Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:26]([CH3:29])[C:27]#[N:28])C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[C:26]([CH3:29])[C:27]#[N:28])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=2)[CH:3]=1
Reactant: CC(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(C#N)=Cc1ccc(-c2cc(C)ccn2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A suspension of 4-(4-methylpyridin-2-yl)-2-nitrobenzaldehyde (203 mg) and 2-(triphenylphosphoranylidene)propionitrile (0.45 g) in toluene (10 ml) was refluxed for 3 hours. After cooling, to the reaction mixture were added magnesium sulfate and silica gel (10 g), and the suspension was stirred for 30 minutes. The solid was removed by filtration and washed with toluene (10 ml) three times. The combined filtrate was evaporated under reduced pressure to give 2-(4-(4-methylpyridin-2-yl)-2-nitrobenzylidene)propionitrile (221 mg) as a mixture of regioisomers.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[C:5]([CH3:7])[N:6]=1.[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>C(#N)C>[CH3:1][C:2]1[S:3][C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])=[CH:11][CH:10]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1nc(C)c(Cc2ccc(N)cc2)s1
Solvent: CC#N
Product: Cc1nc(C)c(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.7 %

Procedure:
3 g of 2,4-dimethyl-5-(4-aminobenzyl)thiazole are dissolved in 75 ml of acetonitrile, and 2 g of phthalic anhydride are added in portions. The medium is stirred for 6 hours at room temperature and the precipitate is then filtered off and washed with ethyl acetate to give 3.3 g of 2-[4-((2,4-dimethylthiazol-5-yl)methyl)phenylaminocarbonyl]benzoic acid in the form of crystals melting at 182° C.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][NH:16][C:17]([C:19]2[O:20][CH:21]=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:18])=[O:14])=[CH:11][C:10]=1[O:38][CH3:39])C1C=CC=CC=1.O1CCOCC1>[C].[Pd].CO>[OH:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][NH:16][C:17]([C:19]2[O:20][CH:21]=[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:18])=[O:14])=[CH:11][C:10]=1[O:38][CH3:39]
Reactant: COc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Reaction time: 6 h
Yield: 60.5 %

Procedure:
A mixture of the compound of Example 68 (0.80 g), dioxane (100 ml), methanol (10 ml) and 10% palladium carbon (0.16 g) was hydrogenated at 40° C. with stirred for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/chloroform=1/9) and recrystallized from ethanol, thereby giving 0.40 g of the desired compound. Melting point: 216-220° C.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH3:28]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=3[CH3:28])[CH2:30][CH2:31]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cccc(C)c2C)CC1
Yield: 72 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,3-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][Cl:8])(=[O:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.C(O)(C)C>CC(C)=O>[C:1]([O:4][CH2:5][C:6](=[O:9])[CH2:7][Cl:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(O)CCl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(=O)OCC(=O)CCl
Yield: 59.6 %

Procedure:
To a solution of 1-acetoxy-3-chloro-2-propanol (15.3 g) in acetone (250 ml) is dropwise added Jones reagent (37.4 ml) containing chromic anhydride (10.39 g) and conc. sulfuric acid (10.18 ml) in 1 hour, and the resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is mixed with isopropanol (10 ml) and the insoluble material is filtered off. The organic layer is concentrated in vacuum, and the residue is distilled to give 1-acetoxy-3-chloro-2-propanone (9 g) as an oil boiling at 102°-104° C./15 mm Hg. The yield is 60.0%.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH:14]3[CH:12]([CH:13]3[N:16]3[C:20](=[O:21])[C:19]([CH2:47][C:48]4[N:49]=[CH:50][N:51]([C:53]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)([C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[CH:52]=4)([CH2:22][C:23]4[N:24]=[CH:25][N:26]([C:28]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:27]=4)[NH:18][C:17]3=[S:72])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:73]([C:75]1[CH:84]=[CH:83][C:78]([C:79](=[O:82])[CH2:80]Br)=[CH:77][CH:76]=1)#[N:74].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[C:1]1([S:7]([N:10]2[CH2:15][CH:14]3[CH:12]([CH:13]3[N:16]3[C:20](=[O:21])[C:19]([CH2:47][C:48]4[N:49]=[CH:50][N:51]([C:53]([C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)[C:54]5[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=5)[CH:52]=4)([CH2:22][C:23]4[N:24]=[CH:25][N:26]([C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:27]=4)[N:18]=[C:17]3[S:72][CH2:80][C:79]([C:78]3[CH:83]=[CH:84][C:75]([C:73]#[N:74])=[CH:76][CH:77]=3)=[O:82])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: O=C1N(C2C3CN(S(=O)(=O)c4ccccc4)CC32)C(=S)NC1(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: N#Cc1ccc(C(=O)CSC2=NC(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(=O)N2C2C3CN(S(=O)(=O)c4ccccc4)CC32)cc1

Procedure:
Using the same procedure as described in Example 1C, the title compound of 53C (0.548 g, 0.558 mmol) and 4-cyanophenacyl bromide (138 mg, 0.614 mmol) in the presence of potassium bis(trimethylsilyl)-amide (129 mg, 0.614 mmol) reacted to yield the title compound of 53D, after chromatographic purification, 0.46 g (0.41 mmol, 73% yield).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([O:7][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:1]([OH:13])=[O:12])[CH:11]=[CH:10][C:8]=1[O:9][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Solvent: c1ccncc1
Product: O=C(O)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
3 g of dihydrocaffeic acid was dissolved in 20 ml of pyridine, and 5 g of benzoyl chloride was then gradually added thereto under cooling. After stirring at room temperature for 2 hours, the solvent was distilled off, and the resultant residue was then poured into 50 ml of ice water. This solution was neutralized with 6N hydrochloric acid and then extracted with 50 ml of chloroform twice. After washed with a saturated saline solution, the extracted material was dried over Glauber's salt, and the solvent was then distilled off under reduced pressure, thereby obtaining 6.8 g of 3-(3,4-dibenzoyloxyphenyl)propionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][O:34][C:35]1[CH:41]=[CH:40][CH:39]=[C:37]([OH:38])[CH:36]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([O:34][CH3:33])[CH:36]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OC(=O)c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.43 g (11.5 mmol) of resorcinol monomethyl ether and 20 ml of dry dimethylformamide is stirred at room temperature for 2 days, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel while eluting with ethyl acetate/n-hexane (3:1) and subsequently crystallized from ethyl acetate. There is obtained m-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 184°-185°.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][OH:10]>>[CH3:9][O:10][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C1CCCCC1Cl
Reactant: CO
Product: COC1CCCCC1=O
Yield: 90 %

Procedure:
2-methoxycyclohexanone was prepared by dissolving 30 gm. 2-chlorocyclohexanone in 160 ml. methanol and heating the solution in a sealed vessel at 125° C. for approximately four hours. The reactionmass was then cooled and the methanol removed by distillation at reduced pressure. After most of the methanol was distilled off, the residue containing the 2-methoxycyclohexanone was diluted with methylene chloride and extracted with an aqueous solution of sodium hydroxide. After distillation a yield of 90-95% 2-methoxycyclohexanone was obtained.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH2:12])[N:11]=2)[N:8]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O>CC(N(C)C)=O>[I:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:11]=2)[N:8]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Compound 3C was synthesized according to a procedure analogous to that described in International Patent Publication No. WO 2008/06192 (Takeda Pharmaceutical Company Limited), which is incorporated by reference herein in its entirety. 6-Iodoimidazo[1,2-b]pyridazin-2-amine hydrochloride (4.45 g, 17.11 mmol) and cyclopropanecarbonyl chloride (1.35 mL, 18.82 mmol) were dissolved in DMA (85 mL) and stirred for 3 hours at ambient temperature. The reaction mixture was then poured into water (400 mL) resulting in the formation of a brown precipitate. The solid was filtered and dried under vacuum to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (4.2 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ=11.21 (s, 1 H), 8.26-8.17 (m, 1 H), 7.74 (d, J=9.3 Hz, 1 H), 7.49 (d, J=9.1 Hz, 1 H), 2.07-1.87 (m, 1 H), 0.97-0.77 (m, 4 H) ESI-MS:m/z 329.1 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:15][C:16]([OH:18])=[O:17])=[CH:9][NH:10]2.[C:19](=O)([O-])O.[Na+]>CO>[CH3:19][CH:15]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[Br:5])[NH:10][CH:9]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1c[nH]c2cccc(Br)c12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(C(=O)O)c1c[nH]c2cccc(Br)c12
Reaction time: 0.5 h

Procedure:
To methanol (10 mL), thionyl chloride (0.76 mL) was added dropwise at −15 to −10° C., followed by stirring for 30 minutes. To the mixture, (4-bromo-1H-indol-3-yl)acetic acid (Chemical and Pharmaceutical Bulletin, 33(9), 3696-3708 (1985), 1.32 g) was added, followed by stifling at room temperature for 2 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried and then concentrated. The residue was washed with diisopropyl ether/n-hexane (1:2) to obtain the titled compound having the following physical properties (1.26 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][C:19]=1[Cl:33])([CH2:11][CH:12](OC)[O:13]C)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)=O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:34])[C:5]([CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][C:21]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:20][C:19]=1[Cl:33])([CH2:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)(CC(OC)OC)C(=O)OCC
Solvent: CC(C)=O
Solvent: O=CO
Product: CCOC(=O)C(CC=O)(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)OCC
Reaction time: 24 h

Procedure:
To a solution of 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2,2-dimethoxy-ethyl)-malonic acid diethyl ester (10.0 g, 18.5 mmol) (Preparation 9) in 95 mL of acetone, add 10 ml of formic acid. After 24 h, concentrate the reaction to 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethyl ester as yellow oil product (6.7 g, 80%).
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([C:8](=[C:22]([S:29][C:30](=[O:32])[CH3:31])[S:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:33])[CH2:5]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH:4]1[N:7]([C:8](=[C:22]([S:29][C:30](=[O:32])[CH3:31])[S:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:10])[C:6](=[O:33])[CH2:5]1)=[O:42])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Solvent: ClCCl
Product: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1S(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.4 g p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-3-acetylthio-3-(2-ethoxyethylthio)acrylate in 75 ml. methylene chloride was cooled to 0° C. under a nitrogen atmosphere. A solution of 0.551 g m-chloroperbenzoic acid in 25 ml methylene chloride was added dropwise, then the reaction mixture was stirred at 0° C. for 1 hour. The methylene chloride solution was then washed with two 25 ml portions of saturated aqueous sodium bicarbonate solution and two 25 ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. The crude title compound (1.25 g) was used without further purification. The NMR spectrum of a deuterochloroform solution showed peaks at 1.24(m,6H); 2.27-3.74(c,13H); 4.7-5.46(c,3H); 7.75(m,2H); and 8.23(m,2H) ppm. The infrared spectrum of a dichloromethane solution has absorption bands at 5.6 and 5.79 microns.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:11][OH:12])[NH2:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[C:25]([C:31](OC2C=CC(F)=CC=2)=O)[NH:26]3)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[N:10]=[C:31]([C:25]3[NH:26][C:27]4[C:23]([CH:24]=3)=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)[CH:30]=[CH:29][CH:28]=4)[O:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: CN1CCN(c2cccc3[nH]c(C(=O)Oc4ccc(F)cc4)cc23)CC1
Reactant: NC(Cc1ccc(Cl)cc1)=NO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3[nH]c(-c4nc(Cc5ccc(Cl)cc5)no4)cc23)CC1
Yield: 4.4 %

Procedure:
To a stirred solution of (4-chlorophenyl)acetamidoxime (2.21 g from above, assumed 10 mmol, 15 equivalents) and sodium hydride (60% in oil, 0.460 g, 11.5 mmol, 17 equivalents) in anhydrous tetrahydrofuran (25 mL) was added crude 4-methyl-1-(2-(4-fluorophenoxycarbonyl)-1H-indol4-yl)piperazine (0.225 g from above, assumed 0.68 mmol), and the resulting reaction mixture was heated at reflux under nitrogen for 6 hours. A saturated solution of sodium hydrogen carbonate (25 mL) was added, and the resulting aqueous mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 25 g) and elution with methylene chloride/methanol/ammonium hydroxide [10:1:0.1] to afford the title compound (0.013 g, 0.03 mmol, 4%) as an off-white foam: 13C NMR (acetone-d6) δ170.3, 169.5, 147.2, 139.7, 135.0, 132.3, 130.7, 128.5, 126.2, 121.5, 119.9, 107.0, 106.4, 106.2, 55.3, 51.2, 45.5, 31.0; LRMS (m/z, relative intensity) 409 ([M+ with 37Cl], 30), 408 (27), 407 ([M+ with 35Cl], 100), 392 (7), 337 (23), 322 (16), 170 (16), 70 (41); HRMS calculated for C22H22ClN5O [with 35Cl] 407.1516, found 407.1516.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:23]([NH:25][C@H:26]([C:37]([OH:39])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:37]([OH:39])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-phenylalanyl-L-tryptophan in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-phenylalanyl-L-tryptophan.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1

Procedure:
Prepared from the coupling of 2e and methylsulfonamide by the method described in Procedure 1, Method A. Yield (68%); 1H NMR (CDCl3) δ 7.66 (d, J=15.7 Hz, 1H), 7.18 (m, 10H), 6.95 (d, J=8.1 Hz, 2H), 6.84 (d, J=7.3 Hz, 1H), 6.28 (d, J=15.7 Hz, 1H), 3.36 (s, 3H), 2.82 (t, J=7.0 Hz, 2H), 2.41 (t, J=7.0 Hz, 2H), 2.19 (m, 2H); ESI m/z: 442 (M−H−, 100%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Cl:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[NH:29][N:30]=[CH:31][C:24]=12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[N:30]=[CH:31][C:24]=12
Reactant: C1=COCCC1
Reactant: Clc1ncnc2[nH]ncc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 80 %

Procedure:
3,4-Dihydro-2H-pyran (10 mL) and 10-camphorsulfonic acid (200 mg, 0.86 mmol) were added to a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 30; 2.1 g, 13.6 mmol) in ethyl acetate (80 mL). The mixture was stirred at room temperature for 70 h, poured into saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography eluting with 20% ethyl acetate/hexanes to give 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (2.61 g, 80%) as a lavender-colored crystalline solid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[CH3:17][C:18](=[O:23])[CH2:19][C:20](=[O:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=[C:19]([C:18](=[O:23])[CH3:17])[C:20](=[O:22])[CH3:21])=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)C(=Cc1cc(F)c(F)c2c(=O)cc(C)oc12)C(C)=O

Procedure:
250 mg (1.12 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 0.14 ml (1.34 mmol) of 2,4-pentanedione and 212.1 mg (1.12 mmol) of para-toluenesulfonic acid are heated in 100 ml of toluene under reflux with a water trap for 10 h. After cooling, 100 ml of ethyl acetate are added, and the reaction mixture is washed with water and with brine. Drying of the organic phase and concentration result in 269.7 mg (79% of theory) of the title compound as beige-coloured crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution (70 ml) of 4-chloro-N-hydroxybenzenimidoyl chloride (3.28 g) and methyl 4-ethynylbenzoate (3.00 g) in tetrahydrofuran was added dropwise a solution (5 ml) of triethylamine (2.8 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into dilute hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, volume ratio) to give methyl 4-[3-(4-chlorophenyl)-5-isoxazolyl]benzoate (4.40 g, yield 81%). Recrystallization from hexane-acetone gave colorless prism crystals. melting point: 225–226° C.