Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:24])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([NH:59][CH2:60][C:61]4[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=4)=[O:23])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:24])=[CH:26][CH:27]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Reaction time: 18 h
Yield: 27 %

Procedure:
To a stirred mixture of crude 2-(3-(2-(4-fluorobenzylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.18 g, 0.46 mmol), 1-hydroxybenzotriazole (0.09 g, 0.69 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.13 g, 0.69 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.24 mL, 1.38 mmol) and 3-(aminomethyl)pyridine (0.05 mL, 0.46 mmol). The resulting reaction mixture was stirred for 18 h and diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 5-15% methanol in dichloromethane to afford the title compound as a colorless foamy solid (0.06 g, 28%): 1H NMR (300 MHz, CDCl3) δ 8.57-8.54 (m, 1H), 8.51-8.47 (m, 1H), 7.71-7.65 (m, 1H), 7.30-7.22 (m, 3H), 6.97-6.90 (m, 2H), 6.43 (br s, 1H), 6.05 (t, J=5.8 Hz, 1H), 4.55 (d, J=5.8 Hz, 2H), 4.51 (s, 2H), 4.01 (s, 2H), 3.63-3.53 (m, 4H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5, 167.7, 162.4, 160.7, 157.1, 154.2, 149.1, 148.8, 135.7, 134.1, 131.6 (d, JC-F=3.2 Hz), 130.4 (d, JC-F=8.2 Hz), 123.6, 115.5 (d, JC-F=21.5 Hz), 113.2, 50.3, 42.9, 42.6, 41.8, 41.3, 17.5; MS (ES+) m/z 483.2 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)CC2COc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c32)cc1
Yield: 85 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 4-methoxybenzylamine to give Compound 28 (0.28 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([C:15]1[N:16]=[CH:17][N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=1)=[O:14]>C(O)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)=[O:14]
Reactant: COc1cccc(CCC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1OC
Solvent: O=CO
Product: COc1cccc(CCC(=O)c2c[nH]cn2)c1OC
Temperature: 25 °C
Yield: 46.7 %

Procedure:
17.88 g (0.0687 mole) of 3-(2,3-dimethoxyphenyl)-1-(1-triphenylmethyl-1H-imidazol-4-yl)-1-propanone prepared in Example 2.3.a are heated in 100 ml of formic acid for half an hour at 80° C. The reaction medium is then cooled to room temperature and the triphenylmethanol which has precipitated during cooling is filtered off. Formic acid is distilled off and the residue is taken up in water. The aqueous phase is then brought to pH 9 by addition of a 12 mole/l aqueous solution of ammonia. The precipitate which has formed is filtered off and dried and 8.35 g of 3-(2,3-dimethoxyphenyl)-1-(1H-imidazol-4-yl)-1-propanone are obtained.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].[F:14][C:15]1[CH:16]=[C:17]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)=[C:26]([CH3:35])[CH:25]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)(=[O:23])=[O:22])=[CH:25][C:26]=2[CH3:35])[CH2:31]1
Reactant: COC(=O)CBr
Reactant: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Triethylamine (0.387 mL, 1.533 mmol) and methyl bromoacetate (0.146 mL, 1.533 mmol) were added at 0° C. to a solution of 3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidine (0.445 g, 1.393 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, and the crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.410 g (84% yield) of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH3:23])([CH3:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[N:5]=[CH:6]1)([CH3:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCNS(=O)(=O)c2ccccc2)c1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.05 g) was reacted with benzenesulphonyl chloride (1.15 g) in a similar manner to Example 55 to give N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-4-yl}ethyl]benzene-sulphonamide, as an oil. The compound contained 7% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)-propyl]imidazol-5-yl}ethyl]benzenesulphonamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: [OH:1][CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[OH:1][CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N+:28]=1[O-:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(C(O)c4ccccn4)cc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(C(O)c4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.2 %

Procedure:
In THF (10 ml) was dissolved (E)-N-[4-[hydroxy(2-pyridyl)methyl]phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 70% mCPBA (152 mg). The mixture was stirred at room temperature for 6 hours, and to the solution were added saturated sodium thiosulfate solution (10 ml) and saturated potassium carbonate (10 ml). The mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give (E)-N-[4-[hydroxy(1-oxido-2-pyridyl)methyl]phenyl]3-(4-methylphenyl)cinnamamide (Compound 80) (123 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.ClC1C=C(C[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])C=CN=1>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Br)c1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Product: O=C(Cc1ccnc(Br)c1)c1ccc(F)cc1

Procedure:
21c was prepared from 2-bromo-4-methylpyridine (9.6 g; 56 mmol) using the method described in the synthesis of 21a.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Nc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2cccnc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and 3-aminopyridine (175 mg, 1.36 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (42 mg, 22% yield).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[N:27]=[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]3=[N:24]2)=[CH:7][CH:6]=1.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1>[N:27]1[N:23]([C:17]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([CH:4]([CH3:33])[C:3]([OH:2])=[O:32])=[CH:10][CH:9]=2)[N:24]=[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(OCCCOc2ccc(Cl)cc2-n2nc3ccccc3n2)cc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(OCCCOc2ccc(Cl)cc2-n2nc3ccccc3n2)cc1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of Compound 490 (0.45 g, 1 mmol) in THF (15 mL) was added KHMDS (3 mL, 1.5 mmol) at −78° C. under N2. The mixture was stirred at −78° for 0.5 hr and MeI (0.56g, 4 mmol) was added. The mixture was stirred at −78° for 2 hrs and was quenched with saturated aqueous NH4Cl, diluted with EtOAc organic layer was dried over NaSO4, evaporated and the residue was purified by flash chromatography on silica gel to afford 0.36g desired product.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:3]([C:5]([OH:7])=O)[CH3:4].[NH:18]1[CH2:29][CH2:28][CH2:27][C@H:19]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:1][N:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:3]([C:5]([N:18]1[CH2:29][CH2:28][CH2:27][C@H:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[O:7])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)N(C)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of N-methyl-N-[(phenylmethoxy)carbonyl]-L-alanine (4.74 g., 20 mmole) in distilled tetrahydrofuran (50 ml.) is added L-proline, 1,1-dimethylethyl ester (3.42 g., 20 mmole), hydroxybenzotriazole hydrate (3.06 g., 20 mmole) and dicyclohexylcarbodiimide (4.12 g., 20 mmole). The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue is dissolved in ethyl acetate (50 ml.) and washed with saturated sodium bicarbonate (twice), 10% potassium bisulfate (twice), and water (twice), dried (Na2SO4), and concentrated to give 6.4 g. of 1-[N-methyl-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline,1,1-dimethylethyl esters as an oily residue.
Reaction SMILES: [C:1]([N:8]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[N:10][CH:9]1S(C)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:1]([N:8]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[N:10][CH:9]1[C:20]#[N:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C=C(CN)C=NC1S(C)(=O)=O
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C=C(CN)C=NC1C#N
Temperature: 60 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
1 Eq. of N-Boc-5-aminomethyl-2-methylsulfonylpyrimidine was dissolved in DMF and introduced into a reflux apparatus. After addition of 2 eq. of KCN and catalytic amounts of 18-crown-6, the reaction mixture was stirred at 60° C. for 4 h. The suspension was then concentrated and poured into 200 ml of water. The precipitated solid was filtered off with suction and dissolved in ethyl acetate. The solution was washed with water and saturated NaCl solution, dried and evaporated in a rotary evaporator. N-Boc-5-aminomethyl-2-cyanopyrimidine was used as crude product without further purification in the next reaction. Yield: 46%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[CH:10]=[C:11]([C:13]([O:15]CC)=O)[N:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[NH2:18][NH2:19]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]2[CH:10]=[C:11]([C:13]([NH:18][NH2:19])=[O:15])[N:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1cn2c(n1)CN(C(C)=O)CC2
Product: CC(=O)N1CCn2cc(C(=O)NN)nc2C1
Reaction time: 0.33 h

Procedure:
6 g of the ester thereby obtained, in 10 ml of hydrazine, are brought to the refluxing temperature for 20 min. The excess hydrazine is evaporated off and the oil obtained purified by chromatography on a silica column (methylene chloride/methanol/ammonia solution 19:10:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3cc(Cl)ccc23)CC1
Reactant: Cc1ccccc1O
Product: Cc1ccccc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
From the compound of step 4 (100 mg, 211 μmol), the title compound was prepared analogously as described in example 1, step 2, using 2-methylphenol. Yield: 29 mg.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@:55]1([CH3:63])[C:60](O)=[O:61])=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@@H:40]([NH:41][C:60]([C@@:55]1([CH3:63])[CH2:56][CH2:57][CH2:58][CH2:59][N:54]1[C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:61])[CH:42]([CH3:44])[CH3:43])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:6]
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](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)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](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Yield: 41.5 %

Procedure:
According to the general procedure D, from #86 (400 mg, 0.6 mmol, 1 eq.), #157 (146 mg, 0.6 mmol, 1 eq.), dichloromethane (10 mL), HATU (259 mg, 0.72 mmol, 1.2 eq.) and N,N-diisopropylethylamine (158 mg, 1.2 mmol, 2 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0.01 to 0.05% methanol in dichloromethane) to afford #189 (220 mg, 37%) as a white solid. HPLC (Protocol W): m/z 883.7 [M+H+], retention time=4.12 minutes (purity=95%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C([Mg]Cl)(C)C.[O:14]=[C:15]1[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:17][CH2:16]1.Cl.[NH4+].[Cl-]>C1COCC1.CCCCCCC.CC(OC)(C)C>[C:23]([O:22][C:20]([NH:19][C@@H:18]([CH2:17][CH2:16][C:15]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1)=[O:14])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: Fc1cncc(Br)c1
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@H](CCC(=O)c1cncc(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
A solution of 3-bromo-5-fluoropyridine (4.28 g, 24.3 mmol) in dry THF (25 mL) was cooled to −40 to −50° C. and 2M isopropylmagnesium chloride in THF (10.2 mL, 20.4 mmol) was added. The mixture was allowed to warm to 0° C. and was stirred for 30 minutes. The mixture was cooled to −20° C. and a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (5.00 g, 19.4 mmol) in dry THF (15 mL) was added. The mixture was allowed to reach ambient temperature over 30 minutes and was stirred at ambient temperature for 30 minutes. The reaction was slowly quenched with 2M HCl (10 mL, 20.0 mmol) followed by 10% aqueous NH4Cl (10 mL). The mixture was stirred for 10 minutes and was transferred to a separatory funnel using MTBE rinses (10 mL). Heptane (15 mL) was added and the organic layer was removed. The organic layer was washed 10% aqueous NH4Cl (25 mL) and DI H2O (25 mL). The organic layer was concentrated to provide the crude product as a yellow oil (7.03 g, 102%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: NCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: O=C(NCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)c1ccccc1
Yield: 58.9 %

Procedure:
A procedure similar to that described in Example 15 was carried out with 9-bromo-5-aminomethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione hydrochloride (800 mg, 2.31 mmol) and benzoic acid (312 mg, 2.56 mmol) to give 564 mg of the title compound (59%): mp 169~175° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.03 (s, 1H), 8.66 (t, 1H, J=5.4 Hz), 7.77 (d, 2H, J=8.6 Hz), 7.41~7.56 (m, 3H), 7.24 (s, 1H), 7.19 (s, 1H), 5.03~5.13 (m, 1H), 3.62 (dt, 1H, J=11, 6.5 Hz), 3.28~3.40 (m, 1H), 3.10 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.78 (dm, 1H, J=17.1 Hz), 2.14 (dm, 1H, J=13.5 Hz), 1.73~1.89 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:18]3[CH:19]=[N:20][N:21]([CH2:22][CH3:23])[C:17]=3[N:16]=[CH:15][C:4]=2[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[N:6][N:7]=1.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH2:34][NH2:35])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C(N(C(C)C)CC)(C)C.ClCCl.CO>CN1CCCC1=O>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:34][NH:35][C:2]2[C:3]3[C:18]4[CH:19]=[N:20][N:21]([CH2:22][CH3:23])[C:17]=4[N:16]=[CH:15][C:4]=3[C:5]([N:8]3[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]3)=[N:6][N:7]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCn1ncc2c3c(Cl)nnc(N4CCC(O)CC4)c3cnc21
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc2c3c(NCc4ccc(OC)c(Cl)c4)nnc(N4CCC(O)CC4)c3cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
1-(9-Chloro-3-ethyl-3H-pyrazolo-[4′,3′:5,6]pyrido-[3,4-d]pyridazin-6-yl)-4-piperidinol (2.4 g, 7.2 mmol) and (3-chloro-4-methoxyphenyl)methylamine hydrogen chloride (7.5 g, 5 eq) were suspended in N-methylpyrrolidinone (20 mL) and diisopropylethylamine (5 eq) in a 100 mL pressure tube. The reaction tube was submerged in a preheated oil bath at 170° C. for 2 h. HPLC analysis showed complete consumption of starting material. The reaction was cooled to rt and diluted with EtOAc (250 mL). This solution was washed consecutively with water (200 mL×3) and brine (200 mL×2) and dried over sodium sulfate. The solvent was removed via evaporation under reduced pressure to afford a brown foam. Column chromatography of this foam using silica gel and dichloromethane-methanol (30:1) afforded the title compound as an orange solid (2.0 g, 60%): mp 109-110.5° C. The material was analyzed by HPLC and showed 95% purity: HPLC (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.22 minutes; LRMS (m/z) 468 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11e, and benzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.87 (m, 3H), 7.80 (d, 2H), 7.62 (m, 1H), 7.56 (m, 2H), 7.33 (d, 1H), 7.11 (m, 3H), 7.03 (d, 1H), 6.87 (d, 1H), 6.78 (s, 1H), 4.34 (s, 2H), 4.32 (s, 2H), 3.65 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 507 (M+1).