Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>CO>[ClH:12].[C:25]([NH:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:16]1[CH:10]=[C:11]([Cl:12])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1]1=[NH:2])(=[O:27])[CH3:26]
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CC(=O)Nc1cccc(CN)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.70 g) and N-[3-(aminomethyl)phenyl]acetamide hydrochloride (1.20 g) in methanol (10 ml) was added triethylamine (1.66 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (10 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the aqueous layer was basified with 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (43.4 mg, 36%).
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([CH:12]2[C@@H:16]([F:17])[C@H:15]([O:18]CC3C=CC(Cl)=CC=3)[C@@H:14]([CH2:27][O:28]CC3C=CC(Cl)=CC=3)[S:13]2)[C:8](=[O:37])[N:7]=1.CO>C(Cl)Cl>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([CH:12]2[S:13][C@H:14]([CH2:27][OH:28])[C@@H:15]([OH:18])[C@@H:16]2[F:17])[C:8](=[O:37])[N:7]=1
Reactant: Nc1ccn(C2S[C@H](COCc3ccc(Cl)cc3)[C@@H](OCc3ccc(Cl)cc3)[C@@H]2F)c(=O)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
In a nitrogen atmosphere, 6.8 mL of a methylene chloride solution of 1 mol/L boron trichloride was added to a solution of 0.17 g of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorothiolane in 11 mL of methylene chloride under cooling on dry ice/acetone, and the obtained mixture was then stirred at the same temperature as described above for 3.5 hours. Thereafter, the temperature of the reaction mixture was increased to 0° C., and the reaction mixture was then stirred for 30 minutes. Thereafter, 7.5 mL of methanol was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, a solid was collected by filtration, and it was successively washed with ethyl acetate and hexane. The obtained solid was purified by silica gel column chromatography (chloroform/methanol=100/0 to 60/40), so as to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)thiolan-3-ol in the form of a white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[C@H:21]1[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](O)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:21]1[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1COCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)[C@H]1COCc1ccccc1
Reaction time: 14 h
Yield: 78.5 %

Procedure:
A solution of 0.52 ml (3.31 mmol) of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was slowly added at room temperature to a solution of 1.00 g (3.25 mmol) of (2R, 3R)-1-t-butoxycarbonyl-2-benzyloxymethyl-3-hydroxypyrrolidine [prepared as described in step (a) above], 0.87 g (3.31 mmol) of triphenylphosphine and 0.42 g (3.47 mmol) of benzoic acid in 5 ml of tetrahydrofuran, and the mixture was stirred for 14 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash chromatography through silica gel, using a 20:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.05 g of the title compound as an oil.
Reaction SMILES: [OH-].[Na+].O.Cl.[Cl:5][C:6]1[CH:7]=[C:8]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CC(C)=O>[Cl:5][C:6]1[CH:7]=[C:8]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Reaction time: 18 h
Yield: 9 %

Procedure:
To a solution fo 7.36 g. (0.184 mole) of sodium hydroxide in 75 ml. of water and 75 ml. of acetone there is added 17.16 g. (0.074 mole) of 1-(3-chlorophenyl)piperazine hydrochloride and 11.59 g. (0.074 mole) of 1-bromo-3-chloropropane, and the resulting mixture is stirred at 27° for 18 hrs. The organic layer is then separated and concentrated to an oil under reduced pressure. The oil is treated with hot (85°) 6 N HCl until solution is complete, and the resulting solution is filtered and stored at 5° for 18 hrs. The precipitate which forms is collected on a filter to afford 17.52 g. (87%) of the hydrochloride salt of the product, m.p. 198°-200°. Concentration of the mother liquor under reduced pressure and recrystallization of the residue from water affords an additional 1.82 g (9%) of product, m.p. 196°-198°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([O:35]C)=[O:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)OC)O3)[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)O)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.1 %

Procedure:
Methyl 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole-5-carboxylate (60.5 mg, 0.114 mmol) synthesized in Example (27b) was dissolved in ethanol (4 mL). An aqueous sodium hydroxide solution (5M, 2 mL) was added, and stirring was carried out at 70° C. for 2.5 hours. After cooling to room temperature, hydrochloric acid (2M, 5 mL) and ethyl acetate (10 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (69.3 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: COc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]CCCC)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
Into a 50-mL round-bottom flask, was placed butyl 2-(4-fluorophenyl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.37 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (74 mg, 1.85 mmol, 5.02 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Gilson Pre-HPLC (Max. pressure: 8 MPa)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (70% CH3CN up to 77.5% in 6 min, up to 100% in 0.1 min, hold 100% in 1.9 min); Detector, UV 220 NMnm. This resulted in 70 mg (52%) of 2-(4-fluorophenyl)-3-(piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH3:24][O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][C:31]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:18][C:17]=3[CH:19]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g) and 4-(methoxycarbonyl)phenyl boronic acid (565 mg) in N,N-dimethylformamide (50 mL) a 2 M aqueous Na2CO3 solution (3.27 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene].CH2Cl2 complex (213 mg) is added. The resulting mixture is stirred for 5 h at 90° C. After cooling to room temperature water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and the solvent is evaporated. The residue is mixed with trifluoroacetic acid (1.4 mL), dichloromethane (1.4 mL), and water (0.15 mL) and stirred for 3 h. The solvents are evaporated and the residue is mixed with diethyl ether. The title compound is collected by filtration as the trifluoroacetic acid salt. LC (method 8): tR=1.19 min; Mass spectrum (ESI+): m/z=338 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[N+:21]([C:16]1[CH:15]=[CH:14][C:13]2[O:8][CH2:9][CH2:10][O:11][C:12]=2[C:17]=1[C:18]([OH:20])=[O:19])([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c1OCCO2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1c([N+](=O)[O-])ccc2c1OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1,600 ml of acetic acid, 1,600 ml of acetic anhydride, and 1000 g of 1,4-benzodioxane-5-carboxylic acid were introduced in a 6-liter balloon flask provided with an agitator and a thermometer. The mixture was heated to 40° C. and a solution of 400 ml of nitric acid in 400 ml of acetic acid was added. After the introduction, the mixture was stirred at 40°-45° C. for two hours and then cooled to 5° C. The precipitate was dried off, washed with 600 ml of acetic acid and then with water and dried at 40° C. 700 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were collected, the structure of which was confirmed by nuclear magnetic resonance (M.P: 246° C.). The mother liquors were diluted with 25 liters of water and the obtained precipitate was dried off, washed with water and dried. 6-nitro-1,4-benzodioxane-5-carboxylic acid was obtained (M.P.: 188° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[N:11]([Si](C(C)(C)C)(C)C)[C:10](=[O:19])[C@@H:9]1[C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:21])[CH3:7])=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[NH:11][C:10](=[O:19])[C@@H:9]1[C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH3:21])[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-t-butyldimethylsilyloxyethyl)-1-t-butyldimethylsilyl-2-azetidinone (46.3 g) in dry tetrahydrofuran (60 ml) was treated with a 1 M tetrahydrofuran solution of tetra-n-butylammonium fluoride (96 ml) at room temperature for 45 minutes. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with brine (60 ml). The washing was extracted with ethyl acetate (50 ml). The extract and the ethyl acetate layer were combined together, washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave and oily residue, which was purified by silica gel chromatography to yield (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-t-butyl-dimethylsilyloxyethyl)-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39]Br>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:39][CH2:38][O:37][CH3:36])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: COCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Product: COCCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[1-(2-methoxyethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-])[C:10]=2[CH:11]=1.[Cl-].C(=O)([O-])[O-:15].[K+].[K+]>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)=[N:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: [O-][n+]1cccc2ncc(Br)cc21
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2ncc(Br)cc2[nH]1
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a mixture of 3-bromo-1,5-naphthyridine-5-oxide (C-3) (70.0 g, 311 mmol, 1.0 eq) and 4-toluolsulfonyl chloride (71.16 g, 373 mmol, 1.2 eq) in CHCl3 (1200 mL) was added a solution of potassium carbonate (146 g, 1056 mmol, 3.4 eq) in H2O (500 mL) at RT. The resulting mixture was stirred overnight and diluted with H2O (500 mL). The solid was collected by filtration, washed with water, dried in vacuo to afford the desired product 7-bromo-1,5-naphthyridin-2(1H)-one (C-4) (28.8 g, 41.2% yield). 1H NMR (300 MHz, DMSO-d6) δ: 11.90 (bs, 1H), 8.51 (s, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 6.74 (d, J=9.6 Hz, 1H); ESI-MS m/z: 225.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.BrBr.[Cu](C#N)[C:13]#[N:14]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[C:13]#[N:14]
Reactant: N#C[Cu]C#N
Reactant: COc1cccc(F)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(C#N)c(F)c1
Temperature: 60 °C

Procedure:
A stirred solution of 3-fluoroanisole (7.0 g, 50.3 mmol) in 50 mL of chloroform is treated with bromine (2.59 mL, 50.3 mmol) over 30 minutes at room temperature. The reaction is heated to 60° C. for 7 hours and concentrated in vacuo. The resulting material is dissolved in 10 mL of N,N-dimethylformamide and treated with copper cyanide (5.9 g, 65.39 mmol). After refluxing overnight, the reaction is partitioned between ethyl acetate and acidic ferric chloride solution (a mixture of 19.2 g of ferric chloride hexahydrate, 44.8 mL of hydrochloric acid, and 48 mL of water). The organic phase is washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (210 g) with 10% ethyl acetate/hexane as the eluent to afford 2-fluoro-4-methoxy-benzonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:34][CH3:35])=[C:7]([C:9]2[N:13](CCOC[Si](C)(C)C)[N:12]=[CH:11][C:10]=2[NH:22][C:23]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=23)=[O:24])[CH:8]=1)#[N:2].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:34][CH3:35])=[C:7]([C:9]2[NH:13][N:12]=[CH:11][C:10]=2[NH:22][C:23]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=23)=[O:24])[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCOC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C#N)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
To a solution of N-(5-(5-cyano-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.04 mmol) in 20 mL ethanol was added HCl (2.0 mL of a 6 M solution in water, 12 mmol). The reaction mixture was then stirred at 70° C. for 4 hours. After cooling to room temperature, a light yellow precipitate formed, which was filtered off and rinsed with methanol and diethyl ether. The filtrate was reduced in volume to precipitate more solid product, which was filtered off. The combined collected solids were dried under vacuum to yield 530 mg (72%) of N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=360.1; 1H NMR (400 MHz, DMSO-d6) δ12.98 (s, 1H), 9.59 (s, 1H), 9.30 (dd, 1H), 8.73 (d, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 7.78 (s, 1H), 7.43 (d, 1H), 7.25 (s, 1H), 3.9 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.[H-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
Diethyl 4-nitrobenzylphosphonate (36 g, 132 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (26.3 g, 132 mmol) were stirred in tetrahydrofuran (230 mL) and cooled in an ice bath. Sodium hydride was added (6.85 g, 171 mmol) and the reaction was taken off the ice bath and stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane, dried (magnesium sulphate), filtered and evaporated under reduced pressure. The crude material was purified by silica chromatography using a dichloromethane solvent system. The oil obtained was triturated with heptane and filtered to give the title compound as a yellow solid (34.24 g). 1H NMR (CDCl3, 400 MHz): δ 8.18 (d, 2H), 7.33 (d, 2H), 6.40 (s, 1H), 3.54 (t, 2H), 3.43 (t, 2H), 2.46 (t, 2H), 2.38 (t, 2H), 1.48 (s, 9H)