Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=4)[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)-c1nc(S)sc1CC2
Product: O=C(O)COc1ccc2c(c1)-c1nc(SCC(c3ccccc3)c3ccccc3)sc1CC2
Yield: 69 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 69%.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSc2n[nH]c(SCc3ccccc3)n2)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nc(SCc3ccccc3)n(-c3ncccn3)n2)cc1
Temperature: 0 °C
Yield: 62.4 %

Procedure:
3,5-Bis(benzylthio)-1,2,4-triazole (50 g), 2-chloropyrimidine (18.3 g) and potassium carbonate (22.1 g) were heated in dimethylformamide (200 ml) at 100° C. for 12 hours. After addition to ice-water, the product was extracted into dichloromethane (twice). The dichloromethane solution was washed with water (3 times), dried over magnesium sulphate and run down, leaving 64.4 g of crude title. Recrystallisation from methanol gave 39 g of the desired product, mp 86°-88° C.
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1.NCC1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.CCN(CC)CC.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:6]([NH:8][CH2:9][C:10]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[O:7])[CH:14]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: OCc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Reaction time: 1.25 h

Procedure:
A solution of CDI (107 g, 662 mmol) in dry THF (700 mL) was treated with a solution of pyridin-3-ylmethanol (72.2 g, 662 mmol) in THF (300 mL) dropwise over 10 minutes. The resulting solution was stirred for 1.25 hours and then added dropwise over 15 minutes to a water bath cooled suspension of 4-(aminomethyl)benzoic acid (100 g, 662 mmol), Et3N (92 mL, 662 mmol) and DBU (100 mL, 662 mmol) in dry THF (1400 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue suspended in water (2500 mL), cooled in an ice-water bath and the pH adjusted to 5 with 6 N HCl (˜300 mL). The precipitate was collected by filtration, washed with cold MeOH and dried to give 4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]benzoic acid as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 12.82 (br s, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.51 (dd, J=4.8 and 1.8 Hz, 1H), 7.93 (t, J=6.3 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.76 (t, J=8.4 Hz, 1H), 7.38 (dd, J=7.2 and 4.8 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 4.25 (d, J=6.3 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])Cl.[OH:23][Ge:24][OH:25].[CH:26]1[CH:27]=[CH:28][C:29]2[C:30](=[C:32]3[N:64]=[C:63]4[N:65]=[C:56]([C:57]5[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=54)[N:55]=[C:53]4[NH:54][C:46]([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:52]=54)=[N:45][C:43]4=[N:44][C:36]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=54)=[N:35][C:34]=2[NH:33]3)[CH:31]=1>N1C=CC=CC=1>[CH3:1][Si:2]([CH3:22])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:23][Ge:24][O:25][Si:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH3:56])([CH3:1])[CH3:22].[CH:27]1[CH:26]=[CH:31][C:30]2[C:29](=[C:34]3[N:35]=[C:36]4[N:44]=[C:43]([C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=54)[N:45]=[C:46]4[NH:54][C:53]([C:52]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=54)=[N:55][C:56]4=[N:65][C:63]([C:62]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=54)=[N:64][C:32]=2[NH:33]3)[CH:28]=1
Reactant: O[Ge]O
Reactant: CCCCCCCCCCCCCCCCCC[Si](C)(C)Cl
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC[Si](C)(C)O[Ge]O[Si](C)(C)CCCCCCCCCCCCCCCCCC

Procedure:
In analogy to a procedure by Wheeler et.al., J. Am. Chem. Soc. 106, 7404 (1984)] 3.3 g (9.5 mmol)of dimethyl-octadecyl-chlorosilane and 0.5 g (0.8 mmol) of dihydroxygermanium-phthalocyanine in 50 ml of pyridine are stirred for 2 hours at 50°. The solution is cooled and filtered using a suction filter. The solvent is removed in vacuo, and 250 ml of hexane are added to the residue. The resulting precipitate is filtered off with suction and washed fast with hexane, then in portions with 200 ml of acetone/water (1:1). The residue is dried overnight under a high vacuum, then extracted with toluene in a Soxhlet, freed of solvent and dried, yielding bis(dimethyl-octadecyl-siloxy)germanium-phthalocyanine; NMR (pyridine-d5): δ=9.8-9.9 (m, 8H); 8.3-8.5 (m,8H): aromatic H's; 0.75-1.46 (various m's); 0.45(m); -0.03 (m); -0.88 (m); -1.91 (m); -2.48 (m, 4×CH3 : silyl side chains) ppm.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH2:4][O:3]1.CO.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCOC(C)=O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (0.210 g, 0.40 mmol) was suspended in 10:1 methanol/H2O and pTsOH.H2O (0.008 g, 0.04 mmol) was added. The mixture was stirred at ambient temperature for 18 hrs, during which all solids dissolved to give a colorless, clear solution. The solution was diluted with EtOAc. The organic solution was washed with sodium bicarbonate (2×), brine (1×) and dried over Na2SO4. After filtration, the filtrate was concentrated, and recrystallized from EtOAc and heptane. This solid was washed with heptane-CH2Cl2 (1:1 and dried in vacuo at 60 C to give N-((R)-2,3-Dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as a white solid, (0.136 g, 70%). Product shrinks at 90.8 C, melts at 115–117° C. Analysis shows C, 40.92; H, 3.16; N, 5.41, F, 11.30; I, 23.92 (6.75% EtOAc, 0.96% heptane).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].[CH3:21][CH:22]([NH:24][CH:25]([CH3:36])[CH2:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:23]>O1CCCC1>[OH2:10].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:9](=[O:10])[N:24]([CH:22]([CH3:21])[CH3:23])[CH:25]([CH3:36])[CH2:26][S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CCN
Reactant: CC(C)NC(C)CS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)N(C(C)C)C(C)CS(=O)(=O)c1ccccc1
Product: O

Procedure:
A solution of 3.71 g (0.032 mole) of N,N-diethylethylenediamine and 5.83 (0.036 mole) of 1,1'-carbonyldiimidazole in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 8.30 g (0.030 mole) of N-(2-propyl)-1-(phenylsulfonyl)-2-propanamine in 50 ml of tetrahydrofuran was added and the solution was refluxed overnight. The solvent was removed in vacuo, and the residue was partitioned between ether and water. The ether solution was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil. The oil was flash chromatographed (silica gel; elution with methanol) to give an oil. Crystallization from ether gave 0.54 g (4.5%) of white, crystalline solid, m.p. 75°-80° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4].[CH3:24][NH:25][CH2:26][C:27]#[N:28].CCN=C=NCCCN(C)C>C(O)C.ClCCl>[C:27]([CH2:26][N:25]([CH3:24])[C:19]([C:17]1[S:18][C:14]([C:11]2[N:12]=[C:13]3[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:22])[CH3:23])=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)=[CH:15][CH:16]=1)=[O:20])#[N:28]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(C(=O)O)s3)nc12
Reactant: CNCC#N
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Solvent: ClCCl
Product: CN(CC#N)C(=O)c1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)s1
Yield: 58.3 %

Procedure:
A solution of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid (0.060 g, 0.18 mmol), methylaminoacetonitrile (0.200 mL, 1.64 mmol) and EDCI (0.315 g, 1.64 mmol) in 3 mL of ethanol and 3 mL of dichloromethane was stirred for 1 h, then concentrated. The resulting residue was partitioned between 30 ml of ethyl acetate and 30 mL of a 10% citric acid solution, and the aqueous layer was extracted 30 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->40% EtOAc/hexanes) afforded 0.040 g (58%) of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid cyanomethyl-methyl-amide as a pale yellow solid.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:7]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:34])=[O:33]
Reactant: c1ccc(NCCOCCCSc2cccc3nccn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(CCOCCCSc1cccc2nccn12)c1ccccc1
Yield: 1.2 %

Procedure:
To a solution of 5-[3-[2-(phenylamino)ethyloxy]propylthio]imidazo[1,2-a]pyridine (1.034 g, 3.158 mmoles) and triethylamine (0.88 ml, 6.3 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.37 ml, 4.7 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 16 mg of the desired product (brown oily product)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].CN1CCN(C)C1=O.P(Cl)(Cl)([Cl:26])=O.[CH2:29]([NH2:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O>[Cl:26][C:9]1[N:8]=[C:7]([NH:36][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCCCCCCN
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CCCCCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To 300 mg (1.45 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione were added 1 ml of 1,3-dimethyl-2-imidazolidinone and 2.22 g (14.48 mmol) of phosphorus oxychloride, and the resulting mixture was subjected to heating under reflux for 3 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 3 ml of acetonitrile, followed by addition of 5.38 ml (36.25 mmol) of heptylamine and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 247 mg (yield: 52.8%) of the title compound (yield: 52.8%).
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:18])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:24]([CH:25]=O)=[N:23][CH:22]=[N:21]1.[CH3:27][CH2:28][O-:29].[Na+]>C(OCC)(=O)CC>[CH3:19][N:20]1[C:24]([CH:25]2[C:28](=[O:29])[C:27]3[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:23][CH:22]=[N:21]1
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Reactant: CC[O-]
Reactant: Cn1ncnc1C=O
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccccc1)N2
Temperature: 41 °C
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a solution of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (1.78 g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01 g, 9.16 mmol) in ethyl propionate (110 mL) was added EtONa (sodium (490 mg, 21 mmol) in 35 mL ethanol) at 40° C., then the mixture was stirred at 41° C. for 3 hr. The resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (150 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=200:1 to 50:1) to obtain a green solid (400 mg, yield 14%). LC-MS (ESI) m/z: 377 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CC(C)COC(=O)Cl
Product: Cc1c(N2CCN(C(=O)OCC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and isobutyl chloroformate to give isobutyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 0.86-0.92 (m, 6H), 1.86-1.91 (m, 1H), 2.09 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.28-3.32 (m, 4H), 3.57 (br s, 4H), 3.69 (t, J=4.4 Hz, 4H), 3.83 (d, J=6.4 Hz, 2H), 6.50 (s, 1H), 7.13-7.19 (m, 1H), 7.28-7.32 (m, 1H), 7.517 (s, 1H), 7.78 (d, J=2 Hz, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=541.4 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:19][CH:20]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])(=[O:18])[CH3:17]>>[C:16]([O:19][CH:20]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:32])(=[O:18])[CH3:17]
Reactant: O=C(OCCOCCO)c1ccccc1
Reactant: CCCCCCC(C/C=C\CCCCCCCC(=O)Cl)OC(C)=O
Product: CCCCCCC(C/C=C\CCCCCCCC(=O)OCCOCCOC(=O)c1ccccc1)OC(C)=O

Procedure:
2-Benzoyloxyethoxyethyl 12-acetoxyoleate was prepared by the procedure of Example 1 from 21 gms (0.1 mole) of diethylene glycol monobenzoate and 36 gms (0.1 mole) of 12-acetoxyoleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]2[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[CH2:2][O:1]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: CC(CO)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COc1ccc(C2OCC(C)(C(=O)O)CO2)cc1
Temperature: 22.5 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
2,2-bis(hydroxymethyl)propionic acid (10 g) and anisaldehyde dimethyl acetal (20.4 g) were added to acetone (50 ml) at 20-25° C. p-Toluenesulfonic acid (0.51 g) was added to the reaction mixture and stirred at 20-25° C. for 5 hours. The mixture was then cooled to 0-5° C. and stirred for 1 hour. The slurry was filtered and the solid was washed with chilled (0-5° C.) acetone (10 ml). The solid was dried under vacuum at 45-50° C. for 4 hour. The solid was added to toluene (150 ml) and the resulting mixture was heated at 65-70° C. for 2 hours. The mixture was then cooled to 5-10° C. and stirred for 30 minutes. The slurry was filtered and the solid was washed with toluene (10 ml) followed by drying under vacuum at 30-35° C. for 4 hours to obtain title compound (14.0 g, 74.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].C([O:16][C:17]([C:19]1[CH:42]=[CH:41][C:22]2[N:23]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([CH:33]=O)[CH:27]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18])C.[OH-].[K+].Cl.[CH2:46]([OH:48])[CH3:47]>>[CH:35]1([N:23]2[C:22]3[CH:41]=[CH:42][C:19]([C:17]([OH:16])=[O:18])=[CH:20][C:21]=3[N:25]=[C:24]2[C:26]2[CH:27]=[C:28]3[C:29](=[CH:30][CH:31]=2)[N:32]=[C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[O:48][CH2:46][CH3:47])[CH:12]=[CH:33]3)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc([N+](=O)[O-])cc1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-(2-Bromo-5-nitro-phenyl)-ethanone (61 mg, 0.25 mmol) prepared similarly to the procedure described in Meisenheimer, J., Zimmermann P., and v. Kummer, U. Ann. der. Chem. 446, pp. 205-228) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 16 mg (97.33% pure) of product.
Reaction SMILES: C([S:9][CH:10]([CH2:21][C:22](OC)=O)[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1.C(SCC(C[C:43]([O:45][CH3:46])=[O:44])C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:9][CH:10]([CH2:21][CH2:22][C:43]([O:45][CH3:46])=[O:44])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)CC(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(=O)CCC(S)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-(benzoylthio)-3-(methoxycarbonyl)propanoyl]-L-proline for the 1-[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-proline in the procedure of Example 4, 1-[2-mercapto-3-(methoxycarbonylmethyl)propanoyl]-L-proline is obtained.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:15]([C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27])=[C:14]([CH2:33][CH3:34])[NH:13][C:12]=1[CH2:35][CH3:36])=[O:10])C1C=CC=CC=1.C(O)=O.CO>C(Cl)(Cl)Cl.[Pd]>[C:31]([CH2:30][CH2:29][O:28][C:26]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH2:35][CH3:36])[NH:13][C:14]=1[CH2:33][CH3:34])=[O:27])#[N:32]
Reactant: CCC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(CC)N1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(CC)N1

Procedure:
The solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-2,6-diethyl-1,4-dihydro-4-(4-nitrophenyl)pyridine (6.30 g, 13.0 mmol) in 250 ml of 4.4%(w/w) formic acid/MeOH mixture was stirred with Pd/C (10%, 6.0 g) for 30 min., the reaction was quenched by addition of 100 ml of CHCl3. The mixture was filtered and concentration of filtrate give a yellow powder, which was dissolved in CHCl3, washed with water and 1N HCl. After filtration and removal of solvent, 3-(2-cyanoethoxy)carbonyl-2,6-diethyl-1,4-dihydro-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (4.5 g, 87%).
Reaction SMILES: [CH2:1](Br)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][O:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([O:40][CH3:41])[C:32]=1[CH:33]=O>O1CCCC1>[CH3:41][O:40][C:35]1[CH:36]=[C:37]([OH:39])[CH:38]=[C:31]([O:30][CH3:29])[C:32]=1[CH2:33][CH2:1][CH3:2]
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OC)cc(O)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
Anhydrous tetrahydrofuran (36 ml) was added to triphenylphosphine ethyl bromide (12.3 g) prior to stirring at room temperature for 20 minutes. To the resulting mixture was added potassium tert-butoxide (4.5 g), for stirring at room temperature for 30 minutes. Then, 2,6-dimethoxy-4-hydroxybenzaldehyde (3.0 g) was added to the resulting mixture for stirring at room temperature for 2 hours. After the termination of the reaction, the resulting solution was partitioned with ethyl acetate and dilute hydrochloric acid, and the resulting ethyl acetate phase was washed in water and subsequently in a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1), followed by addition of a catalytic amount of platinum dioxide for hydrogenation, to recover 3,5-dimethoxy-4-propylphenol (1.8 g; yield of 55%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].CC1CCCCC1.Cl.C([O:26][N:27]=O)CCCC>>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])/[C:2](=[N:27]/[OH:26])/[CH3:1]
Reactant: CCC(=O)c1ccc(F)cc1F
Reactant: CCCCCON=O
Agent: Cl
Solvent: CC1CCCCC1
Product: C/C(=N\O)C(=O)c1ccc(F)cc1F
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a solution of 170 g (1.00 mol) of 2,4-difluoropropiophenone in 200 g methylcyclohexane 37 g (1.01 mol) of gaseous hydrochloric acid is dosed over 3 hours at 0° C. Thereafter 120 g (1.04 mol) of pentylnitrite are added over a period 3 to 4 hours to the reaction mixture at +10° C. to +15° C. Following the end of the addition the batch is stirred for an hour at +10° C. to +15° C. during which time a suspension is formed. The reaction mixture is then cooled to 0° C. and stirred for a further hour. The product is isolated by filtration and the filter cake is washed with 75 g of methylcyclohexane at 0° C.: 176 g of (E)-1-(2,4-difluoro-phenyl)-propane-1,2-dione-2-oxime (m.p. 99-101° C.) are obtained in 88.6% yield.