Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.CN(C)C=O.S(C1C=CC(C)=CC=1)(O[CH2:17][C@@H:18]1[CH2:32][C@H:31]2[C@@H:21]([CH2:22][C:23]3[C:33]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]2=4)[NH:25][CH:24]=3)[N:20]([CH3:34])[CH2:19]1)(=O)=O>O>[CH3:34][N:20]1[C@H:21]2[C@@H:31]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:33]=3[C:23]([CH2:22]2)=[CH:24][NH:25]4)[CH2:32][C@@H:18]([CH2:17][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2cncn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
0.4 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.0 g of 1,2,4-triazole and 20 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1 hour. After allowing the mixture to cool, water was added to the reaction mixture, and the precipitated crystals were separated by filtration, washed with water and purified by alumina column chromatography (eluted with dichloromethane). The product was recrystallized from methanol to obtain 0.8 g of the titled compound as colorless needles having a melting point of 245°-253° C.
Reaction SMILES: CON(C)[C:4](=[O:24])[C:5]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[C:7]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:6]=1.[CH3:26][Si](C)(C)N[Si](C)(C)C.[Li].C[Mg]Br.Cl>C1COCC1.C(OCC)(=O)C.O>[C:4]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH:8]=[C:9]([S:11]([F:15])([F:13])([F:14])([F:12])[F:16])[CH:10]=1)(=[O:24])[CH3:26]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CON(C)C(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: C[Mg]Br
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C

Procedure:
N-Methoxy-N-methyl-5-pentafluorosulfanyl-3-(2,2,2-trifluoroacetylamino)benzamide (20 mg) was dissolved in absolute THF (2 ml) and stirred at RT with lithium hexamethyldisilazane solution (45 μl, 1 M in THF) for 30 min. Methylmagnesium bromide solution (17 μl, 3 M in diethyl ether) was then added dropwise with stirring at 0° C. After stirring at RT for 1 h, 1N hydrochloric acid was added dropwise with cooling, followed by water and ethyl acetate. The organic phase was separated off and the water phase was additionally extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, filtered and concentrated. 17 mg of crude product were obtained. After further N-methoxy-N-methyl-5-pentafluorosulfanyl-3-(2,2,2-trifluoroacetylamino)benzamide (60 mg) was reacted in the manner described (crude product obtained: 60 mg), the crude products were combined and purified by means of preparative chromatography. The product-containing fractions were combined, freed from the acetonitrile, rendered basic with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 37 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
6-Chloro-2-(4-methoxyanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (2.72 g, 7.40 mM) was stirred in methanol (200 mL), and methanesulfonic acid (50 mL) was added. The tan suspension was heated to reflux for 16 hours during which it turned yellow. This yellow suspension was cooled to room temperature and filtered (the filtrate was saved for use in Example 8). The collected solids were washed with methanol to give the title compound as a yellow powder (1.19 g, 44%), mp 371-373° C.; MS(CI): 370 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C.[CH3:23]N(C)C=O>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][CH2:14][OH:15])=[CH:3][CH:4]=1)=[CH2:23]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: C=Cc1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
4-Hydroxybenzaldehyde (3.664 g) was dissolved in N,N-dimethylformamide (60 ml), followed by the addition of 60% sodium hydride (1.44 g) under ice-cooling. The resulting mixture was stirred at room temperature for 40 min. To the mixture was added (2-bromoethoxy)-t-butyldimethylsilane (8.612 g), and the resulting mixture was stirred at 100° C. for 30 min. After the mixture was cooled as it was, it was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was dissolved in N,N-dimethylformamide (70 ml), followed by the addition of (ethyl)triphenylphosphonium bromide (13.218 g) and 60% sodium hydride (1.623 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, extracted with hexane extraction, and then the resulting organic layer was evaporated. The resulting residue was dissolved in tetrahydrofuran (50 ml), followed by the addition of 2N hydrochloric acid (20 ml) and stirring for 1 hr. The reaction mixture was extracted with ethyl acetate, and the resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless solid (3.025 g, yield; 60%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1)#[N:2].O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: COc1cc(C#N)ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1OC
Yield: 367.6 %

Procedure:
To a mixture of 4-cyano-2-methoxybenzoic acid (1.00 g, 5.648 mmol, Biogene) in methanol (15.0 mL) was added p-toluenesulfonic acid monohydrate (286 mg, 1.48 mmol, Aldrich) and it was heated to reflux under an argon atmosphere for 16 hrs. The solvent was removed and the reaction mixture was extracted with EtOAc, washed with saturated Na2CO3, water, and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-cyano-2-methoxy-benzoic acid methyl ester (1.04 g, 96.4%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])[CH2:13]1)C1C=CC=CC=1.C(Cl)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:25][C:19]1[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Clc1cccc(OC2CCN(Cc3ccccc3)C2)c1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2cccc(Cl)c2Cl)C1
Reaction time: 8 h

Procedure:
To a solution of 200 ml of 2M phosgene in benzene, stirred under nitrogen gas, was added 96 g (0.3 mole) of 1-benzyl-3-(2,3-dichlorophenoxy)pyrrolidine in 300 ml of benzene. The reaction mixture was allowed to stir overnight and then concentrated to an oil. The oil was triturated with 30/60 petroleum ether to give an oil. Solid product, 89 g, was obtained containing a trace of benzyl chloride. The yield was nearly quantitative.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([Cl:19])[CH:18]=1>>[ClH:1].[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[C:13]([Cl:12])[CH:18]=[C:17]([Cl:19])[CH:16]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Cl
Product: Clc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Yield: 57.8 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol) was reacted with (3,5-dichlorophenyl)boronic acid (0.396 g, 2.07 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.310 g, 100%) as a white solid. MW=335.06. 1H NMR (CD3OD, 300 MHz) δ 14.06 (s, 1H), 8.02-7.93 (m, 2H), 7.71 (s, 1H), 7.50 (t, J=1.8 Hz, 1H), 3.17-3.01 (m, 4H), 2.27-2.17 (m, 2H); APCI MS m/z 297 [M+H]+.
Reaction SMILES: [Cl:1][C:2]12[C:15]([Cl:17])([Cl:16])[C:5]([Cl:18])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[C:8]([CH3:13])[C:7]3=[O:14])[C:4]([Cl:19])=[C:3]2[Cl:20].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:15]([Cl:16])([Cl:17])[C:5]([Cl:18])([C:6]3[C:7]([OH:14])=[C:8]([CH3:13])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:19])=[C:3]2[Cl:20]
Reactant: CC1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
30 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-6-methyl-1,4-methanonaphthalene-5,8-dione, prepared according to Example 45, were suspended in 150 ml. of methanol. 2 ml. of pyridine were added and the mixture was refluxed for 4 hours. Upon cooling in an ice-water bath, a crude white solid formed. This solid was recrystallized from methanol and white crystals were obtained. m.p. 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
2,4-Dichloropyrimidine (50.0 g, 333 mmol) and 1-ethynyl-4-fluorobenzene (40.0 g, 333 mmol) were added to triethylamine (200 mL) at 25° C. To the reaction mixture were added dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol) and copper iodide (1.0 g, 5.2 mmol). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 18 h. The residue was partitioned between water (400 mL) and dichloromethane (400 mL). The organic layer was washed with water (2×400 mL), dried (MgSO4) and evaporated under reduced pressure to give an oil. Flash chromatographic purification on silica gel with 0 to 50% ethyl acetate/hexanes as eluant gave 69.5 g of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3].[Br-:12].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:12][CH2:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To 2,5-dichloroacetophenone (5.0 g, 26.45 mmol) in anhydrous tetrahydrofuran (53 mL) under argon was added phenyltrimethylammonium tribromide (9.94 g, 26.45 mmol, 1.0 eq) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, concentrated, and re-dissolved in ethyl acetate. The organic layer was washed with water (2×250 mL) and brine (1×150 mL), dried (MgSO4), filtered, and evaporated in vacuo. Purification using MPLC chromatography (Biotage) gave 3.47 g (52.5%) of 2-bromo-1-(2,5-dichlorophenyl)ethanone as a clear oil. 1H-NMR (DMSO-d6) δ 7.93 (dd, J=2.1 Hz, 0.9 Hz, 1H), 7.61 to 7.60 (m, 2H), 4.86 (s, 2H);
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/B(O)O)=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][N:15]=1.[OH-].[Tl+]>O1CCCC1.O.ClCCl.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>[Br:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14](/[CH:7]=[CH:6]/[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[CH:19]=1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: Brc1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [OH-]
Agent: [Tl+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(/C=C/c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (E)-4-fluorostyrylboronic acid (5 g, 30.1 mmol) and 2,4-dibromopyridine (6.49 g, 27.4 mmol) in tetrahydrofuran (150 mL) was purged with nitrogen for 20 min. To this was added Pd(Ph3P)4 (2.37 g, 2.05 mmol) and a 10% w/w solution of thallium(I) hydroxide (137 g, 62 mmol) in water. The reaction was stirred under nitrogen at room temperature. After 3 h, the gray suspension was diluted with dichloromethane and filtered through celite. The organics were washed with water, dried over magnesium sulfate, and concentrated. The resulting residue was purified by column chromatography (5%→13% EtOAc/Hex) to give 2.65 g (33%). 1H NMR (CDCl3) Shift: 8.43 (d, J=5.2 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.50-7.59 (m, 3H), 7.34 (dd, J=5.3, 1.7 Hz, 1H), 7.10 (t, J=8.7 Hz, 2H), 7.02 (d, J=16.2 Hz, 1H). 13C NMR (CDCl3) Shift: 163.1, 157.0, 150.4, 133.3, 133.2, 132.5, 129.0, 126.4, 125.3, 116.0. 19F NMR (CDCl3) Shift: −112.69 (bs, 1F). Mass spec.: 278.2 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([CH3:35])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[O:31][C:32]([CH3:35])=[N:33][N:34]=5)[CH:28]=4)[N:23]=[CH:22][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 1-(3-fluorobenzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.80(1H,s), 9.45(1H,s), 8.90(1H,s), 8.60(1H,d), 8.25(1H,s), 8.13(2H,m), 7.87(1H,d), 7.79(1H,d), 7.39(1H,dd), 7.10(3H,m), 5.75(2H,s) 2.65 (3H,s); m/z (M+1+) 452.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:25]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([C:43]([OH:45])=[O:44])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:28])[CH:23]=[CH:22][C:11]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:8].CI>CN(C)C=O>[CH2:7]([O:9][C:10]1[CH:25]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([C:43]([O:45][CH3:1])=[O:44])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:28])[CH:23]=[CH:22][C:11]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:8]
Reactant: CCOc1cc(CC(=O)NC(C(=O)O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOc1cc(CC(=O)NC(C(=O)OC)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (0.28 g, 2 mmol) is added to a solution of benzyl 2-ethoxy-4-[N-(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (1.06 g, 2 mmol) in anhydrous dimethyl formamide (8 ml). The mixture is stirred for 10 minutes at ambient temperature, then methyl iodide (0.125 ml, 2 mmol) is added and the resulting mixture is stirred overnight at ambient temperature. It is filtered and the filtrate is concentrated by evaporation to dryness in vacuo. The evaporation residue is partitioned between aqueous sodium bicarbonate solution (pH=9) and methylene chloride. The organic phase was poured over sodium sulphate, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=4/1) and crystallised from ether/petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[CH2:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[CH2:38][CH2:37][N:36]([CH2:19][C:10]2[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:25])[CH:4]=3)[CH:9]=2)[CH2:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)ccc1F
Yield: 98.6 %

Procedure:
Following the procedure of Example 1(10), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 98.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:16]3[CH:24]=[CH:25][C:13]([Cl:12])=[CH:14][CH:15]=3)[CH2:23][CH2:22]2)=[O:9])=[CH:10][CH:11]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C=NCc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)N1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 54.4 %

Procedure:
To a solution of 4-chlorobenzylisocyanate (0.59 g, 3.5 mmol) in anhydrous THF (15 mL) at 0° C. was added 1-(4-chlorobenzyl)piperazine (0.74 g, 3.5 mmol). The resultant mixture was stirred at ambient temperature. After 20 hours the mixture was concentrated of volatiles. The resulting solid was washed with ethyl acetate and dried in vacuo to afford 0.72 g of 1-(((4-chlorobenzyl)amino)carbonyl)-4-(4-chlorobenzyl)piperazine as a white solid; NMR (CDCl3) 7.4 (m, 4), 7.3 (m, 2), 7.2 (m, 2), 4.4-4.1 (m, 6), 3.6 (m, 4), 3.0 (m, 2) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl-].O[NH3+:13]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:13]
Reactant: O=Cc1cccc(O)c1Cl
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-hydroxybenzaldehyde [(2 g, 12.8 mmol) WO 2005007633, p 34] and hydroxylammonium chloride (1.33 g, 19.6 mmol) in acetic acid (20 mL) was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a white solid. The solid was then dissolved in ethyl acetate washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid in quantitative yield.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([F:27])[CH:21]=1)[C:14]([O:16]CC)=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.CO>[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([F:27])[CH:21]=1)[C:14]([OH:16])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1ccc(Cl)c(F)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Cl)c(F)c1)C(=O)O
Reaction time: 8 h
Yield: 100.5 %

Procedure:
A solution of Boc2O (1.3 g, 6.1 mmol) and ethyl 3-amino-2-(4-chloro-3-fluorobenzyl)propanoate (1.6 g, 6.1 mmol) in DCM (10 mL) was stirred overnight. The mixture was concentrated in vacuo and chromatographed (SiO2) using DCM as eluent to give ethyl 3-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorobenzyl)propanoate. LiOH—H2O (0.26 g, 6.1 mmol) in H2O (7 mL) was added to a solution of ethyl 3-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorobenzyl)propanoate (0.55 g, 1.5 mmol) in THF/MeOH (7/7 mL) and stirred overnight. The mixture was concentrated in vacuo, acidifed to a pH of 1 with 1.0N HCl, and extracted with DCM. The DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using 10% MeOH/DCM as eluent to give 3-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorobenzyl)propanoic acid (0.5 g). LCMS (APCI+) [M−Boc+H]+ 232.0; Rf: 2.09 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](=O)[CH3:8].C([O-])(=O)C.[NH4+:14]>CO.C([BH3-])#N.[Na+]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH3:8]
Reactant: CC(=O)c1cnccn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 749 %

Procedure:
To a solution of 1-pyrazin-2-yl-ethanone (2.0 g, 15.85 mmol) and ammonium acetate (19.337 g, 158.5 mmol) in methanol (50 mL) was added sodium cyanoborohydride (0.7 g, 11.1 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. After removal of methanol, water (20 mL) was added to the residue and the resulting solution was basified by addition of sodium hydroxide to pH=13. The aqueous solution was extracted with dichloromethane and the combined organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 14.62 g of 1-pyrazin-2-yl-ethylamine, yield: 75%. MS (M+H)=124.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH:9]([C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: Clc1ccccc1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2ccccc2Cl)c1

Procedure:
To a solution of 2-bromochlorobenzene (0.24 mL, 2 mmol) and 3-formylbenzeneboronic acid (0.35 g, 2.2 mmol) in toluene (20 mL) were added 2M aq. sodium carbonate (2.6 mL) followed by (Ph3P)4Pd (0.34 g, 0.3 mmol). The resulting reaction mixture was refluxed for 3 h, cooled and diluted ethyl acetate. The organic phase was washed with water, saturated aq. sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography (hexane:ethyl acetate; 4:1) to yield the title product.