Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[CH3:16][N:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20](=O)[O:19]C1=O.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:17]([CH3:16])[C:22]2[C:21]([C:20]=1[OH:19])=[CH:26][C:25]([CH3:27])=[CH:24][CH:23]=2)=[O:4])[CH3:7]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(C)ccc2n(C)c1=O
Temperature: 90 °C
Yield: 87.5 %

Procedure:
Neat diethyl malonate (2.28 g, 14.26 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 628 mg, 15.69 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min. and cooled to room temperature. A solution of Compound 14 (10 g, 56 mmol) in dimethylacetamide was added slowly and the mixture heated overnight at 120° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 3.26 g (87%) of white solids. M.P. 132° C. 1H NMR (DMSO-d6): δ 1.30 (t, J=6.9 Hz, 3H), 2.50 (s, 3H), 3.50 (s, 3H), 4.33 (q, J=6.9 Hz, 2H), 7.41 (d, J=8.6 Hz, 1H), 7.56 (dd, J=1.7, 8.5 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 13.03 (s, 1H). EIMS m/z 262 (M+1), 284 (M+23).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]=[N:16][C:17]([C:35]([NH2:37])=[O:36])=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[N:19]=2)[CH2:9]1)=[O:6].[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[N:29]1([C:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:18]3[N:19]=[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:8]([N:7]5[CH2:2][CH2:3][CH2:4][C:5]5=[O:6])[CH2:9]4)[N:15]=[N:16][C:17]=3[C:35]([NH2:37])=[O:36])=[CH:22][CH:23]=2)=[O:28])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[ClH:1]
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)CCCCl)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: NC(=O)c1nnc(N2CCC[C@@H](N3CCCC3=O)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-3-(3-aminopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide HCl salt (6) (90 mg, 0.19 mmol) in NMP (3 mL) was added DIEA (0.27 mL, 1.52 mmol) and then 3-bromopropanoyl chloride (108 mg, 0.58 mmol). The mixture was stirred at RT for 1 h and then at 60° C. for 1 h. The mixture was cooled to RT, diluted with EtOAc, washed with water and concentrated in vacuo to afford crude (R)-3-(3-(4-chlorobutanamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide. To a solution of (R)-3-(3-(4-chlorobutanamido)piperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide in DMF (3 mL) was added NaH (60% in mineral oil, 30 mg, 0.75 mmol). The mixture was stirred at RT for 1 h. The mixture was diluted with water, acidified with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (52) as HCl salt (31 mg). MS found for C24H30N8O4 as (M+H)+ 495.1, (M−H)− 493.2. UV: λ=275 nm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)=[CH:10][CH:9]=1)([O-])=O.[H][H]>CN(C)C=O>[NH2:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=[C:4]([NH2:1])[CH:5]=2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Oc2ccc(Oc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(Oc3cc(N)cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Yield: 70.5 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 36.5 g (0.0747 mol) of 1,4-bis(3-nitro-5-trifluoromethylphenoxy)benzene, 250 ml of N,N-dimethylformamide and 1.8 g Pd-alumina were charged and reacted in a hydrogen atmosphere at 50° C. for 6 hours. After finishing the reaction, the catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain 1,4-bis(3-amino-5-trifluoromethylphenoxy)benzene as colorless crystals. The product was 36.5 g (70.5% yield) and had a melting point of 157.4~158.0° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:26][N:15]1[CH2:16][CH2:17][N:18]2[C:19](=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]2)[C@@H:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=S1(=O)CCN2CCN[C@@H](c3ccc(Oc4ccccc4)cc3)C2=N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN2CCS(=O)(=O)N=C2[C@@H]1c1ccc(Oc2ccccc2)cc1
Reaction time: 20 h
Yield: 13.4 %

Procedure:
A mixture of (9S)-9-(4-phenoxyphenyl)-3,4,6,7,8,9-hexahydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (129 mg), potassium carbonate (100 mg) and iodomethane (0.022 mL) in DMF (4 mL) was stirred at 0° C. to room temperature for 20 hr. The reaction mixture was added with NH silica gel, evaporated, and purified by column chromatography (NH silica gel, eluted with EtOAc in hexane then 20% MeOH in EtOAc) then preparative HPLC (C18, MeCN in H2O with 0.1% TFA). The combined collected fractions were concentrated in vacuo. The resulting aqueous solution was added with NaHCO3 and NaCl, then extracted with EtOAc (2×100 mL). The organic layer was combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from EtOAc —IPE to give the title compound (18 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]3[CH2:23][CH2:22][O:21][C:20]3=[O:24])[CH:16]=2)[NH:11][C:10]1=[O:25].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[CH2:33]=O.[ClH:35]>C(O)(=O)C>[ClH:35].[ClH:35].[CH3:1][C:2]1[C:6]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]3[CH2:23][CH2:22][O:21][C:20]3=[O:24])[CH:16]=2)[NH:11][C:10]1=[O:25]
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccc(CN4CCOC4=O)cc32)[nH]1
Reactant: CN1CCNCC1
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(CN4CCOC4=O)cc32)c(C)c1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Step A of Example 25 (1.18 mmoles) in acetic acid (20 ml) there are added at 0° C. 1-methyl-piperazine (1.18 mmoles) and formaldehyde (37% aq., 1.18 mmoles). The reaction mixture is stirred overnight at ambient temperature. After acid-base extraction, the product obtained is converted into the hydrochloride as described in Step E of Example 19 to yield the title product. Z isomer.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: ClCCCN1CCOCC1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Product: CCCCN(CCCC)C(=O)c1cn(CCCN2CCOCC2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (130 mg, 0.26 mmol) and 4-(3-chloropropyl)morpholine (53 mg, 0.27 mmol) were converted to the title compound. (65 mg, 40%). 1H NMR (CD3OD) δ 8.67 (d, J=2.0 Hz, 1H), 8.33 (dd, J=8.0, 1.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.38-7.32 (m, 5H), 5.21 (s, 2H), 4.01 (s, 3H), 3.84-3.80 (m, 4H), 3.59-3.50 (m, 6H), 2.20-2.11 (m, 6H), 1.70-1.60 (m, 6H), 1.45-1.25 (m, 4H), 1.05-0.82 (m, 6H); MS(ESI+) m/z 619 (M+H)+.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[C:14]([CH3:20])=[C:15](O)[CH:16]=[CH:17][CH:18]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:3][CH2:4]2)[C:14]=1[CH3:20]
Reactant: Cc1c(O)cccc1Br
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1c(Br)cccc1OCC1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexylmethanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 0.17 h

Procedure:
A mixture of 5-hydroxy-2-nitropyridine (7 g), K2CO3 (6.9 g) of DMF (100 ml) is stirred for about 10 minutes. To the mixture is added 4-chlorobenzyl chloride (8.1 g) in portions over about 15 minutes. The reaction mixture is stirred about 16 hours and then heated to 45° for about 30 minutes. After cooling, the reaction is diluted with CHCl3, washed with water and saturated NaCl, dried (Na2SO4) and stripped. The crystalline solid is washed with 20% ethyl acetate/hexane, giving 5-(4-chlorobenzyloxy)-2-nitropyridine.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]([CH2:25][C@@H:26]([OH:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:16]=1[Cl:33].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:46][CH2:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[NH:42][C:41]2=[O:51])[CH2:36][CH2:35]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:51]=[C:41]1[NH:42][C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[CH2:45][CH2:46][N:40]1[CH:37]1[CH2:36][CH2:35][N:34]([C:2]([O:32][C@@H:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][C:18]2[CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[C:15]([NH2:14])=[C:16]([Cl:33])[CH:17]=2)=[O:3])[CH2:39][CH2:38]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)[C@H](O)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5.2 g (25.6 mmol) 4-nitrophenyl chloroformate were added under protective nitrogen gas to a mixture of 3.1 g (25.6 mmol) DMAP and 70 ml of pyridine and stirred for 1.5 hours at ambient temperature. Then 8.0 g (25.7 mmol) ethyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionate, dissolved in 30 ml of pyridine, were slowly added dropwise at ambient temperature, the reaction mixture was stirred for 2 hours at ambient temperature, 6.3 g (25.6 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one were added as a solid substance and the mixture was stirred overnight at ambient temperature. The reaction mixture was evaporated down under reduced pressure and distributed between 200 ml of ethyl acetate and 200 ml aqueous 10% citric acid solution. The organic phase washed twice with 200 ml 10% citric acid solution and five times with 150 ml 15% aqueous potassium carbonate solution, dried over sodium sulphate and evaporated down under reduced pressure. The residue was purified by column chromatography.
Reaction SMILES: [NH:1]([C:24]([O:26]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(O)(C(F)(F)F)=O.[NH:38]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:39](C(O)=O)[CH2:40][CH2:41][S:42]([CH3:44])=[O:43].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:38]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:39]([C:24]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:26])[CH2:40][CH2:41][S:42]([CH3:44])=[O:43]
Reactant: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CS(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCS(C)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50.0 g of Boc-Asn-Thr-OBzl is added 170 ml of TFA and the mixture is shaken at room temperature for 30 minutes. The solution is concentrated and treated with 500 ml of diethyl ether. The resultant powder is collected by filtration and dried. It is dissolved in 400 ml of THF, and under ice-cooling 20 ml of TEA is added. To this solution is added Boc-Met(O)-ONB (prepared by dissolving 31.3 g of Boc-Met(O).OH and 23.3 g of HONB in 200 ml of THF, adding 26.8 g of DCC under ice-cooling and stirring the mixture for 4 hours). The mixture is stirred for 15 hours, after which time the solvent is distilled off under reduced pressure. To the residue are added ethyl acetate (200 ml) and ether (200 ml), and the resultant powders are collected by filtration and reprecipitated from acetonitrile. Yield 48.5 g (72.0%), m.p. 145°-147° C., [α]D23 -6.5° (c=1.1, DMF), Rf1 =0.19.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([N:8]=[C:15]=[S:16])[N:7]=1
Reactant: Nc1cccc(Br)n1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: S=C=Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
A mixture of 6-bromopyridin-2-amine (253 mg, 1.46 mmol), chloroform (2 mL), sodium bicarbonate (850 mg, 10.12 mmol) and water (3 mL) was assembled, and to this was added a solution of thiophosgene (190 mg, 1.65 mmol) in chloroform (1 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to give a yellow solid. The solid was purified by column chromatography (5% ethyl acetate/hexanes) to afford 2-bromo-6-isothiocyanatopyridine (281 mg, 1.31 mmol, 89% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.50-7.62 (m, 1 H), 7.34-7.43 (m, 1 H), 6.91-7.11 (m, 1H). MS (LC/MS) R.T.=1.92; [M+H]+=216.86.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].CO>CN(C=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[N:6][N:5]=[N:4]1
Reactant: c1nnn[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: ClCCCn1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To anhydrous DMF (25 mL) was added NaH (0.70 g, 17.50 mmol, 60%) in one portion in an ice bath, and the mixture was warmed to rt and stirred at rt for 30 min. Then a solution of 1H-tetrazole (1.00 g, 14.28 mmol) in anhydrous DMF (6 mL) was added dropwise to the mixture cooled in an ice bath. The reaction mixture was then warmed to rt and stirred for 1.5 h followed by dropwise addition of 1-bromo-3-chloropropane (2.35 g, 14.93 mmol) to the mixture. The reaction mixture was stirred further at rt overnight. MeOH (1 mL) was added in one portion, and the mixture was filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[O:31]CC1C=CC=CC=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[OH:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cccc(OC)c1OCc1ccccc1
Solvent: CCOCC
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cccc(OC)c1O

Procedure:
Following a similar procedure to that described in Preparation 124, but using N-(2-t-butyl-5-carbamoylphenyl)-3-(2-benzyloxy-3-methoxyphenyl)octanamide (prepared as described in Example 119), the title compound was obtained as crystals, melting at 118-121° C. (from diethyl ether).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:38])=[C:21]([C:31]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:22](=[O:30])[N:23]3[CH2:26][C:27]([OH:29])=O)=[N:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH:46]1([NH:50][C:27](=[O:29])[CH2:26][N:23]2[C:24]3[C:19](=[N:18][CH:17]=[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[CH:25]=3)[C:20]([OH:38])=[C:21]([C:31]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:22]2=[O:30])[CH2:49][CH2:48][CH2:47]1
Reactant: NC1CCC1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CCC2)c1=O

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniuum hexafluorophosphate (57 mg, 0.15 mmol) was added to a mixture of [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid, the title compound in Example 171 (50 mg, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and cyclobutylamine (0.012 mL, 0.15 mmol) in DMF (1 mL) at rt. After 1 h, the mixture was diluted with H2O (4 mL) and the title compound was collected by filtration to give a white solid: 1H NMR (d6-DMSO) δ 10.22 (1H, m), 8.54 (1H, s), 8.42 (1H, m), 7.75 (1H, s), 7.31 (2H, m), 7.10 (2H, m), 4.81 (2H, s), 4.13 (1H, m), 4.10 (2H, s), 3.52 (4H, m), 3.27 (3H, s), 2.09 (2H, m), 1.84 (2H, m), 1.59 (2H, m); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2049.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 77 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-4-oxobutanoate (Compound IV-17) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: Cl.CO[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:15])[CH3:14]>C(O)C.O>[CH2:13]([NH:15][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: COc1ccncc1[N+](=O)[O-]
Reactant: CCN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96 %

Procedure:
4Methoxy-3-nitropyridine hydrochloride (11.2 g, 58.9 mmol) in ethanol (75 ml) was treated with a 70% solution of ethylamine in water (64 ml) and heated under reflux for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and water. The mixture was extracted (×3) with ethyl acetate, washed with water and saturated aqueous sodium chloride solution before drying over magnesium sulfate. Evaporation of the solvent afforded the title compound (11.7 g, 96%).
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][N:3]2[C:4]3=[N:9][C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[CH:7][C:6](=[O:16])[N:5]3[CH2:17][C@@:2]2([CH3:1])[C:18]([F:21])([F:19])[F:20])[CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: COc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cccc(CCN2c3nc(N4CCOCC4)cc(=O)n3C[C@@]2(C)C(F)(F)F)c1

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 85 mg of 1-(2-bromoethyl)-3-methoxybenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 65 mg of (2S)-1-[2-(3-methoxyphenyl)ethyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Product: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Temperature: 110 °C

Procedure:
Chlorosulfonic acid (70 mL, 1.05 mol) cooled to 0° C. was added dropwise with stirring to 4-bromo-benzoic acid (50 g, 0.29 mol). The reaction mixture was heated at 110° C. for 10 h, cooled to room temperature and poured onto crushed ice slowly with stirring. The title compound obtained was filtered, washed with water and dried. Yield: 51 g, (84%); mp: 198-199° C.; MS: m/e (EI+) 299 (M+).