Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])C1C=CC=CC=1.C([O:32][CH2:33][CH3:34])(=O)C>CN(C)C=O.C(N(CC)CC)C>[NH:18]1[C:22](=[O:26])[CH2:23][CH2:25][C@H:34]1[C:33]([NH:24][C@H:23]([C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([OH:9])=[O:28])=[O:27])=[O:26])[CH3:25])=[O:32]
Reactant: CCOC(C)=O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (2.46 g, 6 m mole) was dissolved in dimethylformamide (10 ml, and triethylamine (0.84 ml, 6m mole) was added thereto under cooling to neutralize it and then benzyloxycarbonyl-L-pyroglutamic acid N-hydroxysuccinimide ester (2.38 g, 6.6 m mole) was added thereto. The mixture was stirred for 2 days while the solution had been adjusted to a pH of about 7 with triethylamine and then ethyl acetate (150 ml) was added thereto. The solution was washed with 1N hydrochloric acid, 5% aqueous sodium bicarbonate and water in order. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the thus obtained residue, n-hexane was added to form a powder. This powder was purified by column chromatography. (Silica gel, developing solvent; chloroform:ethanol:ethyl acetate=5:1:5). The fractions of the main ingredient were collected together and then concentrated. To the residue, n-hexane was added to precipitate the powder. They were dissolved in methanol (50 ml) and then hydrogen gas passed through the solution in the presence of palladium-carbon as a catalyst for 4 hours. The catalyst was separated by filtration and the solvent was distilled off. The thus obtained residue was recrystallized with methanol-ether to give L-pyroglutamyl-L-alanyl-L-prolyl-L-proline (880 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[CH:11]1(O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][O:12]1.C([BH3-])#N.[Na+].N.[C:27]([OH:30])(=[O:29])C>CO.C(O)(C)C.C(#N)C>[C:3]([O:30][C:27](=[O:29])[N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:11][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][CH2:13][OH:12])([CH3:8])([CH3:4])[CH3:2]
Reactant: NCCc1ccccc1F
Reactant: OC1OCCc2ccccc21
Reactant: CC(=O)O
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCc1ccccc1F)Cc1ccccc1CCO
Reaction time: 1 h

Procedure:
2-(2-Fluoro-phenyl)-ethylamine (0.34 mL) was added to a solution of iso-chroman-1-ol (0.26 g) and acetic acid (0.1 mL) in methanol (5 mL). After stirring for 1 hour, sodium cyanoborohydride (0.17 g) was added and stirred for 18 hours. A few drops of 0.880 ammonia solution was added and the resulting mixture concentrated. The residue was dissolved in methanol (5 mL) and loaded onto a conditioned SCX cartridge (10 g Varian). The cartridge was washed with methanol (3×20 mL), then eluted with a methanolic ammonia solution (2×15 mL) and the combined elution fractions evaporated. The residue was dissolved in dimethylformamide (5 mL) and triethylamine (0.37 mL) added, followed by di-tert-butyl dicarbonate (0.57 g) and the resulting mixture was stirred for 72 hours. The reaction was concentrated, partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organics were washed sequentially with water (50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated. Purification on silica, eluting with a gradient of iso-hexane:ethyl acetate [1:0 to 4:1], afforded the subtitle compound as a yellow oil (250 mg).
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(OOC[C@@H:27]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:28][CH3:29])(=O)=O)=CC=1.CN(C)[CH:40]=[O:41]>>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]1[O:30][CH2:27][CH2:28][CH2:29][CH2:40][O:41][C:11]1[CH:12]=[CH:2][CH:3]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC[C@@H](COOS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccccc1OCCCCO[C@H]1CCCCO1
Temperature: 25 °C

Procedure:
5 g (0.030 mol) of ethyl 4-hydroxybenzoate was added to 1.6 g (0.033 mol) of 50% sodium hydride and 50 ml of dimethylformamide under stirring at room temperature. The mixture was stirred for 30 min. 9.9 g (0.030 mol) of (S)-2-tetrahydropyranyloxybutoxy p-toluenesulfonate was added thereto and the mixture was stirred at 80° C. for 10 h. Then, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a 10% aqueous sodium hydroxide solution and then with a saturated aqueous common salt solution, dried and concentrated to obtain 8.8 g of the crude product.
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]([C:11]([OH:13])=[O:12])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.ClCCl>[C:20]([NH:8][C@@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:9]([C:11]([OH:13])=[O:12])[OH:10])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H](c1ccccc1)[C@@H](O)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of compound 5.HCl (219 mg, 1.00 mmol) in water (10 mL) containing sodium bicarbonate (500 mg, 5.95 mmol) was added a solution of benzoyl chloride (0.14 mL, 1.20 mmol) in dichloromethane (5.0 mL). The mixture was vigorously stirred for 16 h at room temperature. The reaction mixture was acidified with 0.1N HCl and the crude product was extracted with ethyl acetate (40 mL×3). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to dryness. The residue was purified on a short silica gel column using chloroform/methanol (2/1) as the eluant to give N-benzoyl-(2R,3S)-3-phenylisoserine (6) (205 mg, 72%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccc(Br)s1
Temperature: 25 °C

Procedure:
3 g (15.7 mmol) of 5-bromo-thiophene-2-carbaldehyde were dissolved in 30 ml of pyridine and 1.96 g (18.8 mmol) of malonic acid and 133 mg (1.6 mmol) of piperidine was added. The reaction mixture was boiled under reflux for 6 h. After cooling to room temperature, it was poured into a mixture of ice and concentrated aqueous hydrochloric acid whereupon the product precipitated. The product was isolated by filtration, dissolved in ethyl acetate, and the solution was washed with 0.1 M hydrochloric acid. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. Yield: 3.0 g.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:34]([C:36](OCC)=[O:37])[NH2:35]>CCOC(C)=O>[O:37]=[C:36]1[NH:34][N:35]=[C:1]([C:3]2[N:4]=[C:5]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1nc(C#N)cc2ccccc12
Reactant: CCOC(=O)NN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (S)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (0.562 g) was added NMP (2 mL) followed by ethyl hydrazinecarboxylate (0.663 g, 6.36 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with brine. The organic layer was separated, dried over Na2SO4, and concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C[N:13](C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:13])=[O:7]
Reactant: CN(C)C=O
Reactant: CSc1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CSc1cccc(C(N)=O)c1
Temperature: 120 °C

Procedure:
10 g of 3-methylsulfanylbenzoic acid and 0.05 ml of DMF were suspended in 50 ml of DCM. 9 ml of thionyl chloride were added and the mixture was heated under reflux for 4 h. The volatiles were removed in vacuo and the residue was taken up in 30 ml of toluene and transferred to a pressure bottle. 180 ml of a 0.5 M solution of ammonia in dioxane were added, the bottle was sealed and the mixture was heated to 120° C. for 5 h. The solvent was removed in vacuo and the residue taken in water and EA. The phases were separated and the aqueous layer was extracted with EA. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. 8.6 g of the title compound were obtained as a brown solid.
Reaction SMILES: [NH:1]1CCC[CH2:3][CH2:2]1.C1C2C(COC(=O)NC(N3C4[C:30](=[CH:31][CH:32]=[C:33]5[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:34]5=4)[CH:29]=[N:28]3)(C)C)C3C(=CC=CC=3)C=2C=CC=1.C([O-])(O)=O.[Na+].C[N:49]([CH:51]=O)[CH3:50]>>[CH3:41][O:40][C:38]1[CH:37]=[CH:36][C:34]2[C:33]([CH:39]=1)=[CH:32][CH:31]=[C:30]1[C:50]=2[N:49]([CH2:51][CH:2]([NH2:1])[CH3:3])[N:28]=[CH:29]1
Reactant: C1CCNCC1
Reactant: COc1ccc2c(ccc3cnn(C(C)(C)NC(=O)OCC4c5ccccc5-c5ccccc54)c32)c1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc2c(ccc3cnn(CC(C)N)c32)c1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
A solution of piperidine in DMF (1:4, 5 mL) was added to the product of Step C (0.1 g, 0.2 mmol) and the solution was stirred for 5 minutes at 23° C., poured into aqueous NaHCO3, and extracted with ethyl acetate (2×20 mL). The combined extracts were dried (MgSO4) and concentrated to a residue, which was purified by chromatography (silica, gradient, 3 to 10% methanol in dichloromethane) to give an oil (0.035 g, 64%): 1H NMR (CDCl3) δ 8.27 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.26 (m, 1H), 4.76 (dd, J=14.4, 4.8 Hz, 1H), 4.63 (dd, J=14.4, 8.4 Hz, 1H), 3.96 (s, 3H), 3.67 (m, 1H), 1.25 (d, J=6.0 Hz, 3H); MS m/z 256 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([F:13])=[C:6](F)[C:3]=1[CH2:4][OH:5].[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:16].C(N(CC)CC)C>C(O)C.O>[F:13][C:7]1[C:6]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:25][CH2:24]2)=[C:3]([C:2]([F:1])=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)[CH2:4][OH:5]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(CO)c1F
Reactant: CCOC(=O)N1CCNCC1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g) in ethanol (64 ml) and water (7 ml) is added a mixture of 4-ethoxycarbonylpiperazine (11 g), triethylamine (12.5 g) and ethanol (18 ml) at one time. The mixture is stirred at room temperature overnight, and the resulting precipitates are separated by filtration. The crystals are washed with a small amount of diethyl ether and recrystallized from ethanol to give 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (8.7 g), as yellow needles, m.p. 147°-149° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH:18][CH2:19][C:20]12[CH2:27][CH2:26][C:23]([CH3:28])([CH2:24][CH2:25]1)[CH2:22][CH2:21]2.O>C(OCC)(=O)C>[S:7]([O:18][CH2:19][C:20]12[CH2:25][CH2:24][C:23]([CH3:28])([CH2:26][CH2:27]1)[CH2:22][CH2:21]2)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC12CCC(CO)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC23CCC(C)(CC2)CC3)cc1
Reaction time: 2 h

Procedure:
0.156 Mole of p-toluenesulfonyl chloride is dissolved in 150 ml. of anhydrous pyridine at 0° C, under nitrogen, and then 0.078 mole of 1-(hydroxymethyl)-4-methylbicyclo[2.2.2]octane is added slowly and the mixture then stirred for two hours. 2 Ml. of water is then added and the mixture stirred for five minutes and then poured into 600 ml. of ethyl acetate. The organic phase is washed twice with water, then washed with 2 Normal aqueous hydrochloric acid until no more pyridine remains. The ethyl acetate solution is then washed with aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate is then evaporated under vacuum affording 4-methylbicyclo[2.2.2]oct-1-yl methanol tosylate.
Reaction SMILES: [CH2:1]([C:3]([CH3:8])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[CH3:9][O:10][CH2:11][CH:12]=O.C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:9][O:10][CH2:11][CH:12]1[O:7][CH2:6][C:3]([CH2:1][CH3:2])([CH3:8])[CH2:4][O:5]1
Reactant: CCC(C)(CO)CO
Reactant: COCC=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1(C)COC(COC)OC1
Yield: 89 %

Procedure:
A mixture of 590 g (5 moles) of 2-ethyl-2-methyl1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 500 ml of chloroform was heated with 10 g of pyridinium p-toluenesulfonate under a water separator until water no longer separated off. The remaining solution was deionized using a mixed-bed ion exchanger, the solvent was removed under reduced pressure and the residue was distilled. 774 g (89% yield) of 2-methoxymethyl-5-ethyl-5-methyl-1,3-dioxane of boiling point 58° C./1 mbar were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>ClCCl>[C:14]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])(=[O:17])[CH:15]=[CH2:16]
Reactant: CC(C)=CCO
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCC=C(C)C
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A 1-liter flask was charged with 43.9 g (0.51 mol) of 3-methyl-2-buten-1-ol, 51.6 g (0.51 mol) of triethylamine and 300 ml of dichloromethane, and the mixture was cooled down to 0° C. While stirring the mixture at 0° C., 45.3 g (0.50 mol) of acryloyl chloride were added dropwise over 1 hour, and the mixture was stirred additionally for 5 hours at room temperature. Solids were separated by filtration from the resultant reaction mixture, and the filtrate was washed 3 times with water and then distilled in the presence of 5 g of p-methoxyphenol to obtain 50.5 g of 3-methyl-2-butenyl acrylate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1.[CH2:46]([C:48]1[CH:49]=[C:50]([CH2:56][CH:57]([NH:61][C:62]([N:64]2[CH2:69][CH2:68][CH:67]([N:70]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]3=[O:80])[CH2:66][CH2:65]2)=[O:63])[C:58](O)=[O:59])[CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH3:47]>C1COCC1.C(N(CC)CC)C>[CH2:46]([C:48]1[CH:49]=[C:50]([CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH2:56][CH:57]([NH:61][C:62]([N:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:79][C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[NH:72][C:71]2=[O:80])[CH2:66][CH2:65]1)=[O:63])[C:58]([N:43]1[CH2:44][CH2:45][CH:40]([N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)[CH2:41][CH2:42]1)=[O:59])[CH3:47]
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
336 mg (1.05 mmol) of TBTU, 161 mg (1.05 mmol) of HOBt, 0.75 mL of triethylamine and 192 mg (1.05 mmol) of 1-methyl-4-piperidin-4-yl-piperazine were added to a solution of 500 mg (1.05 mmol) of 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid in 100 mL of THF, and stirred for 4 h at RT and 2 h at 40° C. The solvent was removed in vacuo, the residue taken up in 40 mL of saturated NaHCO3 solution, exhaustively extracted with EtOAc and dried over MgSO4. After elimination of the desiccant and solvent the crude product was purified by chromatography (silica gel, MeOH/NH3 100:3).
Reaction SMILES: [C:1]1(=[O:8])[O:7]CCCC[CH2:2]1.CCCC[CH:13]([C:16]([O-:18])=[O:17])CC.[CH3:19][CH2:20][CH2:21][CH2:22][CH:23]([C:26]([O-:28])=[O:27])CC.[Sn+2]>C(O)COCCO>[CH2:2]1[O:18][C:16](=[O:17])[CH2:13][O:8][C:1]1=[O:7].[C:26]1(=[O:28])[O:27][CH:22]([CH2:21][CH2:20][CH3:19])[CH2:23]1
Reactant: O=C1CCCCCO1
Reactant: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: OCCOCCO
Product: CCCC1CC(=O)O1
Product: O=C1COC(=O)CO1
Temperature: 200 °C

Procedure:
ε-caprolactone (Cap), diethylene glycol (DEG), and stannous octoate were combined and melted under a nitrogen atmosphere. The mixture was charged into a nitrogen purged stirred reactor at 200° C. The contents were stirred at this temperature until maximum melt viscosity was achieved. Glycolide was melted under nitrogen and charged into the reactor. The temperature was increased to 225° C. over a 15 minute period, and the contents maintained at 225° C. until maximum melt viscosity was obtained. The polymer was discharged from the reactor, ground and dried in a vacuum oven for 12-18 hours at 100° C. and 0.2 mm Hg. Specific examples of polymers prepared by this procedure are summarized in Table 7.
Reaction SMILES: [CH3:1][SiH:2]([CH3:14])[NH:3][CH2:4][CH:5]=[CH:6]CC1C=CC=CC=1.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:21]([N:3]1[CH2:4][CH2:5][CH2:6][Si:2]1([CH3:14])[CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccccc1
Reactant: C[SiH](C)NCC=CCc1ccccc1
Product: C[Si]1(C)CCCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Into a glass tube with an outside diameter of 10 mm and a length of 10 cm were introduced 5 mg ((1,5-cyclooctadiene)RhCl)2 and 2 mL of a mixture of 1 part N-dimethylsilyl-N-benzylallylamine and 2 parts toluene, and the tube was sealed. After this had been left quiescent for 30 minutes at room temperature, the conversion of N-dimethylsilyl-N-benzylallylamine was 100 weight %. 1-Benzyl-2,2-dimethyl-1-aza-2-silacyclopentane was obtained in a yield of 96%. No production of 1-benzyl-2,2,3-trimethyl-1-aza-2-silacyclobutane was observed.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[I:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([NH2:20])=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[I:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]#[N:20]
Reactant: Cc1ccc(C(N)=O)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(C#N)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
2,2,2-trifluoroacetic anhydride (8.00 mL, 57.5 mmol) was added dropwise to a stirred solution of 3-iodo-4-methylbenzamide (preparation 48a, 6.00 g, 23.0 mmol) and triethylamine (8.10 mL, 57.5 mmol) in dichloromethane (50 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. Further dichloromethane and saturated aqueous potassium carbonate solution were added and the organic layer was washed with 2M aqueous hydrochloric acid, 2M aqueous sodium hydroxide solution, brine, dried (MgSO4) and evaporated to give the title compound (4.50 g, 80%) as a pale orange solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].N1CCCCC1>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-Cyanobenzaldehyde (3.00 g, 22.9 mmol) ad ethyl cyanoacetate (2.59 g, 22.9 mmol) are dissolved in absolute ethanol (100 ml). Piperidine (0.097 g, 1.14 mmol) is added, and the solution is stirred at room temperature until no more starting material is apparent by tic. This takes approx. 2 hours during which time a precipitate is formed. The precipitate is filtered and recrystallised, or alternatively, the crude reaction mixture is concentrated in vacuo and chromatographed over silica with cyclohexane/ethyl acetate mixtures as eluent to yield a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH:18]([CH2:21][CH2:22][F:23])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH:35]([C:37]([CH3:39])=[O:38])=[CH2:36]>C1COCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([CH2:21][CH2:22][F:23])([CH2:36][CH2:35][C:37](=[O:38])[CH3:39])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc3nn(Cc4ccccc4)cc3c2CC1CCF
Reactant: C=CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(=O)CCC1(CCF)Cc2c(ccc3nn(Cc4ccccc4)cc23)C1=O
Temperature: 55 °C

Procedure:
To a solution of 2-benzyl-7-(2-fluoroethyl)-7,8-dihydrocyclopenta[e]indazol-6(2H)-one (11.8 g, 38.3 mmol) in dry THF (100 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (12 mL, 80 mmol) and methyl vinyl ketone (6.4 mL, 77 mmol) and the solution was heated to 55° C. After heating for 72 hours, analysis of an aliquot by 1H NMR showed the reaction to be complete. After cooling to room temperature, the solution was partitioned between 5% MeOH/CH2Cl2 and water and the organic phase was washed with 5% aqueous NaHCO3. The solvent was removed by evaporation under vacuum and the residue was purified by chromatography on silica gel (1:2 to 1:1 EtOAc/hexanes) to give 2-benzyl-7-(2-fluoroethyl)-7-(3-oxobutyl)-7,8-dihydrocyclopenta[e]indazol-6(2H)-one as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([NH:16][S:17]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH:29]=O)(=[O:19])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([NH:16][S:17]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1/[CH:29]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)(=[O:19])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To the mixture of 6-chlorooxindole (3.05 g, 10 mmol) and N-tert-butyl-C-(4-chloro-2-formyl-phenoxy)-methanesulfonamide (1.65 g, 10 mmol)) in methanol (20 mL) was added pyrrolidine (1.41 g, 20 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound (4 g).