Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12](OCC)=[O:13])=O)C.O.[NH2:27][NH2:28]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[N:8]=[C:7]([CH3:25])[C:6]3[C:4](=[O:3])[NH:27][NH:28][C:12](=[O:13])[C:11]=3[CH:10]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc(C)c1C(=O)OCC
Reactant: NN
Solvent: O
Product: COc1ccc(-c2cc3c(=O)[nH][nH]c(=O)c3c(C)n2)cc1

Procedure:
10 parts by weight of 3,4-diethoxycarbonyl-6-(p-methoxyphenyl)-2-methylpyridine is incorporated into 40 parts by volume of hydrazine hydrate, and the resulting mixture is refluxed for three hours. The precipitated crystals are collected by filtration, washed with ethanol and suspended in 100 parts by volume of water. The mixture is acidified by the addition of acetic acid to obtain 1,2,3,4-tetrahydro-7-(p-methoxyphenyl)-5-methyl-1, 4-dioxopyrido-(3,4-d)pyridazine as colorless fine crystals. A mixture is made of 3.0 parts by weight of the fine crystals, 45 parts by volume of phosphorus oxychloride and 4.5 parts by volume of N,N-dimethylaniline. The mixture is heated at temperatures ranging from 90° to 100° C for three hours. Then, the reaction mixture is left standing at room temperature overnight. The precipitated crystals are collected by filtration, washed with ether, recrystallized from chloroform to obtain the desired compounds melting at 214° to 219° C (decomposition) as pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.CN.[C:39](P(=O)(OCC)OCC)#[N:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][CH3:39])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: CCOP(=O)(C#N)OCC
Agent: CN
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5-chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and methlamine using diethyl cyanophosphonate as a coupling reagent. Mass: 520.15 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccc(F)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13i, and 3-fluorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 569 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:15]=[N:14][C:8]2[S:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>>[O:13]=[C:11]1[CH2:10][S:9][C:8]2[N:14]=[CH:15][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[NH:12]1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CS2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CSc2ncc(C(=O)O)cc2N1
Yield: 95.2 %

Procedure:
The ester (b) (2.8 g) was hydrolysed with aqueous sodium hydroxide then acidified with 2M HCl and filtered to afford a solid (2.5 g) by the method of Example (1 h).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[F:11][C:12]([F:18])=[C:13]([F:17])[CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:12]([F:18])=[C:13]([F:17])[CH2:14][CH2:15][S:10][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1nc2ncccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)=C(F)CCSc1nc2ncccc2s1
Temperature: 60 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
A solution of thiazolo[4,5-b]pyridine-2-thiol (6.2 g, 0.037 mol) in N,N-dimethylformamide under nitrogen is treated with 1,1,2-trifluoro-4-bromobutene (8.3 g, 0.046 mol) and potassium carbonate (1.5 g), heated to and stirred at 60° C. for 24 hours, cooled, and poured into water. The resultant aqueous mixture is extracted with diethyl ether. The organic extract is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a 9:1 hexanes/ethyl acetate solution gives the title product as a colorless oil (8.9 g, 64% yield).
Reaction SMILES: FC(F)(F)C1C=CC(O)=CC=1.BrCCCCCCCCCO.[F:23][C:24]([F:43])([F:42])[C:25]1[CH:41]=[CH:40][C:28]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])=[CH:27][CH:26]=1.FC(F)(F)C1C=CC(OCCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH2:83])[CH2:79][N:80]([CH3:82])[CH3:81])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH:83][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:28]1[CH:40]=[CH:41][C:25]([C:24]([F:42])([F:43])[F:23])=[CH:26][CH:27]=1)[CH2:79][N:80]([CH3:81])[CH3:82])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: OCCCCCCCCCOc1ccc(C(F)(F)F)cc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccc(C(F)(F)F)cc1
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccc(C(F)(F)F)cc1

Procedure:
The title compound, m/e=447.4 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, 4-trifluoromethyl-phenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(4-trifluoromethyl-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(4-trifluoromethyl-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(4-trifluoromethyl-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH2:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:24][C:25]([F:43])([F:42])[C:26]1[CH:41]=[CH:40][C:29]([O:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH:22][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][C:31]([O:30][C:29]2[CH:40]=[CH:41][C:26]([C:25]([F:24])([F:42])[F:43])=[CH:27][CH:28]=2)=[CH:32][CH:33]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-[4-(trifluoromethyl)phenoxy]benzoic acid used in Example 41 (41a) to give the title compound.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[OH-].[Na+].[CH:8]1([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1.CCCCCC>[CH:17]1([NH:16][C:15](=[N:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)=NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of acetone oxime (3.65 g, 0.05 mol) in dry THF (35 ml) is added finely powdered NaOH (0.2 g) and dicyclohexylcarbodiimide (10.3 g, 0.05 mol). The mixture is then stirred 5 h at room temperature under argon. The turbid mixture is thereafter diluted with hexane (30 ml) filtered and evaporated under reduced pressure to afford 13.8 g of the title compound as a slightly yellow liquid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([O:43][C:44](=[O:46])[CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.FC(F)(F)S(O[Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])(=O)=O>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([O:48][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[CH:41]6[CH:42]([O:43][C:44](=[O:46])[CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C

Procedure:
100 mg of compound (3) was dissolved in 0.7 ml of anhydrous dichloromethane and stirred together with 70 mg of dimethylaminopyridine and 49 μl of t-butyldimethylsilyl trifluoromethanesulfonate for 1 hour under cooling with ice. The reaction solution was concentrated in vacuo, dissolved in methanol, charged onto a silica gel column (Kieselgel 60, Merck, 1.5φ×22 cm) and eluted with n-hexane-ethyl acetate (4:1). The fraction containing the desired product was concentrated in vacuo to give 99 mg of compound (5) as a colorless oily substance.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[CH3:11][C:9]1[CH:10]=[C:2]([O:32][CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: Cc1cc(I)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: OCc1ccncc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2ccncc2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 47 %

Procedure:
To a solution of 5-Iodo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (100 mg, 0.22 mmol) in toluene (3 ml), pyridin-4-yl-methanol (26.4 mg, 0.24 mmol), copper(I) iodide (40 mg, 0.022 mmol), cesium carbonate (143 mg, 0.44 mmol), and 1,10-phenanthroline (7.9 mg, 0.044 mmol) were added. The resulting mixture was refluxed overnight, After cooling, the mixture was filtered through Celite® and concentrated. Column chromatography (80% EtOAc/Hexanes to 10% MeOH/EtOAc) provided the title compound as a yellow oil (44.3 mg, 47%). 1H NMR (300 MHz, CDCl3): δ 8.56 (br, 2H), 7.31-7.36 (m, 3H), 7.16-7.20 (m, 3H), 6.83 (s, 1H), 6.75 (s, 1H), 5.14 (s, 2H), 4.75 (s, 2H), 4.19 (s, 2H), 2.74 (s, 3H). GTPγS (0.0645).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=2)O1>>[CH:12]1([NH:11][C:10]2[C:5]3[N:6]([C:2]([C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=4)=[CH:3][N:4]=3)[CH:7]=[CH:8][N:9]=2)[CH2:14][CH2:13]1
Reactant: Brc1cnc2c(NC3CC3)nccn12
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(=O)Nc1ccc(-c2cnc3c(NC4CC4)nccn23)cc1
Yield: 12 %

Procedure:
Using Method 2, the title compound was prepared in 12% yield from 3-bromo-imidazo[1,2-a]pyrazin-8-yl)-cyclopropyl-amine (Example 6) and N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (from Aldrich).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:28]=[CH:27][C:8]([CH:9]=[C:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O>[Pd].CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:27][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=c2c3ccccc3c3[nH]c(=O)c4nccn4c23)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)cc1
Yield: 25.4 %

Procedure:
The process is performed as in Example 3 but starting with 4.7 g of 10-(4-acetylaminobenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 250 ml of dimethylformamide, 50 ml of methanol and 0.6 g of 10% palladium-on-charcoal for 26 hours. 1.2 g of 10-(4-acetylaminobenzyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained in the form of a cream-white solid melting above 260° C. (Analysis, % calculated C: 71.34, H: 4.90, N: 15.13, O: 8.64, % found C: 71.3, H: 4.7, N: 15.3, O: 8.3).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[NH:9][C:8]1([CH3:14])[CH3:13]>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]1[O:11][C:10](=[O:12])[NH:9][C:8]1([CH3:14])[CH3:13]
Reactant: CC1(C)NC(=O)OC1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)NC(=O)OC1CCl
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Thionyl chloride (0.13 ml, 1.72 mmol) was added to a mixture of 5-(hydroxymethyl)-4,4-dimethyloxazolidin-2-one (50 mg, 0.34 mmol) in pyridine (1 mL) at −20° C. The mixture was allowed to stir for 15 minutes and then warmed to 60° C. for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica (20-100% ethyl acetate/hexanes) to afford 5-(chloromethyl)-4,4-dimethyloxazolidin-2-one. 1H NMR (500 MHz, CDCl3) δ 6.20 (br s, 1H), 4.38-4.35 (m, 1H), 3.75-3.70 (m, 1H), 3.62-3.57 (m, 1H), 1.42 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[CH3:31])[C:6]([N:8]([CH2:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24](O)=[O:25])[N:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:46][N:47]([CH3:52])[S:48]([NH2:51])(=[O:50])=[O:49].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[CH3:31])[C:6]([N:8]([CH2:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24]([NH:51][S:48]([N:47]([CH3:52])[CH3:46])(=[O:50])=[O:49])=[O:25])[N:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)O)c(C)s2)cc(OC)c1C
Reactant: CN(C)S(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)NS(=O)(=O)N(C)C)c(C)s2)cc(OC)c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxylic acid (150 mg) and CDI (78 mg) was added to anhydrous THF (5 mL), followed by heating at 60° C. for about 1 hour. To the reaction mixture were added N,N-dimethylsulfamide (60 mg) and DBU (73 mg) under ice-cooling, respectively, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and neutralized by the addition of an appropriate amount of purified water and 1 M hydrochloric acid, and then extracted from chloroform. The obtained organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:2) to obtain 2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(dimethylamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide (111 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:9]2=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].O>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:9]2=[O:10])=[CH:6][CH:7]=1)=[O:31]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: Nc1ccc(N2C(=O)CCc3ccccc32)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc(N3C(=O)CCc4ccccc43)cc2)c(OC)c1
Yield: 57.9 %

Procedure:
To a solution of 1-(4-aminophenyl)-3,4-dihydrocarbostyril (0.45 g) in dichloromethane (15 ml) is added triethylamine (0.29 g). Thereto is added 2,4-dimethoxybenzoyl chloride (0.42 g) with stirring under ice cooling. The mixture is refluxed with heating for 0.5 hour. After cooling, water is added thereto and the mixture is extracted with dichloromethane, washed with water and then dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography and recrystallized from ethanol/diethyl ether/n-hexane to give 1-[4-(2,4-dimethoxybenzoylamino)phenyl]-3,4-dihydrocarbostyril (0.44 g) as white powder, m.p.: 226°-227° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[C:10]1([CH2:16][CH2:17][NH:18][C:19](=[O:51])[C@H:20]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[NH:21][C:22](=[O:43])[C@H:23]([CH2:39][C:40](=[O:42])[NH2:41])[NH:24][C:25](=[O:38])[C@H:26]([CH2:36][OH:37])[NH:27][C:28](=[O:35])[CH2:29][NH:30][C:31](=[O:34])[CH2:32][NH2:33])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N=C=N>>[C:10]1([CH2:16][CH2:17][NH:18][C:19](=[O:51])[C@H:20]([CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:21][C:22](=[O:43])[C@H:23]([CH2:39][C:40](=[O:42])[NH2:41])[NH:24][C:25](=[O:38])[C@H:26]([CH2:36][OH:37])[NH:27][C:28](=[O:35])[CH2:29][NH:30][C:31](=[O:34])[CH2:32][NH:33][C:7](=[O:9])[C@@H:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:1]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1ccccc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: N=C=N
Product: NC(=O)C[C@H](NC(=O)[C@H](CO)NC(=O)CNC(=O)CNC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1ccccc1
Yield: 82 %

Procedure:
Pyroglutamyl-glycyl-glycyl-seryl-asparaginyl-phenylalanine 2-phenylethylamide is prepared from pyroglutamic acid and glycyl-glycyl-seryl-asparaginyl-phenylalanine 2-phenylethylamide using the carbodiimide method similar to that described in the preceding example 5. Yield 82 %, m.p. 209°-211° C., Rf 0.25/S1, 0.67/S2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([Br:16])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([Br:16])=[C:11]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2c(sc(CCCl)c2Br)C1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)N1CCc2c(sc(CCN3CCC(c4noc5cc(F)ccc45)CC3)c2Br)C1
Yield: 6.4 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.5 g of 6-acetyl-3-bromo-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.05 g of 6-acetyl-3-bromo-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 114°-117° C. as an oxalate thereof.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:26])=[CH:9][CH:8]=1)([O-])=O>C(O)(=O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:26])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc([N+](=O)[O-])cc3)c2c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3)c2c1
Yield: 100.9 %

Procedure:
Six milliliters of ethanol and 0.8 ml of acetic acid were added to 0.50 g of 1-(4-nitrobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole and 0.47 g of reduced iron, and the mixture was refluxed for 4.5 hours. The reaction mixture was extracted with water and with ethyl acetate. The organic layer was washed with water, dried, and then concentrated under reduced pressure to give 0.46 g of 1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (363).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH:22]3[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2ccc(O)cc2s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(OC3CCN(C(C)C)CC3)cc2s1

Procedure:
To 6-hydroxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.300 g, 1.35 mmol, prepared as described above, but using ethyl instead of methyl thioglycolate), dissolved in 13.5 mL of THF, was added successively at 10° C. 1-isopropyl-piperidin-4-ol (0.387 g, 2 eq.), triphenylphosphine (0.708 g, 2 eq.) and DIAD (0.530 mL, 2 eq.), and the mixture then kept at this temperature for another 2 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of all solvents, followed by flash chromatography (SiO2, MeOH/AcOEt=1/9), delivered 0.360 g of the title compound as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[N+:14]([C:17]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:18]=1[CH:19]=[O:20])([O-:16])=[O:15].[Cl-].[NH4+]>O1CCCC1>[N+:14]([C:17]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:18]=1[CH:19]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[F:8])[OH:20])([O-:16])=[O:15]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Fc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1cc(F)ccc1F
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To 15 g of 2,5-difluorobenzene dissolved in 150 ml of tetrahydrofuran are added, at −70° C., 50 ml of 1.6M butyllithium solution. After 2 hours at −70° C., 9.616 g of 2-nitro-5-chlorobenzaldehyde are introduced and the mixture is left at this temperature for 3 hours and then at room temperature for 18 hours. The medium is hydrolysed with ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is filtered through silica, eluting with dichloromethane, to give 8.89 g of the expected product.