Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([C@H:49]([OH:51])[CH3:50])[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:62]=[C:63]1[CH:67]=[CH:66][C:65](=[O:68])[N:64]1[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][C:74]([NH:76][NH2:77])=[O:75]>>[O:68]=[C:65]1[CH:66]=[CH:67][C:63](=[O:62])[N:64]1[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][C:74]([NH:76][NH:77][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([C@H:49]([OH:51])[CH3:50])[C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:75]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)NCc1ccccc1)[C@@H](C)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)NCc1ccccc1)[C@@H](C)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157 from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3R)-1-(benzylamino)-3-hydroxy-1-oxobutan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[I:16]I.C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>C(#N)C>[I:16][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: II
Reactant: CCOC(=O)CCc1cccc(OC)c1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OC)ccc1I
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of ester 25 (1.618 g, 7.77 mmol) in acetonitrile (100 mL), iodine (1.972 g, 7.77 mmol) and n-butyltriphenylphosphonium peroxodisulfate (6.455 g, 7.77 mmol) were added and refluxed for 45 min. The reaction mixture was cooled to room temperature and the excess of iodine was removed by dropwise addition of 1M Na2S2O3 solution. The colourless solution was transferred to a separatory funnel and the organic layer was separated and dried over Na2SO4. Evaporation of the solvent followed by means of column chromatography on silica gel (hexane/isopropylether 10:1) gave 1.982 mg of iodinated ester 26 as a yellowish oil. Yield 76%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.65 (d, J=8.7 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H), 6.51 (dd, J1=8.7 Hz, J2=3.0 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 3.00 (t, J=7.9 Hz, 2H), 2.60 (t, J=7.9 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 172.4, 160.0, 144.0, 139.9, 115.5, 114.1, 88.6, 60.5, 55.3, 35.9, 34.4, 14.2; HRMS (EI) m/z: calcd for C12H15|O3: 334.0065. found: 334.0082.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][CH:18]1[CH2:19][CH2:20][CH:21]2[CH:26]=[N:27][OH:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:26]([Cl:8])=[N:27][OH:28])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1N2CC(CCC2C=NO)N1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
NCS (295 mg, 2.2 mmol) was added to a solution of 6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbaldehyde oxime (560 mg, 2.0 mmol) in dry DCM (15 mL) at rt. Pyridine (one drop) was then added, and the reaction mixture was stirred at rt for 18 hrs. The solution was evaporated to afford (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride, which was directly used in the next step. ESI-MS (EI+, m/z): 274 [M-Cl]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:5]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)OCc1ccc2ccccc2c1)C(F)(F)F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.96 g, 19.0 mmol), 2-(bromomethyl)naphthalene (4.19 g, 19.0 mmol), and potassium carbonate (7.86 g, 56.9 mmol) in 50 ml of anhydrous DMF was stirred at 30° C. overnight. Diluted with 150 ml of EtOAc, washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl, diced (Na2SO4) and concentrated to give an oil that was purified by ISCO using EtOAc in hexanes (5%) as eluents to provide the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:3].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:3][C:2]([CH3:12])([C:4](=[O:11])[CH:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:1]
Reactant: BrCCCCOc1ccccc1
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)C(CCCCOc1ccccc1)n1cncn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 14.3 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one (cf. German Laid-Open Application DOS No. 2,638,470) in 20 ml of dimethylformamide was added dropwise, under a dry nitrogen atmosphere, to a stirred suspension of 2.3 g of sodium hydride in 20 ml of dimethylformamide, the reaction temperature being kept at 20°-30° C. by cooling; the mixture was subsequently stirred for 20 hours at room temperature. A solution of 19.5 g of 1-bromo-4-phenoxybutane in 20 ml of dimethylformamide was then added dropwise at 5°-10° C., with continued stirring, and while cooling with ice. After completion of the addition, stirring was continued for 10 hours at 5°-10° C., after which 200 ml of water were added and the mixture was extracted with twice 100 ml of methylene chloride. The combined organic phases were extracted by shaking with water and dried over magnesium sulfate; removal of the solvent under reduced pressure gave an oil from which, on trituration with 20 ml of diisopropyl ether, 17 g of colorless crystals were precipitated; melting point 59°-62° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.Br[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.O.[OH-].[Cs+]>CN(C=O)C>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][N:1]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]3)[N:2]=2)[N:8]=1)[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccn(CCN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40.0 mg; 0.104 mmol) in dry DMF (0.5 mL) was added tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (30.4 mg; 0.104 mmol) and cesium hydroxide hydrate (17.4 mg; 0.104 mmol). The mixture was stirred under a nitrogen atmosphere for 30 minutes. The mixture was filtered, washing with methanol and ethyl acetate, and the solvent was removed under reduced pressure. The residue (a mixture of two regioisomers) was purified by preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The desired isomer tert-butyl 4-(2-(3-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate was isolated (21.5 mg) along with some of the alternate isomer.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(N)CO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CC(C)C(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 45 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-3-methyl-butan-1-ol according to the GPA affording 17 mg (45%) of a red powder. Rt=4.00 min.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][F:15].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:15][CH2:14][CH2:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FCCBr
Reactant: Oc1ccc2c(c1)NCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)N(CCF)CCC2
Yield: 44 %

Procedure:
500 mg (3.35 mmol) 1,2,3,4-Tetrahydro-quinolin-7-ol are dissolved in 8 mL DMF and stirred at 60° C. overnight with 0.325 mL (1.3 eq) 1-bromo-2-fluoroethane, in the presence of 0.63 mL (1.1 eq) diisopropylethylamine. The reaction mixture is extracted with 0.1 N aqu. HCl and ethyl acetate. The combined organic extracts are washed with brine, dried over sodium acetate and evaporated. The residue is column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2 to 1:1) to yield 290 mg (44%) desired product as a brown oil.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH2:9]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH:4]([CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1)[C:23]#[N:24])=[O:5]
Reactant: CCOC=O
Reactant: N#CCc1ccc(Cc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(C=O)c1ccc(Cc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a suspention of sodium methoxide (64.26 g) in toluene (2.5 l) was added dropwise at 0° C. a mixture of ethyl formate (88.14 g) and 4-benzylphenylacetonitrile (189.69 g) with stirring. After 30 minutes, ice bath was removed. After 20 hours, ice water (2.6 l) was added to the reaction mixture, and the aqueous layer was separated. The organic layer was washed with 0.5N sodium hydroxide aqueous solution (500 ml×5). The aqueous layer and the washings were combined, adjusted to acid with conc. hydrochloric acid, and stirred at 0° C. for 30 minutes. The precipitate was separated by filtration, washed, and dried to give the title compound (152.22 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[CH3:39][S:36]([O:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(NC(=O)OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
Benzyl 3-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)phenylcarbamate (4 g) was dissolved in dry DCM (80 mL) and cooled to 0° C. under an argon atmosphere. Triethylamine (5 g) was added, followed by mesyl chloride (3.42 g) added drop-wise over a period of 2 hours. The reaction temp was maintained at 0° C. for further 2 hours. The reaction was quenched by addition of water, extracted into DCM and concentrated under vacuum at a temperature below 25° C. The crude product (3.5 g) was unstable and was used for next step as soon as possible.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[CH:9][C:10]=1[C:11](Cl)=[O:12]>C(Cl)Cl>[CH:1]([O:4][C:11]([C:10]1[CH:9]=[C:8]([CH3:14])[O:7][C:6]=1[CH3:5])=[O:12])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CC(C)O
Solvent: ClCCl
Product: Cc1cc(C(=O)OC(C)C)c(C)o1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Isopropanol (5 ml) was added to a solution of 2,5-dimethylfuran-3-carbonylchloride (1.64 g; 10.3 mmol) in 15 ml of methylene chloride at rt. After allowing the reaction mixture to stand at rt for 30 mins, the volatiles were removed in vacuo and the residue was co-evaporated from isopropanol to afford compound 865A (1.8 g, 96%) as a light amber liquid. 1HNMR (CDCl3): δ 1.30 (d, j=6.5 Hz, 6H), 2.23 (s, 3H), 2.52 (s, 3H), 5.14 (m, 1H), 6.21 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=2)[C:8]([Cl:9])=[CH:7][N:6]=1
Reactant: Clc1cc(CBr)c(Cl)cn1
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Cc2cc(Cl)ncc2Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of 4-bromomethyl-2,5-dichloro-pyridine (500 mg, 2.08 mmol) in toluene (10 mL) was added with stirring the [1,1-bis(diphenylphos-phino)ferrocene]dichloropalladium DCM complex (74 mg, 0.101 mmol), B-(3-fluorophenyl)-boronic acid (290 mg, 2.08 mmol) and sodium carbonate (440 mg, 4.15 mmol) in water (2 mL). The resulting mixture was stirred at 80° C. for 3 h, cooled, poured onto water (20 mL), and partitioned between water and ethyl acetate. The organic portions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to give the title compound (241 mg, 32%) as white solid. LC-MS (UV peak area, m/z) 70%, 255.0, 257.0 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Cl)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13]([O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OCc1ccccc1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
A mixture of 3-(benzyloxy)-5-chloro-2-nitropyridine (1.00 g, 3.78 mmol), potassium carbonate (2.09 g, 15.1 mmol), 2-chlorophenol (1.46 g, 11.3 mmol) and DMF (16 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled, partitioned between a 1:1 mixture of ethyl acetate (60 mL) and ether and water (60 mL). The organic layer was washed with 2N NaOH (30 mL), water, and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford 3-(benzyloxy)-5-(2-chlorophenoxy)-2-nitropyridine (0.73 g, 54.2% yield) as a light yellow solid. 1H NMR (CDCl3) δ 5.16 (s, 2H), 6.90 (s, 1H), 7.09 (d, 1H), 7.28-7.37 (m, 7H), 7.52 (d, 1H), 7.72 (s, 1H).
Reaction SMILES: [N:1]1([C:15]([C@H:17]([NH:27][C:28](=[O:40])[C:29]([NH:32]C(OC(C)(C)C)=O)([CH3:31])[CH3:30])[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH2:7]2)[CH2:3][CH2:2]1.CN1CCOCC1.[CH2:48]([S:50](Cl)(=[O:52])=[O:51])[CH3:49]>ClCCl>[CH2:48]([S:50]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]2([CH2:5][CH2:6][N:1]([C:15]([C@H:17]([NH:27][C:28](=[O:40])[C:29]([NH2:32])([CH3:30])[CH3:31])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])[CH2:2][CH2:3]2)[CH2:7]1)(=[O:52])=[O:51])[CH3:49]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccccc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCS(=O)(=O)N1CC2(CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.158 g the intermediate from Step B in 5 mL of dichloromethane was added 0.053 mL of N-methylmorpholine, and 0.034 mL of ethanesulfonylchloride and stirred at 0° C. for 30 min and RT for 1 h. The reaction mixture was diluted with an additional 5 mL of dichloromethane and washed with 5 mL of saturated sodium bicarbonate solution, brine (5 mL), dried over MgSO4 and concentrated. Flash chromatography of the residue over 10 g of silica gel with CH2Cl2 -ether (3:1) as eluent gave 0.057 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2ccccc2CN1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]([O:17]C1C=CC=CC=1)(=O)[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1.ClC1C=CC(Cl)=CC=1Cl>>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:8](=[O:17])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: Cc1ccccc1N
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: Oc1ccccc1
Product: Cc1ccccc1NC(=O)c1ccccc1O
Yield: 90.2 %

Procedure:
Phenol was distilled from a boiling mixture of phenyl salicylate (42.8 gm, 0.20 mol), 2-toluidine (26.7 gm, 0.25 mol), and 1,2,4-trichlorobenzene (41 mL) as described in the literature procedure (Organic Syntheses, Coll. Vol. 3, 765). The cooled product mixture was transferred to an 250 mL Erlenmeyer flask and boiled with hexanes (75 mL) for 30 minutes. The solid product was isolated from the hot mixture by vacuum filtration. The solid was washed with more hexanes until the filtrate was colorless. Drying gave the pure 2′-methyl-salicylanilide (41 gm, 90%) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([C:18]3[N:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]4=[C:20]([C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=4)[C:30]([NH:32]/[C:33](=[N:36]/[H])/[CH2:34]O)=[O:31])[N:19]=3)=[O:17])[CH:8]=2)[NH:3]1>CN(C=O)C.CCOCC>[CH3:34][C:33]1[N:32]=[C:30]([C:29]2[CH:28]=[C:27]([C:20]3[N:19]=[C:18]([C:16]([C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2](=[O:1])[N:11]([CH2:12][CH2:13][CH3:14])[C:10]5=[O:15])=[O:17])[N:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=34)[CH:40]=[CH:39][CH:38]=2)[O:31][N:36]=1
Reactant: [H]/N=C(\CO)NC(=O)c1cccc(-c2nc(C(=O)c3ccc4[nH]c(=O)n(CCC)c(=O)c4c3)n3ccccc23)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(-c5nc(C)no5)c4)c4ccccn34)cc2c1=O
Yield: 86.2 %

Procedure:
A solution of 0.1 g (0.19 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}-N-[(1E)-hydroxyethanimidoyl]benzamide in 3 ml of DMF is heated at 120° C. for 5 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in dyethyl ether, filtered, and then dried under reduced pressure at 40° C. overnight. 0.083 g of a yellow solid is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:17])[N:3]=1.Cl.[OH-].[Na+].[CH2:21]([NH2:23])[CH3:22]>>[CH2:21]([NH:23][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:17])[N:3]=1)[CH3:22]
Reactant: CCN
Reactant: Cc1cccc(C(=O)c2ccc(C)nc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(C)ccc1C(=O)c1cccc(C)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A mixture of 2-chloro-6-methyl-3-(3-methylbenzoyl)pyridine (2.45 g, 10 mmol) and 70% ethylamine aqueous solution (10 ml) was sealed in a tube and stirred for 4 hours at 100° C. The reaction solution was cooled to room temperature and transferred into a separating funnel. This was adjusted to pH 1 with 1 N hydrochloric acid, vigorously shaken, adjusted to pH 10 by adding 1 N sodium hydroxide aqueous solution and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-ethylamino-6-methyl-3-(3-methylbenzoyl)pyridine (2.10 g, 83%) as a yellow oily material.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-difluoronitrobenzene and 4-aminophenylethyl alcohol.