Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1.[CH3:16][N:17]([CH3:30])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([CH3:29])=[C:23]([CH:27]=O)[NH:24][C:25]=1[CH3:26]>N1CCCCC1.C(O)C>[CH3:30][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([CH3:29])=[C:23]([CH:27]=[C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)[NH:12][C:11]2=[O:15])[NH:24][C:25]=1[CH3:26]
Reactant: O=C1Cc2ccc(-c3cccs3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccs4)ccc32)c(C)c1CCCN(C)C

Procedure:
A mixture of 6-thiophen-2-yl-1,3-dihydroindol-2-one (100 mg, 0.46 mmol), 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (100 mg, 0.48 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-thiophen-2-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:30]([C:25]5[CH2:29][CH2:28][CH2:27][CH:26]=5)=[O:31])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)C1=CCCC1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)C1=CCCC1
Yield: 26.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), N,N-dimethylacetamide (4.0 mL), 1-cyclopentenecarboxylic acid (139 mg, 1.24 mmol), O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (704 mg, 1.86 mmol), 1-hydroxybenzotriazole (251 mg, 1.86 mmol) and N,N-diisopropylethylamine (323 μL, 1.86 mmol), and in the same manner as in Example 219, the title compound (69 mg, 21%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH2:17][NH:18][O:19][CH3:20]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:18]([CH2:17][C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([F:13])[CH:15]=2)[O:19][CH3:20])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1cccc(F)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1cccc(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 94 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as a white solid (94% yield): mp 110-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.70 (3H, s, OCH3), 4.82 (2H, s, NCH2). 6.40 (1H, s, CH), 6.96-7.32 (4H, m, aromatics). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.00; H, 5.30; N, 4.49.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:26]([N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: COCCNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-(2-methoxyethyl)-2-methylpropan-2-amine (CAN 22687-22-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=398.4 [MH+].
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[OH-].[Na+].[C:12]([OH:19])(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16].Cl>CCO>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:17][C:15](=[O:16])[CH2:14][CH2:13][C:12]([OH:19])=[O:18])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=CC(=O)CCC(=O)O)cc1
Yield: 19.4 %

Procedure:
4-Tolualdehyde (39.6 g, 0.33 mol) and 2M NaOH solution (230 ml) are added to a solution of levulinic acid (39.5 g, 0.34 mol) in EtOH (85 ml) over 1 hour. The resulting clear solution is poured into ice and acidified with 6M HCl. The resulting gum obtained is crystallised with acetone/water and recrystallised from CH2Cl2 to yield 14.0 g of 6-(4 methylphenyl)-4-oxo-hex-5-enoic acid as colourless crystals m.p. 129-130.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:68]([O:72][C:73]([NH:75][CH2:76][C:77]1([C:80](O)=[O:81])[CH2:79][CH2:78]1)=[O:74])([CH3:71])([CH3:70])[CH3:69].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:80]([C:77]5([CH2:76][NH:75][C:73](=[O:74])[O:72][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:79][CH2:78]5)=[O:81])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(C(=O)NS(=O)(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzenesulfonamide (1 g, 1.94 mmol) in DCM (10 mL) solution were added PyBOP (1.21 g, 2.33 mmol), 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid (0.46 g, 2.14 mmol) and DIEA (1.36 mL, 7.77 mmol). The mixture was stirred at room temperature for 16 hs. All solvents were removed under vacuum and the residue was purified by silica gel column (MeOH/hexane: 5%) to give tert-butyl (1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)phenylsulfonylcarbamoyl)cyclopropyl)methylcarbamate (1.38 g, 100%) as a brown solid. LC-MS (Condition A), MS m/z 712.0 (M++H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([C:4]2[CH:3]=[C:2]([CH3:1])[S:6][C:5]=2[C:7]([O:9][CH3:10])=[O:8])=[CH:23][CH:22]=1)[CH3:20]
Reactant: COC(=O)c1sc(C)cc1OS(=O)(=O)C(F)(F)F
Reactant: CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1ccc(-c2cc(C)sc2C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed methyl 5-methyl-3-(((trifluoro methyl)sulfonyl)oxy)thiophene-2-carboxylate (1.7 g, 5.59 mmol), (4-ethylphenyl)boronic acid (1.0 g, 6.69 mmol), K3PO4 (3.84 g, 18.1 mmol), Pd(PPh3)4 (157 mg, 0.136 mmol), 1,4-dioxane (40 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 1.46 g (100%) of methyl 3-(4-ethylphenyl)-5-methylthiophene-2-carboxylate as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:27][OH:28]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][O:28][CH3:27])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CO
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Product: COCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Temperature: 60 °C

Procedure:
1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate are dissolved in 10 ml of methanol and the solution is heated at 60° C. for 45 minutes. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in ethyl acetate and shaken with aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure, and the residue is purified by chromatography on a silica gel column using diethyl ether/ethyl acetate (15:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-methoxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 4.40 ppm (d, 1H), 4.33 ppm (d, 1H), 3.49 ppm (s, 3H), 3.39 ppm (s, 3H), 2.43 ppm (s, 3H), 1.35 ppm (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[CH3:14][C@@H:15]1[CH2:21][NH:20][C:19](=[O:22])[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][CH2:21][C@H:15]2[CH3:14])=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: C[C@@H]1CNC(=O)CCN1
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Product: C[C@@H]1CNC(=O)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described in intermediate 78C, (E)-3,4-dichlorocinnamic acid and (R)-2-methyl-[1,4]diazepan-5-one gave the title compound as a colorless gum, MS: m/e=327.3 (MH+).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([CH:10]1[CH:21]2[C:22](=O)[CH:17]([CH2:18][CH2:19][CH2:20]2)[C:16]2(O)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:7][CH2:8][CH3:9]>C(O)(=O)C>[CH2:6]([C:10]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:22]=2[N:5]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:7][CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCCCC1C2CCCC(C2=O)C2(O)CCCCC12
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCCc1c2c(nc3c1CCCC3)CCCC2

Procedure:
A 500 mL, one-necked flask equipped with a magnetic stirring bar, a Claisen adapter, and a reflux condenser equipped with a nitrogen inlet attached to a bubble (Note 6) is charged with 17.0 g (0.22 mol) of ammonium acetate, 82 g (0.41 mol) of cupric acetate monohydrate and 200 mL of glacial acetic acid, then flushed with nitrogen. The mixture is stirred and heated at reflux under a static atmosphere of nitrogen for 15 min., then the resulting solution is cooled slightly as 53 g (0.20 mol) of 8-n-butyl-2-hydroxytricyclo[7.3.1.02,7 ]tridecan-13-one is added in several portions. The blue-green reaction mixture is stirred and heated at reflux under nitrogen for 3 hrs., then the reaction flask is cooled in an ice bath for 2-3 hours. Precipitated cuprous acetate is removed by vacuum filtration using a fitted glass funnel (medium or coarse porosity) and washed with 100 mL of acetic acid. The combined filtrates are diluted with 500 mL of water, cooled in ice and carefully neutralized by slow addition of aqueous sodium hydroxide (Note 7). The resulting cloudy mixture is transferred to a separatory funnel and extracted with ether (400 mL, then 2×200 mL). The combined ether extracts are washed with 140 mL of 3% aqueous sodium hydroxide and 70 mL of saturated aqueous sodium chloride, then dried using anhydrous magnesium sulfate with 1 g of decolorizing charcoal (Norit). The solids are removed by filtration and washed with at least 200 ml of ether. The combined filtrates are concentrated to minimum volume using a rotary evaporator and residual solvent is removed under vacuum (1 mm). The product is obtained as a beige crystalline solid, mp 35°-37° C., 47 g (97%) (Note 8).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Sodium borohydride (1.0 mg, 0.026 mmol), followed by MeOH (0.1 mL), was added to a solution of 4-{2-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-ethylsulfanyl}-butyric acid methyl ester (6.8 mg, 0.017 mmol) in CH2Cl2 (0.3 mL) at 0 ° C. After 15 min at 0° C., the reaction was quenched with aqueous HCl (0.1 M, 4 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 6.8 mg (99%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].C(=O)(O)[O-].[Na+].[CH3:16][CH2:17][C@@H:18]([NH2:21])[CH2:19][OH:20]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:21][CH:18]([CH2:19][OH:20])[CH2:17][CH3:16])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC[C@@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CO)Nc1ccc(C#N)cc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
A 100 mL round bottom flask was charged with 3,4-difluorobenzonitrile (2.013 g, 14.5 mmol), sodium bicarbonate (1.59 g, 18.9 mmol), and L-(−)-2-amino-1-butanol (1.33 mL, 14.5 mmol). The contents were then dissolved in 40 mL N,N-dimethylformamide (anhydrous). The flask was heated to 90° C. and stirred overnight under N2. The reaction mixture was cooled to room temperature, poured onto water, and extracted with EtOAc (2 times). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (gradient from 5% EtOAc/Hexanes to 10% EtOAc/Hexanes followed by 50% EtOAc/Hexanes) to afford 1.00 g (33% yield) of the title compound. 1H NMR (CDCl3, 500 MHz) δ: 7.28 (m, 1H), 7.21 (dd, J=11.3, 1.8 Hz, 1H), 6.72 (t, J=8.5 Hz, 1H), 4.49 (s, 1H), 3.77 (m, 1H), 3.68 (dt, J=10.0, 5.3 Hz, 1H), 3.48 (m, 1H), 1.87 (m, 1H), 1.72 (dqn, J=14.5, 7.5 Hz, 1H), 1.60 (dqn, J=14.5, 7.5 Hz, 1H), 1.00 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH2:29])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH:29][C:13]([C:9]1[CH:10]=[C:11]([OH:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:15])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1

Procedure:
To a solution of 12.1 g 1-phenyl-3-carboxy-5-pyrazolone, 15 g (S)-2-amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester and 22.5 g HATU in 200 ml DCM were added 34 ml triethylamine. After 2 h the mixture was extracted with water and the crude product obtained after evaporation of the solvent reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-(trifluoromethyl)benzoic acid (224 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 2-chloro-5-(trifluoromethyl)benzoyl chloride.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([NH:8][C:9]([CH:11]1[N:15]([C:16]([CH:18]([NH:24][C:25]([CH2:27][NH:28][C:29]([CH:31]([NH:42][C:43]([CH:45]([NH:53][C:54]([CH:56]([NH:64][C:65]([CH:67]([NH:74][C:75]([CH:77]([NH:83][C:84]([CH:86]([NH:91][C:92]([CH:94]([NH:97][C:98]([CH:100]([NH:109][C:110]([CH:112]([NH:115][C:116]([CH3:118])=[O:117])[CH2:113][OH:114])=[O:111])[CH2:101][C:102]2[CH:107]=[CH:106][C:105]([OH:108])=[CH:104][CH:103]=2)=[O:99])[CH2:95][OH:96])=[O:93])[CH2:87][CH2:88][S:89][CH3:90])=[O:85])[CH2:78][CH2:79][C:80]([OH:82])=[O:81])=[O:76])[CH2:68][C:69]2[NH:73][CH:72]=[N:71][CH:70]=2)=[O:66])[CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[CH2:46][CH2:47][CH2:48][NH:49][C:50]([NH2:52])=[NH:51])=[O:44])[CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)=[O:30])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:17])[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:5]([NH2:7])=[O:6])[CH3:3]>[Na+].[Cl-]>[CH3:3][CH:2]([C@H:4]([NH:8][C:9]([C@H:11]1[N:15]([C:16]([C@@H:18]([NH:24][C:25]([CH2:27][NH:28][C:29]([C@@H:31]([NH:42][C:43]([C@@H:45]([NH:53][C:54]([C@@H:56]([NH:64][C:65]([CH:67]([NH:74][C:75]([C@@H:77]([NH:83][C:84]([C@@H:86]([NH:91][C:92]([C@@H:94]([NH:97][C:98]([C@@H:100]([NH:109][C:110]([C@@H:112]([NH:115][C:116]([CH3:118])=[O:117])[CH2:113][OH:114])=[O:111])[CH2:101][C:102]2[CH:107]=[CH:106][C:105]([OH:108])=[CH:104][CH:103]=2)=[O:99])[CH2:95][OH:96])=[O:93])[CH2:87][CH2:88][S:89][CH3:90])=[O:85])[CH2:78][CH2:79][C:80]([OH:82])=[O:81])=[O:76])[CH2:68][C:69]2[NH:73][CH:72]=[N:71][CH:70]=2)=[O:66])[CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[CH2:46][CH2:47][CH2:48][NH:49][C:50]([NH2:52])=[NH:51])=[O:44])[CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)=[O:30])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:17])[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:5]([NH2:7])=[O:6])[CH3:1]
Reactant: CSCCC(NC(=O)C(CO)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(C)=O)C(=O)NC(CCC(=O)O)C(=O)NC(Cc1cnc[nH]1)C(=O)NC(Cc1ccccc1)C(=O)NC(CCCNC(=N)N)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCC(=O)NC(CCCCN)C(=O)N1CCCC1C(=O)NC(C(N)=O)C(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CSCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(C)=O)C(=O)N[C@@H](CCC(=O)O)C(=O)NC(Cc1cnc[nH]1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(N)=O)C(C)C

Procedure:
200 μg: α-melanocyte stimulating hormone/kg b.w. in 0.5 ml 150 mM NaCl.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:17])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]nc1-c1ccccc1
Product: Cc1cc(Cl)nnc1-c1ccccc1

Procedure:
A 24.4 g. portion of 5-methyl-6-phenyl-3(2H)-pyridazinone (prepared as described above) and 250 ml. of phosphorus oxychloride are heated on a steam bath for 6 hours. The reaction mixture is concentrated free of phosphorus oxychloride in vacuo and the concentrate is triturated with cold water. The resulting solid is filtered, washed with water, recrystallized twice from methanol and dried giving a white solid, m.p. 125°-126° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:3]=1.O.[CH3:13][N:14](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[N:14])[N:3]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)c1cccc(C#N)n1
Temperature: 80 °C
Yield: 89 %

Procedure:
To a solution of 2-bromo-6-tert-butylpyridine (Description 14; 9.9 g, 46 mmol) in anhydrous N,N-dimethylformamide (130 ml) was added zinc cyanide (6.48 g, 55.2 mmol) and Pd(PPh3)4 (2.65 g, 2.3 mmol). The mixture was degassed then heated at 80° C. overnight. The cooled reaction mixture was poured into water (500 ml), and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×300 ml), brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with 5% Et2O in iso-hexanes to give the title compound (6.6 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[CH2:7][C:8](=[O:24])[N:9]([CH2:12][CH2:13][CH2:14][N:15](C)[C:16](=O)OC(C)(C)C)[CH:10]=[CH:11][C:5]=2[CH:4]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[CH2:7][C:8](=[O:24])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C(=O)OC(C)(C)C)C=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Temperature: 60 °C
Yield: 78 %

Procedure:
Dissolve 1.9 g (4.86 mmol) of the product obtained in Step 1 in 30 ml of ethanol and add to that solution 7 ml (24.3 mmol, 5 equivalents) of HCl in ethanol (3.5N). Heat overnight at 60° C. and evaporate the reaction mixture to dryness. The residue obtained is taken up in water, and the aqueous phase is then adjusted to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over MgSO4, filtered and then evaporated to dryness. 1.1 g of the title product are obtained in the form of a colourless oil.