Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH3:29])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(-c3nnnn3C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Yield: 45.6 %

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.116 g, 0.331 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.015 g, 0.364 mmol, 60% in mineral oil). Let stir for 20 min, then add methyl iodide (0.022 mL, 0.364 mmol) and let stir for 3 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×30 mL). Combine the organic layers and wash with brine (2×30 mL), aqueous NH4Cl (1×30 mL), aqueous NaHCO3 (1×30 mL) and water (1×30 mL). Dry the organic layer over anhydrous Na2SO4, filter and concentrate under reduced pressure. Separate the two regioisomeric products via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes) and concentrate under reduced pressure the purified fractions. Place the residue under vacuum to give the title compound as a white solid (0.055 g); mass spectrum (m/e): 365.07 (M+H)
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCC1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCC3CCCC3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were introduced portionswise at 20° C in a stirred mixture of 4 g of cyclopentylmethyl amine, 8 g of triethyl amine and 100 ml of ethanol and the reaction mixture was allowed to stand over night. The solvent was distilled off under reduced pressure and the amorphous end product was crystallized under 80 ml of water. Colorless solid body, decomposition beginning at 80° C, γ C=N 1620 cm-1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH:33]=[N:32][NH:31][C:30]2=[O:34])[CH2:25][CH2:24]1.CO>ClCCl>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:24][CH2:25][CH:26]([N:29]3[C:30](=[O:34])[NH:31][N:32]=[CH:33]3)[CH2:27][CH2:28]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O=c1[nH]ncn1C1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC(n4cn[nH]c4=O)CC3)ccc12

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (150 mg) and 2,4-dihydro-4(4-piperidinyl)-3H-1,2,4-triazol-3-one Example 64 (c)) (225 mg). Methanol (10 mL) and dichloromethane (10 mL) were added to the reaction mixture and the solid was collected by filtration to afford the title compound (40 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(F)c(C=O)c1
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
Diisopropylamine (0.35 mL, 2.5 mmol) was dissolved in tetrahydrofuran (3.5 mL) and the temperature was adjusted to 0° C. Then, n-butyllithium (hexane solution) (1.24 mL, 2.0 mmol) was dropped thereto, followed by stirring for 10 minutes. Thereafter the reaction temperature was brought to −78° C. 4-Fluorobenzonitile (0.2 g, 1.65 mmol) was added thereto, stirring for 1 hour. Then, dimethylformamide (0.19 mL, 2.5 mmol) was dropped thereto, followed by stirring for 20 minutes and then the conventional treatment was performed. The residue was purified by thin-layer chromatography (hexane: ethyl acetate=8:1), to give 2-fluoro-5-cyanobenzaldehyde (0.11 g, 43.4%).
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:30])[CH:10]([CH2:14][C:15]1[C:16]([CH3:29])=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][CH:20]=1)[C:11](O)=O)[CH3:7].C=O>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:30])[C:10]([CH2:14][C:15]1[C:16]([CH3:29])=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:19][CH:20]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: CCNCC
Product: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Diethylamine (359 mg, 4.90 mmol) was added dropwise to a solution of 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.44 g, 4.09 mmol) and formaldehyde (464 mg, 5.72 mmol, 37% in water) in methylene chloride (35 mL) at 0° C. under argon. The mixture was stirred at room temperature over night. Methylene chloride was added and the solution was washed with Na2CO3 and brine, dried and concentrated under reduced pressure to give 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (1.03 g, 79%).
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[C:4](OCC)=O)=[O:2].C[O-].[Na+].[N+:20]([NH:23][C:24]([NH2:26])=[NH:25])([O-:22])=[O:21]>CO>[N+:20]([NH:23][C:24]1[NH:26][C:1](=[O:2])[C:3]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:25]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)C(C=O)Cc1ccc(C)nc1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Yield: 27.3 %

Procedure:
A solution of ethyl 2-formyl-3-(6-methyl-3-pyridyl)-propionate (1.55 g) in methanol (20 ml) was added to a stirred solution of sodium methoxide (from 0.161 g sodium) in methanol (20 ml). Dried nitroguanidine (0.73 g) was added and the mixture was heated under reflux overnight and evaporated to dryness. The residue was dissolved in water (50 ml) and the solution was extracted with chloroform and the aqueous phase was adjusted to pH 5 with acetic acid. The solid which precipitated was filtered off and recrystallised from methanol-acetic acid to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.5 g, 27%), m.p. 215°-6° (decomp).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.O.[OH-].[Li+]>C1COCC1.O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccoc3)ccc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Yield: 77.3 %

Procedure:
Methyl 5′-(3-furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylate (980 mg, 2.9 mmol) and lithium hydroxide monohydrate (256 mg, 6.1 mmol) in THF (12 ml) and water (6 ml) were heated at 75° C. for 18 h. The THF was evaporated under vacuum and the aqueous adjusted to pH3 with hydrochloric acid (1M). The precipitate which formed was filtered off, washed with ether and dried under vacuum to give 5′-(3-furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (720 mg, 77%). LCMS: retention time 3.33 min, MH+322.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][CH2:24][OH:25])=[C:13]3[CH3:26])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C1C=CC=CC=1>[C:27]([O:25][CH2:24][CH2:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[C:13]=1[CH3:26])(=[O:29])[CH3:28]
Reactant: COc1ccc2c(c1)c(CCO)c(C)n2-c1ncnc2cc(Cl)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)c(CCOC(C)=O)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A solution of 1-(7-chloroquinazolin-4-yl)-3-(2-hydroxyethyl)-5-methoxy-2-methylindole (0.6g.) and acetic anhydride (0.4g.) in benzene (20ml.; dried over sodium wire) was refluxed for 15 hours. The resulting yellow solution was cooled and washed successively with saturated sodium hydrogen carbonate solution (2 × 20ml.) and water (20ml.), and dried (MgSO4). The solution was evaporated to give 2-[1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-yl]ethyl acetate as an oil [pure by TLC (system A) and having a satisfactory NMR spectrum (--OCH3 τ 6.18)].
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[CH3:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1C
Temperature: 23 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (850 mg, 0.002 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (287 mg, 0.012 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (720 mg, 88%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[O:22].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N+:11]([O-:40])=[CH:10][C:9]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[O:22]
Reactant: Cc1cc(C)c2ncc(NC(=O)Nc3ccc(F)cc3F)c(-c3ccccc3Cl)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)c(-c1ccccc1Cl)c(NC(=O)Nc1ccc(F)cc1F)c[n+]2[O-]

Procedure:
A mixture of 4-(2-chlorophenyl)-3-[3-(2,4-difluoro-phenyl)ureido]- 6,8-dimethylquinoline (1.1 g), m-chloroperbenzoic acid (1.08 g) and dichloromethane (15 ml) was refluxed for 20 hrs. The reaction mixture was washed with aqueous sodium sulfite solution, aqueous sodium hydrogen carbonate solution and water, successively. After being dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from a mixture of methanol and chloroform to give 4-(2-chlorophenyl)-3-[3-(2,4-difluorophenyl)ureido]-6,8-dimethylquinoline 1-oxide as pale yellow prisms. Yield 0.72 g (63.2%). m.p. 230°-232° C.
Reaction SMILES: [CH:1]12[CH:6]([N:7]3[C:11](=[O:12])[C:10]([CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)([CH2:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[NH:9][C:8]3=[CH:27][C:28]([C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)=[O:29])[CH:5]1[CH2:4][NH:3][CH2:2]2.[CH3:38][CH:39]1[CH2:44][CH2:43][N:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:41][CH2:40]1>>[CH3:38][CH:39]1[CH2:44][CH2:43][N:42]([S:45]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[N:7]3[C:11](=[O:12])[C:10]([CH2:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)([CH2:13][C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[NH:9][C:8]3=[CH:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][CH:37]=3)=[O:29])[CH2:2]2)(=[O:47])=[O:46])[CH2:41][CH2:40]1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2C2C3CNCC32)cc1
Reactant: CC1CCN(S(=O)(=O)Cl)CC1
Product: CC1CCN(S(=O)(=O)N2CC3C(C2)C3N2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC1
Yield: 93.1 %

Procedure:
According to the procedure of Example 13, 4-{[1-(3-aza-bicyclo[3.1.0]hex-6-yl)-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene]-acetyl}-benzonitrile (50 mg, 0.102 mmol) and 4-methyl-piperidine-1-sulfonyl chloride (60.2 mg, 0.306 mmol) were reacted to generate the title compound as an off-white solid (62 mg, 0.095 mmol, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([OH:21])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:35])[NH:7]1.[CH3:40][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH:22]([N:12]1[C@@H:11]([C@H:10]2[O:9][C:8](=[O:35])[NH:7][C@H:6]2[CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH2:20][C:19]2[C:14](=[C:15]([O:21][CH3:40])[CH:16]=[CH:17][CH:18]=2)[CH2:13]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3cccc(O)c3CN2C(c2ccccc2)c2ccccc2)O1
Solvent: CO
Solvent: CCOCC
Product: COc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 60 mg (0.11 mmol) portion of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-benzhydryl-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one from Step F (14) was dissolved in 2.5 mL of a 4:1 solution of diethyl ether and methanol. A 0.5 mL portion of 2M trimethylsilyldiazomethane was added and the solution was stirred at rt for 16 h. The excess diazomethane was quenched with the addition of several drops of acetic acid and the solvents were removed in vacuo to provide the desired product. 1H NMR (500 MHz, CDCl3) δ ppm 2.45-2.59 (m, 1H) 3.16-3.22 (m, 1H) 3.25 (dd, J=10.07, 5.49 Hz, 1H) 3.67 (s, 3H) 3.76 (s, 1H) 3.80 (d, J=2.14 Hz, 1H) 3.83 (d, J=2.44 Hz, 1H) 3.97-4.03 (m, 1H) 4.08 (d, J=18.62 Hz, 1H) 4.70 (dd, J=10.22, 6.56 Hz, 1H) 4.85 (s, 1H) 4.92 (s, 1H) 6.66 (d, J=7.93 Hz, 1H) 6.78 (d, J=7.63 Hz, 3H) 7.14-7.19 (m, 1H) 7.20-7.29 (m, 5H) 7.32 (t, J=7.63 Hz, 2H) 7.35 (d, J=7.02 Hz, 2H) 7.42 (d, J=7.32 Hz, 2H).
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.C(N(C(C)C)C(C)C)C.[C:21]([C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][C:37]=3[Cl:46])=[CH:32][CH:31]=2)[C:27]([CH3:47])=[N:26][C:25]=1[CH3:48])(=[O:23])[NH2:22].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:21]([C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43]([N:1]4[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]4)=[O:44])=[CH:38][C:37]=3[Cl:46])=[CH:32][CH:31]=2)[C:27]([CH3:47])=[N:26][C:25]=1[CH3:48])(=[O:23])[NH2:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)Cc2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.6 %

Procedure:
A mixture of ethyl piperidine-4-carboxylate (90 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford ethyl 1-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetyl)piperidine-4-carboxylate (291 mg, 105%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].Br[CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH:18]([CH2:17][CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCOC(=O)CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A reaction vessel was charged with 2.02 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 1.56 g of ethyl 3-bromobutyrate, 1.11 g of potassium carbonate and 20 ml of N,N-dimethylformamide. After stirring at room temperature for 12 hours, the reaction mixture was poured into water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.54 g of ethyl 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxybutyrate (90% yield).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (400 mg,1.70 mmol) in dichloromethane (15 ml) was treated with morpholinomethyl-polystyrene HL resin (1.00 g, 3.4 mmol/g loading) followed by 4-bromo-3-fluorobenzenesulfonyl chloride (0.50 ml, 930 mg, 3.40 mmol). The resulting solution was stirred at room temperature for overnight (20 hours). The reaction mixture and was then filtered, washed with methanol, and the solvent evaporated in vacuo. The residue was applied to an SCX column eluting first with methanol and then 2M ammonia in methanol. The fractions containing product were collected, combined and evaporated in vacuo to afford a crude product which was dry loaded onto a column and purified further by chromatography using a Flashmaster with an eluting gradient of 0 to 5% methanol in dichloromethane over 40 mins. Fractions containing product were combined and evaporated in vacuo to afford the title compound (E105). MS (ES+) m/e 472/474 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](Cl)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:25][C@@H:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1>O1CCOCC1>[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([N:30]2[CH2:29][CH2:28][NH:27][C@H:26]([CH3:25])[CH2:31]2)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Yield: 57.7 %

Procedure:
Solid Na2CO3 (200 mg, 1.9 mmol, 1.9 eq) is added to a solution of 1-benzyl-4-chlorophthalazine (250 mg, 0.98 mmol, 1 eq) and (R)-2-methyl-piperazine (400 mg, 4.0 mmol, 4.0 eq) in dioxane (5 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 150° C. (high absorption setting) for 30 minutes. The reaction mixture is filtered and concentrated, then diluted with EtOAc (50 mL) and water (15 mL). The organic fraction washed with water and then brine, then is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the title compound as a white solid (180 mg, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Br:10])[N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12](Cl)([CH3:14])=[O:13].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Br:10])[N:5]=[C:4]([NH:11][C:12](=[O:13])[CH3:14])[CH:3]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(N)c(C#N)c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
4,6-Diamino-2-bromo-nicotinonitrile (100 mg, 0.47 mmol) was dissolved in 1.0 mL of anhydrous pyridine. AcCl (225 μL, 2.35 mmol) was dropped in slowly. The resulting mixture was shaken overnight at ambient temperature. Water (5 mL) was added to the mixture mixture. The resulting brown solid was collected through filtration, washed with cold water, and dried in a vacuum oven to provide the title compound (100 mg, 83%).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[F:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(F)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2cccc(F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 17.4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(3-fluorophenyl)pyridazin-4(1H)-one (crude, 840 mg, 2.93 mmol) in 20 mL of methanol was added phenylhydrazine (474 mg, 4.39 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(3-fluorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (169 mg, 17% for two steps) as a yellow solid.