the reaction was poured into water and the aqueous mixture back extracted once with DCM (10 mL). The combined organics were washed with 0.5M NaOH and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 100% EtOAc in hexane, to provide 1-(3-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone (100 mg, 0.450 mmol) as a light yellow syrup. MS (ESI, pos. ion) m/z: 223.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:18](=[O:24])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[C:33]1([CH2:39][CH2:40][N:41]2[C:7](=[O:9])[C:6]3[CH:5]=[C:4]([CH2:11][CH2:12][CH3:13])[S:3][C:2]=3[NH:1][C:18]2=[O:24])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCc1ccccc1
Reactant: CCCc1cc(C(=O)OC)c(N)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution (15 mL) of methyl 2-amino-5-propylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.98 g) and triethylamine (1.7 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (0.91 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), sodium methoxide (0.5 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.71 g, 90%).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>O1CCCC1>[CH2:16]([O:20][C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][S:13][CH2:14][CH2:15]2)[S:7][N:6]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(N2CCSCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1nsc(N2CCSCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
In 3 ml of tetrahydrofuran were dissolved 398 mg of 3-methylsulfonyl-5-(thiomorpholino)-1,2,4-thiadiazole and 180 mg of 2-butyn-1-ol, and 102 mg of sodium hydride (oil suspension; content: 60 weight %) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was subjected to recrystallization from a mixed solvent of hexane-ethyl acetate to obtain 246 mg of 3-(2-butynyloxy)-5-thiomorpholino-1,2,4-thiadiazole (hereinafter, referred to as the present compound (23)).
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[Br:13][C:14]1[N:19]=[C:18]([NH:20][C:21]([NH:23]C(OCC)=O)=S)[CH:17]=[CH:16][CH:15]=1>CCO.CO>[Br:13][C:14]1[N:19]2[N:7]=[C:21]([NH2:23])[N:20]=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cccc(Br)n1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2cccc(Br)n2n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) was added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture was stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber was required to quench H2S evolved). After 3 h at reflux, the mixture was allowed to cool and filtered to collect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids were washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound was used as such in the next step without any purification.
Reaction SMILES: [F:1][C:2]([F:12])([C:9]([OH:11])=[O:10])[C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1.[CH:24]1C=CC=C[CH:25]=1>>[F:1][C:2]([F:12])([C:9]([O:11][CH2:24][CH3:25])=[O:10])[C:3]([F:7])([F:8])[C:4]([O:6][CH2:13][CH3:14])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Reactant: O=C(O)C(F)(F)C(F)(F)C(=O)O
Product: CCOC(=O)C(F)(F)C(F)(F)C(=O)OCC
Reaction time: 24 h

Procedure:
First, diethyl tetrafluorosuccinate was prepared. Benzene (1 L) was refluxed in a 2 L 2-necked round bottom flask equipped with a Dean-Stark trap, condenser and magnetic stir bar. The azeotrope was removed. Absolute ethanol (500 ml) was added to the flask. The Dean-Stark trap was filled with activated 4 Å molecular sieves, and the solvents were refluxed through the sieves for 1 hour. The Dean-Stark trap was then placed with a Sohxlet extractor apparatus, and a Sohxlet thimble was filled with activated molecular sieves and placed in the apparatus. The tetrafluorosuccinic acid (50.37 g, 0.265 mol) was added to the flask along with p-toluene sulfonic acid (4 g). The reaction was refluxed for 24 hours. The wet sieves were periodically removed and replaced with fresh sieves. The reaction was followed by NMR. After 24 hours, the reaction was allowed to cool, and the solvents were removed in vacuo. The resulting oil was taken up to 200 ml pentane and washed three times with 50 ml saturated NaHCO3 solution. The pentane was removed in vacuo to give 53.42 g (82%) of the clear oil diethyl tetrafluorosuccinate. The following data verifies the formation of diethyl tetrafluorosuccinate: NMR (360 MHz, CDCl3) 1H δ 1.36 (t, 6H, J=7.16 Hz), 4.39 (q, 4H, J=7.16 Hz).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][N:13]=1)(=[O:10])[CH:7]([CH3:9])[CH3:8].C(O)(=O)C.N>C(#N)C>[C:6]([NH:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:19][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[OH:21])=[CH:14][N:13]=1)(=[O:10])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)C(=O)Nc1ncc(C(=O)CBr)cn1
Reactant: CC(C)(C)N
Agent: N
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1ncc(C(O)CNC(C)(C)C)cn1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.146 g of tert. -butylamine in 200 ml of dry acetonitrile, 2.05 g of solid 2-isobutyramido-5-(bromoacetyl)pyrimidine was added. The reaction mixture was stirred for 30 minutes and then gaseous hydrochloric acid was bubbled into the reaction mixture. The reaction mixture was then diluted with 300 ml of ether and the resulting precipitate collected by filtration. The precipitate was dissolved in 43 ml of anhydrous methanol and the resulting solution cooled to 5° C. Sodium borohydride (1.46 g) was slowly added (vigorous reaction) to this solution and the resulting mixture stirred for 1 hour in the cold. Acetic acid (5 ml) was added and then the pH of the reaction mixture was adjusted with concentrated aqueous ammonia to approximately pH 6. This solution was extracted with methylene chloride (3×50 ml). The combined extracts were washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The extracts were concentrated and the residue chromatographed on silica gel (90/10/1 methylene chloride/methanol/ ammonia) to afford 980 mg of product.
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OCC)OCC)C.[CH:17]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([CH3:38])[C:34]([NH:36][NH2:37])=[O:35])[N:27]=1)([CH3:19])[CH3:18].C(OCC)(=O)C>CCCCCCC>[CH:17]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@H:33]([C:34]2[O:35][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:37][N:36]=2)[CH3:38])[N:27]=1)([CH3:19])[CH3:18]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C(=O)NN)n1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2nnc(-c3ccccc3)o2)n1
Yield: 17.9 %

Procedure:
A solution of (triethoxymethyl)benzene (360 mg, 1.6 mmol, 5.0 equiv. in 5 mL of benzene and 0.5 mL of glacial AcOH) was added to (S)-2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanehydrazide (99 mg, 0.30 mmol, 1.0 equiv.), the reaction mixture was stirred at reflux for 1.5 hours, the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 90%) to yield (S)-4-isopropyl-3-(2-(((S)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21.2 mg, white solid) in 15.9% yield. HRMS(B) m/z 395.1820, (M+H)+, RT=2.42 min
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=3[CH3:33])=[CH:18][CH:17]=2)=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CCN(C(C)C)C(C)C.Br[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[F:51]>CN(C)C=O.CCOCC>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=3[CH3:33])=[CH:20][CH:21]=2)=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)COc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Temperature: 90 °C

Procedure:
The product from Example 306A (86 mg, 0.18 mmoles) in anhydrous dimethylformamide (1 mL) was treated with Hunig's base (0.107 mL, 0.5 mmoles) and 1-(bromomethyl)-2-fluorobenzene (0.198 mL, 0.9 mmoles) in anhydrous dimethylformamide (1 mL) and heated at 90° C. for 72 hours. The reaction was diluted with ether, washed with saturated NH4Cl, water, brine, dried (Na2SO4), filtered, and filtrate concentrated under reduced pressure. The residue purified by using ethyl acetate and hexane gradient on 10 g silica column to provide the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Na].C(=O)=O.C(#N)C.[N:23]([CH:26]1[CH2:30][C:29](=[O:31])[CH:28]=[CH:27]1)=[N+:24]=[N-:25].FC(F)(F)C(O)=O>C(O)C>[N:23]([C@H:26]1[C@H:27]([C:5]([NH:4][C:1]([CH3:2])=[O:3])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:28][C:29](=[O:31])[CH2:30]1)=[N+:24]=[N-:25]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: [N-]=[N+]=NC1C=CC(=O)C1
Agent: O=C=O
Agent: [Na]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)[C@@H]1CC(=O)C[C@H]1N=[N+]=[N-]
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of diethyl acetamidomalonate (Aldrich, 1.25 g, 5.7 mmol) in ethanol (10 mL) under nitrogen was added freshly cut sodium metal (0.03 g, 1.4 mmol). The reaction mixture was stirred at room temperature until all sodium has dissolved. The reaction mixture was cooled to −40° C. (dry ice/acetonitrile) and a solution of 4-azidocyclopent-2-enone (0.7 g, 5.7 mmol) in ethanol (5 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at −40° C. for 30 min and quenched with trifluoroacetic acid (0.1 mL, 1.4 mmol). The solvent was removed in vacuo to furnish a white solid. Purification of the crude by flash column chromatography (60% ether in hexane) gave 1.2 g (63%) of trans-3-azido-4-[(methylcarbonyl-amino)bis(ethoxycarbonyl)methyl]cyclopentanone as a white solid, mp 121-122° C.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[CH2:17][OH:18])=[CH:10][CH:9]=1)[C:3]([O:5]C)=O.[NH2:27][C:28](N)=[S:29].C([O-])(=[O:33])C.[Na+].Cl>C(O)C>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:16]([CH2:17][OH:18])[CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH:2]3[S:29][C:28](=[O:33])[NH:27][C:3]3=[O:5])=[CH:9][CH:10]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: NC(N)=S
Reactant: CCc1ccc(C(CO)COc2ccc(CC(Br)C(=O)OC)cc2)nc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(C(CO)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1

Procedure:
A mixture of methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-3-hydroxypropoxy]phenyl}propionate (12.2 g), thiourea (2.2 g), sodium acetate (2.4 g) and ethanol (100 ml) was heated under reflux for 3 hours, and 3N-hydrochloric acid (100 ml) was added to the mixture, followed by heating under reflux for 12 hours. After concentration, the reaction mixture was neutralized with aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then freed of the solvent. The residue was chromatographed on a silica-gel (200 g) column, and elution was effected with benzene-acetone (5:1, V/V) to give 5-{4-[2-(5-ethyl-2-pyridyl)-3-hydroxypropoxy]benzyl}-2,4-thiazolidinedione in the form of an oily substance. Yield of 4.8 g (42.9%). The substance was dissolved in methanol (15 ml), and sodium methylate (28% methanol solution, 2.9 g) was added to the solution, followed by addition of ethyl ether (150 ml) to give the sodium salt in the form of crystals. Yield of 4.8 g (40.7%). Recrystallization from ethanol-ethyl ether produced colorless prisms. m.p. 237°-238° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7](C)=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:12]C1C(C#N)=NC=CC=1C.CC1C(C)=CN=C(C#N)C=1.C(C1C=C(Cl)C=CN=1)(=O)C>>[C:1]([C:4]1[C:9]([CH3:12])=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccnc(C#N)c1C
Reactant: CC(=O)c1cc(C)c(C)cn1
Agent: CC(=O)c1cc(Cl)ccn1
Agent: Cc1cnc(C#N)cc1C
Product: CC(=O)c1nccc(C)c1C

Procedure:
The title compound was prepared along with 2-acetyl-4,5-dimethylpyridine from 3,4-dimethylpyridine-2-carbonitrile including 4,5-dimethylpyridine-2-carbonitrile in the ratio of 5.5 to 1 according to the procedure for preparing 2-acetyl-4-chloropyridine described in Example 33.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8](=[O:15])(=[O:14])[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2]1[C:7]2[S:8](=[O:15])(=[O:14])[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCS2(=O)=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCS2(=O)=O
Reaction time: 4 h

Procedure:
10.0 g (0.0345 mol) of 8-methyl-2,3-dihydro-1,1,4,4-tetraoxobenz-[1,4]dithiin-7-carboxylic acid were dissolved in 100 ml of toluene, and two drops of dimethylformamide and then 4.5 g (0.038 mol) of thionyl chloride were added. After four hours of stirring under reflux, the mixture was concentrated. The colorless oil that remained (yield 10.6 g) could be directly employed further.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27].C[O-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:13])[F:14]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)cc1Cl)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1I
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2[N+](=O)[O-])cc1Cl)C(F)(F)F
Temperature: 135 °C
Yield: 60.5 %

Procedure:
A mixture of (R)-N-(2-chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (0.1 g), 1-iodo-2-nitrobenzene (0.086 g), sodium methoxide (0.021 g), and cuprous chloride (0.014 g) in DMF (1 ml) was stirred and heated to 135° C. for 2.5 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (5 ml) and poured onto a Varian Chem Elut column. When the liquid had been adsorbed the column was eluted with ethyl acetate and the eluate was concentrated by evaporation. The residue was purified on a silica gel Mega Bond Elut column, eluting with 5-40% ethyl acetate/hexane to give the title compound (0.085 g) as a glass. MS: 419 (M−H)−.
Reaction SMILES: [CH2:1]([N:5]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:6]=O)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O.[Cl:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[N:22][N:21]2[C:27]=1[S:28]([NH2:31])(=[O:30])=[O:29].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[N:22][N:21]2[C:27]=1[S:28]([N:31]=[CH:6][N:5]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:30])=[O:29]
Reactant: NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Reactant: CC(C)CN(C=O)CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12)CC(C)C
Reaction time: 0.5 h

Procedure:
N,N-Diisobutylformamide (5.44 g, 34.5 mmol) was dissolved in chloroform (25.0 mL) and cooled in an ice-sodium chloride bath, and phosphorus oxychloride (3.22 mL, 34.5 mmol) was added dropwise thereto at −2° C. or less. After the mixture was stirred at −2° C. or less for 30 minutes, 2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (6.15 g, 23.0 mmol) was added thereto. After the mixture was stirred at −10° C. for 10 minutes, triethylamine (19.3 mL, 138 mmol) was added dropwise over 20 minutes to the solution at 5° C. or less. The mixture was stirred for 1 hour at 0° C. or less and for 1 hour at room temperature, then poured into an aqueous saturated sodium bicarbonate and extracted 5 times with chloroform. The extracts were combined, dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound as pale yellow crystals. The yield was 5.58 g (59.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:4][N:3]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>N1C=CC=CC=1>[OH:14][C:10]1[CH:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cnc(-c2cccc(O)c2)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cnc(-c2cccc(O)c2)cn1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg) in pyridine (10 mL) was added under ice-cooling phenyl chloroformate (63 μL). The mixture was stirred for 1 hour and then poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (51 mg).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:6]=12.C(N(CC)CC)C.[CH:32]1([C:35]#[CH:36])[CH2:34][CH2:33]1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[CH:32]1([C:35]#[C:36][C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[CH:8]=[C:7]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[C:6]=23)[CH2:34][CH2:33]1
Reactant: Cn1cc(-c2cc(OCc3cccnc3)c3c(I)cnn3c2)cn1
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(OCc3cccnc3)c3c(C#CC4CC4)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-iodo-6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine from Step 2 (11.0 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium (0) (3.0 mg, 2.6 μmol), and CuI (2.9 mg, 0.02 mmol) were suspended in DMF (1 ml). Triethylamine (11 μl, 0.08 mmol) and cyclopropyl acetylene (5.1 mg, 0.08 mmol) were added and the mixture was sparged with argon for 10 minutes. After stirring at ambient temperature for 1.5 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated to afford 3-(cyclopropylethynyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H); 8.65 (s, 1H); 8.57-8.60 (m, 1H); 8.30 (s, 1H); 8.00-8.05 (m, 2H); 7.98 (s, 1H); 7.49 (dd, 1H); 7.12 (s, 1H); 5.37 (s, 2H); 3.87 (s, 3H), 1.39-1.45 (m, 1H); 0.71-0.76 (m, 2H); 0.42-0.46 (m, 2H). LRMS (ESI) calculated for C22H20N5O [M+H]+, 370.2; found 370.0.