Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:39]([CH3:42])=[N:40][N:41]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH2:20][O:21][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:14]=3)[C:6]=2[CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Br:1][C:2]1[C:3]2[N:4]([C:39]([CH3:42])=[N:40][N:41]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CO)c1

Procedure:
4-Bromo-6-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (2.1 g, 3.2 mmol, from Step 3) in THF (30 mL) was treated with 1.0 M TBAF in THF (6.4 mL, 6.4 mmol, Aldrich) for 1 hour. The reaction mixture was diluted with water and extracted with three portions of EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH. Yield: (0.722 g, 54% over the two steps).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:18])[CH2:13][CH2:14][C:15]=2OC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:20]>ClCCCl>[Br:20][C:15]1[CH2:14][CH2:13][C:12](=[O:18])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: COC1=C(c2ccc(C(C)(C)C)cc2)C(=O)CC1
Reactant: BrP(Br)Br
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C2=C(Br)CCC2=O)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of Example 7C (245 mg, 1.003 mmol) in 1,2-dichloroethane (5 mL) was added PBr3 (0.142 mL, 1.504 mmol). The resulting mixture was heated to reflux for 1 hour, then cooled to ambient temperature, and poured over cracked ice. The organic layer was separated, washed with saturated aqueous NaHCO3 (5 mL), and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (on silica gel, eluted with dichloromethane/methanol=200:1, v/v) to afford the title compound (200 mg, 0.682 mmol, 68.0% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.38 (s, 4H), 3.00-3.03 (m, 2H), 2.62-2.65 (m, 2H), 1.26 (s, 9H); LC/MS (ESI) m/z 293 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].S(=O)(=O)(O)O.[CH3:8][C:9]([CH:11]=[O:12])=[O:10].[C:13]1(C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:10]=[C:9]([CH:11]([OH:12])[CH2:13][C:14](=[O:1])[CH2:15][CH2:16][C:17]#[CH:18])[CH3:8]
Reactant: CC(=O)C=O
Reactant: [OH-]
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C#CCCC(=O)CC(O)C(C)=O
Temperature: 30 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
To diethyl 2-(2'-propnynyl)-3-oxoglutarate (24.0 g) was added a 10% aqueous sodium hydroxide solution (sodium hydroxide 8.0 g, water 72 ml) with ice cooling, followed by stirring at 30° C. for 5 hours. The pH of the reaction solution was adjusted to 7.5 with a 10% sulfuric acid with ice cooling, and toluene (60 ml) was added thereto. While passing nitrogen stream, a 40.7% aqueous methylglyoxal solution (20 g) was added dropwise to the reaction solution at 35° C. over 2 hours. Thereafter, the reaction solution was stirred at 35° C. for 15 hours. The reaction solution was separated into two layers, and the aqueous layer was saturated with sodium chloride and extracted three times with ethyl acetate. The toluene layer and the ethyl acetate layer were combined, and the solvent was removed by evaporation to obtain 14.1 g of 2,5-dioxo-3-hydroxy-8-nonyne as a pale yellow oil. Yield 83.8%. nD23 1.4593.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:14]([CH3:15])=[C:13](F)[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Cl[C:18]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:19]=1C#N.FC1C=CC(C#N)=C(C(F)(F)F)C=1>>[Cl:6][C:7]1[C:14]([CH3:15])=[C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:19]=2)[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: C1CCNC1
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: N#Cc1ccc(F)cc1C(F)(F)F
Product: Cc1c(N2CCCC2c2ccccc2)ccc(C#N)c1Cl

Procedure:
Prepare Examples 2 to 20, in the table below, by essentially following the procedures as described in Example 1 above. Use the appropriate pyrrolidine as indicated and 2-chloro-4-fluoro-3-methyl-benzonitrile (Preparation 1), 2-chloro-4-fluorobenzonitrile, or 4-fluoro-2-(trifluoromethyl)benzonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([C:16]2[CH:15]=[C:14]([CH2:13][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]3)[CH:19]=[CH:18][N:17]=2)[CH:21]=[C:22]([O:30][CH3:31])[C:23]=1[O:28][CH3:29]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl piperidine-4-carboxylate (514 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (969 mg) in acetonitrile (20 mL) was added potassium carbonate (452 mg). The mixture was stirred at room temperature for 4 hours and evaporated. The residual oil was subjected to a column of silica gel and eluted using hexane-ethyl acetate (2:1) and then chloroform-methanol (40:1). Fractions containing the product were collected and evaporated to give the title compound as white prisms.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22][CH2:23][C:24]([OH:26])=O.FC(F)(F)C([O-])=O.[NH2:34][C@@H:35]1[C:42](=[O:43])[N:41]2[C@@H:36]1[S:37][CH2:38][C:39](/[CH:47]=[C:48]1/[C:49](=[O:72])[N:50]([CH2:53][C:54]3[CH:59]=[CH:58][N+:57]([CH2:60][C:61](=[O:71])[NH:62][C:63]4[CH:68]=[CH:67][C:66]([OH:69])=[C:65]([F:70])[CH:64]=4)=[CH:56][CH:55]=3)[CH2:51][CH2:52]/1)=[C:40]2[C:44]([OH:46])=[O:45]>CN(C)C(=O)C>[F:70][C:65]1[CH:64]=[C:63]([NH:62][C:61]([CH2:60][N+:57]2[CH:58]=[CH:59][C:54]([CH2:53][N:50]3[CH2:51][CH2:52]/[C:48](=[CH:47]\[C:39]4[CH2:38][S:37][C@H:36]5[N:41]([C:42](=[O:43])[C@H:35]5[NH:34][C:24](=[O:26])[CH2:23][S:22][C:15]5[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=5[Cl:13])[C:40]=4[C:44]([O-:46])=[O:45])/[C:49]3=[O:72])=[CH:55][CH:56]=2)=[O:71])[CH:68]=[CH:67][C:66]=1[OH:69]
Reactant: O=C(O)CSc1cc(Cl)c(Cl)cc1Cl
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5cc(Cl)c(Cl)cc5Cl)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
With 60.0 mg (0.36 mmol) 1,1,-carbonyldiimidazole, 99.0 mg (0.36 mmol) (2,4,5-trichloro-phenylsulfanyl)-acetic acid and 200.0 mg (0.30 mmol) (E)-(6R,7R)-7-amino-3 -[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitril (2:1, 1:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C([C:19]1[C:20](Br)=[C:21]([C:26]([O-:28])=[O:27])[C:22]([CH3:25])=[CH:23][CH:24]=1)C.C(=O)([O-])[O-].[K+].[K+].[CH3:36][C:37](=O)CC>[I-].[K+]>[CH2:36]([O:28][C:26]([C:21]1[CH:20]=[CH:19][CH:24]=[CH:23][C:22]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1)=[O:27])[CH3:37]
Reactant: CCC(C)=O
Reactant: CCOC(=O)CCC(C)c1ccc(O)cc1
Reactant: CCc1ccc(C)c(C(=O)[O-])c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CCC(C)c1ccc(OCc2ccccc2C(=O)OCC)cc1
Yield: 59 %

Procedure:
A mixture of 12 g of ethyl 4-(4-hydroxyphenyl)pentanoate, 16.05 g of ethyl -bromo-o-toluate, 0.5 g of pulverized potassium iodide and 36.49 g of potassium carbonate in 300 ml of 2-butanone was heated under reflux overnight. The salts were collected and washed with ether. The filtrate was evaporated and the residue was partitioned between water and ether. The organic layer was separated, washed with 10% sodium hydroxide solution and water, dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography on a Waters Associates Prep LC-System 500 (two silica gel columns; elution with dichloromethane) gave 12.15 g (59%) of product, as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.CN(C)CCCN=C=NCC>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:15]2[CH2:16][CH2:17][CH:13]([N:12]([CH3:18])[CH3:11])[CH2:14]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN(C)C1CCNC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
A mixture of 4-aminobenzoic acid (1.4 g, 10 mmol), 3-(dimethylamino)-pyrrolidine (1.5 g, 13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.5 g, 13 mmol) in CH2Cl2 is stirred at room temperature for 16 h, diluted with CH2Cl2, washed with water, dried over MgSO4 and concentrated in vacuo to give the title compound (1.1 g), identified by NMR analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CO>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:22](=[O:24])[CH3:23])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)N1C[C@H](C)C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
((3R,5R)-5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (0.422 g, 1.971 mmol) was dissolved in DCM. Pyridine (0.2 ml, 2.56 mmol) was added, followed by acetic anhydride (0.24 ml, 2.56 mmol). The resulting colorless solution was stirred at RT overnight. 1 ml of MeOH was added and the mixture was stirred for about 30 minutes before being evaporated. The residue was partitioned between EtOAc and aqueous 1M HCl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The remaining oil was dried under high vacuum to give 0.51 g of ((3R,5R)-1-acetyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester as an off-white solid (>95% yield).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[P:12]([Cl:17])(Cl)(Cl)(Cl)[Cl:13].Cl.C(O)=[O:20]>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:9][P:12]([Cl:17])([Cl:13])=[O:20])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C(=O)NP(=O)(Cl)Cl)cc1

Procedure:
A suspension of 18.1 g (0.12 mole) of 4-cyanobenzamide, 25.8 g (0.12 mole) of phosphorus pentachloride and 250 ml of AR carbon tetrachloride was stirred and heated at 70° until the HCl gas evolution had subsided; ca. 25 min. The solution was cooled to 30° and 5.9 g (0.12 mole) of 97% formic acid was added while maintaining a temperature of 30°. After stirring for 30 min., the product was collected, washed with AR carbon tetrachloride and dried to give 52 g, m.p. shrinks 162°-165°, darkens 218°, decomposes >300°.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:29][C:28]=1C=O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:29][C:28]=1[CH:1]([O:4][CH3:5])[O:6][CH3:7]
Reactant: COC(OC)OC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(OC)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 0.5 h

Procedure:
170 ml of trimethyl orthoformate were added to a thoroughly stirred suspension of 136 g of montmorillonite K10 in 700 ml of anhydrous toluene, and stirring was carried out for 30 minutes. Thereafter, 68.0 g of 3-(4-chloro-3-formylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine were added dropwise while cooling with ice, and the batch was stirred overnight at 25° C. The montmorillonite K10 was filtered off and washed thoroughly with toluene. The solvent, excess ortho-ester and methyl formate were distilled off under reduced pressure from the combined filtrates. The remaining oil was crystallized with petroleum ether.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]1[CH2:23][C@H:22]1[CH:24]([NH:26][O:27][CH3:28])[CH3:25].C1N2CCN(CC2)C1>C(#N)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]1[CH2:23][C@H:22]1[CH:24]([N:26]([O:27][CH3:28])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:25]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (80 mg; 0.41 mmol) in acetonitrile (1 ml) was added dropwise to a stirred mixture of trans-N-{1-[2-(2,4-dichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine diastereomere A (88 mg; 0.34 mmol), prepared as described in example P13 and DABCO (54 mg; 0.48 mmol) in acetonitrile (1 ml) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (10 g) (eluent: n-hexane/ethyl acetate 1:1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[N:16]3[N:17]=[C:18]([C:21](O)=[O:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:4]=1.F[B-](F)(F)F.[N:31]1([O:40][C:41](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl-].[NH4+].CCN(CC)CC.CN(C=[O:61])C>>[C:41]([OH:40])([C:2]([F:25])([F:24])[F:1])=[O:61].[F:25][C:2]([F:24])([F:1])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[N:16]3[N:17]=[C:18]([C:21]([NH2:31])=[O:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:4]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc2ncc(-c3cc(C(F)(F)F)cc4[nH]ncc34)n2n1
Reactant: CN(C)C=O
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2ncc(-c3cc(C(F)(F)F)cc4[nH]ncc34)n2n1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(6-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid (0.036 g, 0.104 mmol) in DMF (3 mL) was added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.028 g, 0.073 mmol), ammonium chloride (8.32 mg, 0.156 mmol), and Et3N (0.013 g, 0.124 mmol). The reaction mixture was stirred at room temperature overnight and was subsequently filtered and purified by preparative HPLC, eluting with a gradient of 25-50% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give a TFA salt of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.35-7.46 (m, 1H), 7.53 (t, J=7.58 Hz, 1H), 7.71 (d, J=8.59 Hz, 1H), 7.82 (dd, J=18.32, 9.47 Hz, 1H), 7.95-8.05 (m, 2H), 8.40 (t, J=9.35 Hz, 1H), 8.50 (br s, 1H), 8.57-8.66 (m, 1H), 8.70 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H9F3N6O, 347.1. found 347.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29](Cl)[N:28]=[N:27][C:26]=2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1COCC1>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[N:28]=[N:27][C:26]=2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCCN(CC)CC)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-diethylamino-ethanol (0.42 mmol, 50 mg) in THF at room temperature was added NaH (0.85 mmol, 20 mg). Stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.14 mmol, 50 mg) was added. The resulting mixture was stirred at 50-55° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10% methanolic solution of ammonia (2.0 M ammonia in methanol) in ethyl acetate to provide {2-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-ethyl}-diethyl-amine.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=[O:15])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[C:23]1([OH:34])[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1.Cl.O1CCOCC1>CO>[OH:34][C:23]1([CH:3]2[N:4]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5](=[O:15])[CH2:6][N:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]2=[O:1])[CH2:26][NH:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2C(=O)N(Cc3ccccc3)CC(=O)N2Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1C(C2(O)CNC2)N(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 1,1-dimethylethyl 3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate (1.04 g, 2.2 mmol) in methanol (10 mL) was treated with hydrogen chloride in dioxane (4 N, 5.5 mL, 22 mmol) at 60° C. for 25 min. After cooling to room temperature the solution was concentrated. Ethyl acetate and 2 N hydrochloric acid were added to the residue and the phases were separated. The organic phase was discarded. The aqueous phase was basified with 5 M sodium hydroxide and the resulting solution was extracted 4 times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (85% dichloromethane: 14% methanol: 1% aqueous ammonium hydroxide) to provide 3-(3-hydroxyazetidin-3-yl)-1,4-bis(phenylmethyl)piperazine-2,5-dione as a colorless film (493 mg, 1.35 mmol, 61% yield). 1H NMR (400 MHz, CDCl3): 7.39-7.28 (m, 6H), 7.25-7.20 (m, 4H), 5.39 (d, 1H), 4.80 (d, 1H), 4.44 (d, 1H), 4.36 (d, 1H), 4.26 (d, 1H), 4.11 (s, 1H), 3.97 (d, 1H), 3.83 (d, 1H), 3.71 (d, 1H), 3.27 (m, 2H); MS (EI) for C21H23N3O3: 366 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzotrifluoride (1a, 1.0 g, 4.78 mmol), methyl 4-hydroxyphenylacetate (1b, 795 mg, 4.78 mmol) and potassium carbonate (661 mg, 4.78 mmol) in 10 mL of DMSO was allowed to stir at 60° C. for 24 h. Upon completion, the mixture was cooled to room temperature and 50 mL of water was added. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using 20% EtOAc/hexane as the eluent to give 1.31 g of [4-(2-nitro-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester. 1H NMR (CDCl3): δ 8.22 (d, J=2.00 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (d, J=8.36 Hz, 2H), 7.08 9s, 1H), 7.07 (d, J=8.48 Hz, 2H).
Reaction SMILES: C([C:3]1[C:4](=[O:11])[NH:5][CH:6]=[CH:7][C:8]=1[O:9]C)#N.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[OH:11][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:8]([OH:9])[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 177.5 °C
Reaction time: 2 h

Procedure:
86% phosporic acid (90 mL, 151.3 g) and 3-cyano-4-methoxy-2(1H)-pyridinone (Compound X) (30.0 g, 0.20 mole) are combined under argon in a 500 mL flask equipped with a mechanical stirrer, reflux condensor. The mixture is heated in an oil bath at 175-180° C. for 23 hours. The reaction mixture is cooled to 71° C. and glacial acetic acid (90 mL, 94.5 g) added and the mixture heated at 90° C. for about 90 minutes. Fuming nitric acid (density=1.52) (12.6 g, 8.3 ml) is then added carefully over a period of 15 minutes (giving a mild exotherm), and the mixture heated at 90-95° D. for 2 hours. Water (90 mL) is then added to the mixture and heating at 90° C. continued for 1 hour. The mixture is then cooled slowly with stirring to room temperature, filtered through a sintered glass funnel and the residue washed with water to give Compound XII, m.p. 268° C.; NMR (DMSO) δ7.44 (1H, d); 6.0 (1H, d); 3.5 (2H).
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]([CH:12]=[N+](C)C)=[C:5]2[CH:4]=1.C(=O)(O)[O-:25].[K+]>CO>[Br:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]([CH:12]=[O:25])=[C:5]2[CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2C=[N+](C)C)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2nn3ccc(Br)cc3c2C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred solution of N-((5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)methylene)-N-methylmethanaminium chloride (260 mg, 0.66 mmol) in methanol (3 mL) was added a 3% solution of potassium bicarbonate (3.1 mL) and the mixture was stirred at room temperature for 2 h. The solids were collected by filtration and dried under reduced pressure to afford the title compound as a solid (201 mg, 92%). LCMS m/z 331.0, 333.0 (M+H)+, ret. time=2.13 min.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:10](=[O:23])[C:9]2=[O:24])(=[O:5])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:23])[C:9]2=[O:24])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O

Procedure:
A solution of tert-butyl 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetate (0.926 g, 2.51 mmol) and TFA (3 ml, 38.9 mmol) in DCM (10 ml) was stirred at room temperature for 4 hours. The volatiles were removed under vacuum affording 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetic acid which was used as such in the next step (1.29 g, 4.13 mmol).MS/ESI+ 312.9 [MH]+.