Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.S(Cl)([Cl:14])(=O)=O.O.C(Cl)(Cl)Cl>ClCCl>[Cl:14][CH:5]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)CC(=O)C1CC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(Cl)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2 g of methyl 3-cyclopropyl-3-oxopropanoate in 20 ml of dichloromethane was added dropwise 1.24 ml of sulfuryl chloride under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water under ice-cooling, and chloroform was further added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.48 g of methyl 2-chloro-3-cyclopropyl-3-oxopropanoate.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.Br[C:17]1C=CC=C2C=1C(=O)C(=O)N2>>[CH3:17][N:11]1[C:12]2[CH:13]=[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]3=[CH:7][C:8]=2[C:9](=[O:15])[C:10]1=[O:14]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: CN1C(=O)C(=O)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in PREPARATION 79A, and making non-critical variations using 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 4-bromoisatin, 6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione was obtained (68%): 1H NMR (300 MHz, CDCl3) δ 7.09 (s, 1H), 6.74 (s, 1H), 4.41-4.38 (m, 2H), 4.27-4.24 (m, 2H), 3.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ; MS (ES+) m/z 220.2 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([OH:19])/[CH:8]=[CH:9]/[CH:10]2[CH2:17][CH2:16][CH:15]3[CH:11]2[CH2:12][CH2:13][C:14]3=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O>[Si:24]([O:19][CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)/[CH:8]=[CH:9]/[CH:10]1[CH2:17][CH2:16][CH:15]2[CH:11]1[CH2:12][CH2:13][C:14]2=[O:18])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: O=C1CCC2C(/C=C/C(O)C3CCCCC3)CCC12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)C1CCCCC1
Yield: 96.8 %

Procedure:
A mixture of (E)-2-(3-cyclohexyl-3-hydroxyprop-1-enyl)bicyclo[3,3,0]octan-6-one (41 mg), prepared as described in Reference Example 13, and in the form of (±)-(E)-2β-(3-cyclohexyl-3α-hydroxyprop-1-enyl)bicyclo[3,3,0]octan-6-one, tert-butyldimethylchlorosilane (35 mg), and imidazole (29.5 mg) in dimethylformamide (0.25 ml) was stirred at ambient temperature for 3 hours. Water (2.5 ml) was added and the mixture was extracted with diethyl ether. The combined ethereal extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give (E)-2-(3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one (57 mg), in the form of (±)-(E)-2β-(3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:26]=[CH:25][C:10]2[O:11][C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=3[C@@H:14]3[C@H:19]([NH2:20])[CH2:18][CH2:17][CH2:16][N:15]3[C:9]=2[CH:8]=1.Cl[C:28]([O:30][CH2:31][Cl:32])=[O:29].C(OCC)(=O)C>C(Cl)Cl>[Cl:32][CH2:31][O:30][C:28](=[O:29])[NH:20][C@H:19]1[C@@H:14]2[N:15]([C:9]3[CH:8]=[C:7]([Cl:6])[CH:26]=[CH:25][C:10]=3[O:11][C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=32)[CH2:16][CH2:17][CH2:18]1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: O=C(Cl)OCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)OCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
100 μL of saturated aq. sodium bicarbonate was added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (9.5 mg, 0.03 mmol) and chloromethyl chloroformate (64.2 μL, 0.42 mmol) in 250 μL of CH2Cl2. The resulting mixture was stirred at room temperature for 18 h. Subsequently, ethyl acetate was added and the organic layer was washed with water, dried (Na2SO4) and evaporated to give trans-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamic acid chloromethyl ester (9.9 mg, 88%). Data: (m/z)=393 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([O:46][CH3:47])=[C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:42][CH2:41][N:40]([C:38]2[CH:39]=[C:34]([Cl:33])[CH:35]=[CH:36][C:37]=2[O:46][CH3:47])[CH2:45][CH2:44]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: COc1ccc(Cl)cc1N1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 3.5 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(5-chloro-2-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (2.6 mg, 3.5%) as light yellow oil. MS m/e=555.4 [M+H]+.
Reaction SMILES: O.Cl.[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2>C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)O)ccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CCCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a mixture of 6 g zin wool and 0.6 g of mercuric chloride, there are added 9 cm3 of water and 0.3 cm3 of 12N HCl. The mixture is stirred for 10 minutes at ambient temperature. The aqueous phase is removed by decanting. The resulting amalgam is rinsed with 20 cm3 of water. There are added 7.21 g (0.025 mole) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydo-2-naphthyl)-4-oxo butyric acid, described in Example III, 10 cm3 of water, 8 cm3 of toluene and 5 cm3 of 12N HCl. The mixture is heated for 34 hours at reflux with stirring, adding 3 cm3 of 12N HCl every 6 hours. The reaction mixture is diluted by the addition of 100 cm3 of toluene, filtered (separation of residual amalgam) and rinsed with toluene. The toluene phase is separated, washed copiously with water, dried on sodium sulfate and concentrated under reduced pressure. The resulting crude oil is purified by chromatography on silica 60 gel in a 2/8/90 acetic acid/dioxan/ toluene eluant mixture. After evaporation, the recovered solid is taken up in a minimum of isopropyl ether, filtered and dried under a vacuum at 70° C. 4.6 g of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) butyric acid in the form of a white solid whose melting point is 99° C. are obtained.
Reaction SMILES: [C:1](=[N:10][OH:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[H-].[Na+].Cl[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CN(C)C=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:11][N:10]=[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3])#[N:18]
Reactant: N#Cc1ccccc1Cl
Reactant: CCC(=NO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=NOc1ccccc1C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
A solution of 5.0 g of propiophenone oxime in 35 ml of dimethylformamide is added dropwise to a solution of 1.55 g of 62.5% sodium hydride in 80 ml of dimethylformamide under ice-colling, and the mixture is stirred at the same temperature for 20 minutes. A solution of 4.24 g of 2-chlorobenzonitrile in 20 ml of dimethylformamide is added dropwise to the mixture and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=6:1) to give 2.19 g of propiophenone O-(2-cyanophenyl)oxime as oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[Cl:16])[CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].N1C=CC=CC=1>O>[Cl:16][C:10]1[CH:11]=[C:12]([NH:15][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(Oc2cccc(Cl)n2)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1ccc(Oc2cccc(Cl)n2)c(Cl)c1
Reaction time: 18 h

Procedure:
4-((6-Chloro-2-pyridinyl)oxy)-3-chlorobenzeneamine (7.1 grams; .028 mole) and propionyl chloride (2.6 grams; .028 mole) were contacted in the presence of 40 ml. of dry pyridine and the resulting reaction mixture allowed to stand at ambient temperatures for a period of about 18 hours. The reaction mixture was then poured into 250 ml. of cold water and allowed to stand for about 15 minutes. The resulting product precipitate was recovered by filtration and taken up in boiling benzene and the resulting solution dried, treated with Norite and filtered. Hexane was then added to the filtrate which was then cooled to precipitate the desired N-(3-chloro-4-((6-chloro-2-pyridinyl)oxy)phenyl)propionamide compound as a white crystalline solid having a melting point of 166°-168° C. The product was found to have carbon, hydrogen, nitrogen and chlorine contents of 55.0, 3.9, 9.0 and 22.5, respectively, as compared with the theoretical contents of 54.0, 3.9, 9.0 and 22.8, respectively, calculated for the named structure.
Reaction SMILES: [OH:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].CS(O)(=O)=O.[CH2:19]1[O:22][CH:20]1[CH3:21]>ClCCl>[OH:22][CH2:19][CH2:20][CH2:21][O:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: CC1CO1
Reactant: OC[c-]1cccc1
Agent: [Fe+2]
Agent: CS(=O)(=O)O
Agent: c1cc[cH-]c1
Solvent: ClCCl
Product: OCCCOC[c-]1cccc1

Procedure:
21.6 g hydroxymethylferrocene was dissolved in 250 ml dichloromethane and 2.16 g methanesulfonic acid was added. Then 5.8 g of propylene oxide was added dropwise at room temperature while stirring. After this addition was complete, the mixture was stirred for another 24 hours at room temperature. Then the mixture was washed several times with saturated sodium bicarbonate solution and with distilled water. After the solution was dried, the solvent was drawn off by vacuum and 22.5 g of the desired product obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26]Cl)[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][SH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26][S:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Reactant: CN(C)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.4 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.70 g, 1.5 mmol) in DMF (5 mL) was added 2-(dimethylamino)ethanethiol (2.1 g, 15 mmol), followed by potassium carbonate (1.0 g, 7.2 mmol) and the reaction stirred at ambient temperature. After 24 hours, the mixture was poured into water (100 mL) and the resulting solid collected by filtration, washed with water and dried in vacuo. Purification by flash chromatography on silica gel afforded 0.28 g (35% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a cream-colored solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s, 2), 2.5 (t, 2), 2.4 (t, 2), 2.1 (s, 6) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])C.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:30][C@H:25]([C:24]([O:23][CH3:22])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)C1Oc2c(OC)ccc(OC)c2C=C1CN[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 41.6 %

Procedure:
To a solution of 3-formyl-5,8-dimethoxy-2H-chromene-2-carboxylic acid ethyl ester (5.0 g, 17.11 mmol) (Example 13, Step 1) in methanol (40 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-4-methyl-pentanoic acid methyl ester (3.1 g, 17.11 mmol) and N,N′-diisopropylethylamine (4.42 mL, 34.21 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (2.15 g, 34.21 mmol) and acetic acid (1.95 mL, 34.21 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 5,8-dimethoxy-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-2H chromene-2-carboxylic acid methyl ester (2.90 g, 39.2%) as an oil.
Reaction SMILES: [C:1](OC(OCC)OCC)(=O)C.[CH3:12][C:13]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]2[N:27]=[N:28][N:29]=[C:19]2[C:18]=1[NH2:30])([CH3:15])[CH3:14].[OH-].[Na+]>C(O)(=O)C>[CH3:15][C:13]([N:16]1[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]3[N:27]=[N:28][N:29]=[C:19]3[C:18]=2[N:30]=[CH:1]1)([CH3:12])[CH3:14]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CC(C)(C)Nc1c(N)c2nnnn2c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)n1cnc2c1c1ccccc1n1nnnc21

Procedure:
Diethoxymethyl acetate (1.9 mL) was added dropwise to a solution of N5 -(1,1-dimethylethyl)tetrazolo[1,5-a]quinoline-4,5-diamine (1.5 g, 5.9 mmole, Example 19) in acetic acid (15 mL). The reaction mixture was heated on a steam bath for 1 hour then made basic with sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethanol to provide 6-(1,1-dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline, m.p. 224-226° C. Analysis: Calculated for C14H14N6 : % C, 63.13; % H, 5.29; % N, 31.56; Found: % C, 62.90; % H, 5.44; % N, 31.52.
Reaction SMILES: O[CH2:2][C:3](C)(CO)C.C(O)(=O)[C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=1.[C:20]([OH:31])(=[O:30])[C:21]1C=C[C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>>[C:12]([OH:14])(=[O:13])[CH2:11][CH2:15][CH2:16][CH2:17][CH2:9][CH2:10][CH2:2][CH3:3].[C:20]([OH:31])(=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: CC(C)(CO)CO
Product: CCCCCCCCC(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
Typical polyester resins that can be used are those based on a symmetrical glycol e.g. neopentyl glycol and one or more aromatic dicarboxylic acids e.g. isophthalic acid or terephthalic acid, the acid content optionally additionally being provided by an aliphatic mono or dicarboxylic acid e.g. pelargonic acid, adipic acid or trimellitic anhydride. The polyester should preferably have an acid value of 30-100 mg KOH/g, a melting point of 50°-70° C. and a melt viscosity of 10-14 poise at 200° C. (as measured using an I.C.I. Cone and Plate Viscometer).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][C@H:13]1[O:18][C@@H:17]([CH3:19])[CH2:16][NH:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:19][C@H:17]1[O:18][C@@H:13]([CH3:12])[CH2:14][N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:16]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(N)c2)C[C@H](C)O1
Temperature: 110 °C
Reaction time: 48 h
Yield: 68.2 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), cis-2,6-dimethylmorpholine (2.5 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature, poured into water (300 mL). The resulting crude yellow solid was collected by vacuum filtration, air dried, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 95/5 CHCl3/ether) to yield the product as a yellow solid (1.2 g, 68%).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[C:18]([CH2:27]N)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>ClCCl>[Cl:16][C:17]1[C:18]([CH2:27][N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][CH:20]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:22]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: FC(F)(F)c1cnc(CN=C(c2ccccc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzophenone imine (1.67 ml) in dry dichloromethane (25 ml) at 10° C. was added (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (2.47 g). The solution was stirred at room temperature for 3 hours and then filtered. The filtrate was evaporated to dryness and purified by silica gel chromatography [light petroleumidiethyl ether (4:1)] to give the title product.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)([O:3][CH2:4][CH3:5])=[O:2].[CH2:16]([O:18][CH:19](OC(=O)C)OCC)[CH3:17].C(OCC)C>C(O)(=O)C>[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:19][O:18][CH2:16][CH3:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Reactant: CCOC(OCC)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC=C1C(=O)Nc2ncc(C(=O)OCC)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
5-Carboethoxy-7-azaoxindole (0.040 g, 0.19 mmol) and diethoxymethylacetate (0.16 mL, 0.97 mmol) were combined and dissolved in acetic acid (1 mL). The reaction was warmed to 110° C. and stirred at this temperature for 1 h. The reaction was cooled to room temperature and diethyl ether was added to precipitate a beige solid that was collected by filtration (35 mg, 69% yield). 1H NMR 400 M Hz (DMSO-d6) δ 11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H); 4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)=[O:9].Cl.[NH2:20][CH2:21][C:22]#[N:23]>O1CCCC1.CN(C)C=O>[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([CH:22]([NH2:23])[C:21]#[N:20])=[O:15])=[CH:12][CH:11]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: N#CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(N)C(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
First,12.2 g (0.12 mol) of triethylamine and then, dropwise with stirring, a solution of 10.1 g (0.06 mol) of 4-formylbenzoyl chloride in 10 ml of tetrahydrofuran are added at 0° C. to 5.6 g (0.06 mol) of 2-aminoacetonitrile hydrochloride in 50 ml of dimethylformamide at a rate such that the internal temperature does not exceed 10° C. When the addition is complete, the batch is stirred for a further 15 minutes at room temperature, poured into 400 ml of ice water and filtered, and the product thus obtained is dried. Extraction of the filtrate with 5 times 100 ml of ethyl acetate, washing the combined organic phases, drying over sodium sulphate and concentrating in vacuo yields a further fraction. In total, 8.9 g (79% of theory) of 2-(4-formylbenzoyl)-aminoacetonitrile of melting point 122°-125° C. are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[N:14][CH:15]=1)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH3:41])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[K+].[ClH:45]>CCO>[ClH:45].[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([C:40](=[O:42])/[CH:41]=[CH:8]/[C:10]3[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=3)=[CH:38][CH:39]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1ccc(/C=C/C(=O)O)nc1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid trifluoroacetate (272 mg, 0.93 mmol), 4-(4-acetyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (obtained as described in Preparation 9, 283 mg, 0.93 mmol) and 1.7 M KOH (0.820 ml) in EtOH (10 ml) was stirred at 0° C. for 8 h and then at room temperature for 6 days. The mixture was acidified with 10% HCl until reaching a pH value of 3 and the resulting precipitate was filtered to give 184 mg of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester hydrochloride.