Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([NH2:15])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:23][CH2:24][O:25][C:26]2[CH:35]=[CH:34][CH:33]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:27]=2)=[C:8]([NH2:15])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2[nH]cnc2n1
Reactant: COC(=O)c1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2ncn(CCOc3cccc(C(=O)OC)c3)c2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To 2-butoxyadenine (727 mg, 3.5 mmol) and potassium carbonate (727 mg, 5.3 mmol) was added DMF (35 ml), and the mixture was stirred at 70° C. for 2 hours. Then a solution of methyl 3-(2-bromoethoxy)benzoate obtained in Reference Example 1 (1.0 g, 3.9 mmol) in DMF (2 ml) was added thereto under ice-cooling, followed by stirring at room temperature for 3 hours. The solvent was removed under reduced pressure, and to the residue was added water. The mixture was neutralized with concentrated hydrochloric acid and extracted with chloroform (methanol 5%). The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give, as white crystal, 1.1 g (2.9 mmol) of the titled compound. Yield: 81%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:4][CH2:5][C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1
Reactant: CC(=O)OCc1cc2c(cc1CCC(=O)O)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COCc1cc2c(cc1CCC(=O)O)OCO2
Yield: 87.3 %

Procedure:
1.6 g of 3-(6-acetoxymethyl-1,3-benzodioxole-5-yl)propionic acid was dissolved in 100 ml of methanol. A catalytic amount of p-toluenesulfonic acid was added to the solution and the mixture was heated under reflux for 4 h and 15 min. The solvent was distilled off from the reaction mixture. A solution of 1 g of sodium hydroxide in a mixture of 5 ml of water and 45 ml of ethanol was added to the residue and the mixture was heated under reflux for 20 min. The reaction mixture was concentrated. 200 ml of ethyl acetate and 200 ml of water were added to the concentrate. The mixture was acidified with concentrated hydrochloric acid. The layers thus formed were separated. The product was washed with water three times and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 1.25 g of the intended compound in the form of a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([Cl:22])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:22].[ClH:22].[Cl:22][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[C:19]([CH3:21])[N:18]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC2CCNCC2)nc(Cl)n1

Procedure:
A solution of 4-(2-chloro-6-methyl-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 3.52 mmol) in 4 M HCl in dioxane (70 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 225.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C@:19]3([CH3:30])[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[N:22]([CH3:28])[C:21]([NH2:29])=[N:20]3)[CH:13]=2)[C:7]1([CH3:32])[CH3:31])C.[Li+].[OH-]>C1COCC1.CO.O>[NH2:29][C:21]1[N:22]([CH3:28])[C:23](=[O:27])[C:24]([CH3:26])([CH3:25])[C@:19]([C:14]2[CH:13]=[C:12]([NH:11][CH:8]3[CH2:9][CH2:10][CH:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]3([CH3:31])[CH3:32])[CH:17]=[CH:16][C:15]=2[F:18])([CH3:30])[N:20]=1
Reactant: CCOC(=O)CC1CCC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCC(CC(=O)O)C3(C)C)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {3-[3-((S)-2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-4-yl)-4-fluoro-phenylamino]-2,2-dimethyl-cyclopentyl}-acetic acid ethyl ester (example 98, 0.05 mmole) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH (1N, 0.1 mmole) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, the residue was diluted with aqueous HCl (0.5N) until pH=5 and washed with EtOAc. The aqueous phase was basified to pH=8 with a saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated to yield a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=433.5 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C=C>[OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:20][CH:15]=[CH2:16])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C=CCO
Product: C=CCOC(=O)c1ccc(CO)c([N+](=O)[O-])c1

Procedure:
In a 100 mL round bottom flask was placed 4-hydroxymethyl-3-nitrobenzoic acid (1.97 g, 10 mmol). Allyl alcohol (20 mL) was added, followed by p-toluenesulfonic acid (0.190 g, 1 mmol). The mixture was heated to reflux for 24 hr., at which time all the volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with sat'd KHCO3. The organic layer was dried over MgSO4 and concentrated to afford the title compound as a cream colored solid; 2.4 g (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:36])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:35])=[O:34])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[C:28]1([C@@H:17]([NH:16][C:11]2[O:12][C:13]([CH3:15])([CH3:14])[C:8]([CH3:36])([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[S:9](=[O:34])(=[O:35])[N:10]=2)[CH2:18][CH2:19][OH:20])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1(C)c1ccccc1
Yield: 67.5 %

Procedure:
Under inert gas, 50 mg of [5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were initially charged in 4 ml of methanol and, with addition of 18 mg of 10% Pd/C, a gentle hydrogen stream was passed through for 1 hour. The reaction solution was concentrated by rotary evaporation and the residue purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution. Subsequently, this aqueous residue was extracted with ethyl acetate, and the combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (22.8 mg) with a molecular weight of 402.5 g/mol (C21H26N2O4S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[C:11]=2[C:22](OC)=[O:23])[CH2:9][CH2:8]1.C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[CH:7]1([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[C:11]=2[CH2:22][OH:23])[CH2:9][CH2:8]1
Reactant: COC(=O)c1c(-c2ccccc2C)noc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1noc(C2CC2)c1CO
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (1M in tetrahydrofuran, 29 mL, 29 mmol, 2.5 eq) was added to a dry three-necked flask filled with nitrogen and cooled to 0° C. Methyl 5-cyclopropyl-3-(o-tolyl)isoxazole-4-carboxylate (3.02 g, 11.7 mmol) was dissolved in tetrahydrofuran (40 mL) and added dropwise to the flask, ensuring that the internal temperature remained below −10° C. The mixture was stirred for an hour, then ethyl acetate (1.3 mL) was added dropwise, keeping the temperature below 0° C. followed by water (1.3 mL), taking care that the mixture was vigorously stirring at all times. Sodium hydroxide solution (3.9 mL, 15% solution by weight) was added dropwise and the mixture stirred vigorously for a further 30 minutes, warming up to RT. The mixture was filtered through a CELITE® pad, which was washed with ethyl acetate (120 mL). The organics were washed with water (100 mL) and brine (75 mL) then dried over magnesium sulfate and concentrated under vacuum and purified by column chromatography (SiO2, linear gradient, 0-100% ethyl acetate in hexanes) to afford the desired product. 1H-NMR (MeOH-d4, 400 MHz) δ 7.41-7.26 (m, 4H), 4.36 (s, 2H), 2.34-2.27 (m, 1H), 2.26 (s, 3H), 1.19-1.15 (m, 4H), MS m/z 230.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[C:16]([O:17]C)=[CH:15][N:14]=[C:13]([NH:19][C:20]3[C:21]([O:26]C)=[N:22][CH:23]=[CH:24][CH:25]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[C:16]([OH:17])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1cnc(Nc2cccnc2OC)nc1N[C@@H](C)c1ccc(F)cn1
Agent: Br
Product: C[C@H](Nc1nc(Nc2ccc[nH]c2=O)ncc1O)c1ccc(F)cn1
Temperature: 100 °C
Yield: 25.4 %

Procedure:
A mixture of (S)—N4-(1-(5-fluoropyridin-2-yl)ethyl)-5-methoxy-N2-(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine (Preparation 4b, 0.200 g, 0.54 mmol) and 48% aqueous hydrogen bromide solution (1.8 mL) was stirred and heated to 100° C. overnight. The solvent was evaporated under reduced pressure and the residue was treated with a saturated aqueous solution of potassium carbonate and then extracted with ethyl acetate (×3). Concentrated aqueous hydrogen chloride solution was then added to the aqueous solution until an acidic pH was reached and the white solid that formed was filtered and dried to give the title compound (0.047 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CN(C)CCN(C)C.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>CCOCC.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:24]([OH:29])[OH:25])=[CH:7][C:6]=2[CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc2occc2c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc2cc(Cl)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.8 g (57.7 mmol) 5-chlorobenzofuran in 250 ml dry ether were added 7.32 g (63.0 mmol) tetramethylethylenediamine (TMEDA). The solution was kept below −60° C. under argon, while 37.5 ml of a 1.6M solution of butyllithium in hexane was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of 35.7 g (190 mmol) triisopropyl borate. After warming to room temperature the mixture was quenched with 70 ml 2N hydrochloric acid and stirred for 1 h. The organic layer was washed three times with 30 ml 2N hydrochloric acid, twice with water, and extracted with 2N sodium hydroxide solution, successively. The alkaline aqueous layer was brought to pH5 and extracted with tert.-butylmethylether. All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the pale yellow crystalline boronic acid which was used for the next step without further purification.
Reaction SMILES: [N+](=C)=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.CO>[CH2:21]([NH:28][C:12]1[C:11](=[CH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:15][C:14](=[O:16])[C:13]=1[N+:17]([O-:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: O=C1NC(=Cc2ccccc2)C(NCc2ccccc2)=C1[N+](=O)[O-]
Yield: 60 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of benzylamine for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 4-Benzylamino-5-benzylidene-3-nitro-1,5-dihydropyrrol-2-one was obtained with a melting point of 218° C. in a yield of 60%.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br.C([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O>>[CH:10]1[C:11]2[N:12]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([O:15][CH3:14])=[O:24])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccccc1-n1c2ccccc2c2ccccc21
Yield: 79.6 %

Procedure:
A 1 L round bottom flask was charged with carbazole (8.36 g, 50 mmol), methyl-2-bromobenzoate (15 g, 75 mmol), K2CO3 (7 g, 50 mmol), Na2SO4 (7.1 g, 50 mmol), Cu powder (0.3 g, 5 mmol), and nitrobenzene, and the mixture was reacted at 190° C. for 24 hours. After the reaction was completed, the resultant product was extracted with methylene chloride and water. The organic layer was dried with MgSO4, and purified by silica gel column (ethyl acetate:hexane=1:5) to give 12 g of a product (79.6%).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])(O)[CH2:16][N:15]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])([F:7])[CH2:16][N:15]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:13]
Reactant: CCCCC1(O)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCCCC1(F)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To ethyl acetylene (140 mg, 2.6 mmol) in THF (5 mL) at −78° C., n-butyllithium (1.1 mL, 2.6 mmol) was added with stirring at −78° C. for 1 hour. Then 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (prepared as described in the example 56) (570 mg, 2.3 mmol) in THF (5 mL) was added at −78° C. with stirring for 2 h, the reaction mixture was then allowed to warm to −40° C. over 1 hour. The reaction mixture was extracted with EtOAc (20 mL), washed with saturated NH4Cl (5 mL) and dried over sodium sulfate. Purification of the crude product was carried out by silica gel chromatography using 50% EtOAc in hexane to obtain the 4-butyl4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (520 mg, 73%). To the DAST (556 mg, 3.4 mmol) in DCM (5 mL) at −78° C., was added a solution of the above ester (520 mg, 1.7 mmol) in DCM (5 mL) at −78° C. and stirred for 1 hour. The reaction mixture was extracted with DCM (50 mL) and washed with NaHCO3 (30 mL, 10%). The product obtained after removal of solvent was purified by silica gel chromatography using 5% EtOAc in hexanes to obtain 4-butyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (276 mg, 52%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([C@H:28]([OH:30])[CH3:29])[CH2:24][CH2:23]1>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([OH:30])[CH3:29])=[CH:24][CH:23]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: C[C@@H](O)C1CCC(CN)CC1
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc([C@@H](C)O)cc2)c1

Procedure:
Prepared from 2-(3-Acetyl-phenoxy)-nicotinic acid and (R)-(+)-1-(4-Aminomethyl-cyclohexyl)-ethanol. mp 104-6° C. αD (CHCl3) +14.0°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]=[CH:4][CH:5]=O.[CH3:8][N:9]([CH3:15])[C:10](=[O:14])[CH2:11][C:12]#[N:13].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:12]([C:11]([C:10]([N:9]([CH3:15])[CH3:8])=[O:14])=[CH:5][CH:4]=[CH:3][N:2]([CH3:7])[CH3:1])#[N:13]
Reactant: CN(C)C(=O)CC#N
Reactant: CN(C)C=CC=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CN(C)C=CC=C(C#N)C(=O)N(C)C
Yield: 70.4 %

Procedure:
3-Dimethylaminoacrolein (25 g, 0.25 mol) and cyanoacetic acid N,N-dimethylamide (28 g, 0.25 mol) were dissolved in toluene (250 ml) and piperidine (1 ml) and acetic acid (2.5 ml) were then added. The solution was heated under reflux in a water separator until no more water was formed (about 2 hours). The solution was then filtered and reduced to about 100 ml. On cooling, crystals formed which were filtered off under suction and dried to give 34 g 1-cyano-1- dimethylaminocarbonyl-4-dimethylamino-1,3-butadiene as yellow-brown crystals, m.pt. 149°-150° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:30]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:27]([N:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:15]2[C:11]3[CH:10]=[CH:9][C:8]([F:7])=[CH:30][C:12]=3[S:13][CH:14]=2)[CH2:21][CH2:20]1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:29])[CH3:28]
Reactant: CC(=O)NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCCCN1CCN(c2csc3cc(F)ccc23)CC1)C(=O)C(C)C
Yield: 96.6 %

Procedure:
A solution of isobutyryl chloride (2.34 g, 21.9 mmol) in dry dichloromethane (8 mL) was added over 2 minutes to a solution of N-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-acetamide (2.51 g, 7.18 mmol), triethylamine (2.18 g, 21.5 mmol), 4-dimethylaminopyridine (0.877 g, 7.18 mmol), and dry dichloromethane (50 mL) at room temperature under a nitrogen atmosphere. After 2.5 hours the reaction solution was diluted with dichloromethane (100 mL), washed with water (75 mL), dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel with 5% methanol/dichloromethane as eluent to give 2.91 g of an amber solid. Recrystallization from tert-butyl methyl ether/heptane afforded 1.52 g (50%) of the title compound as tan crystals: m.p.=98 °-99° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19]>>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:15]2[C:14]([N:13]([CH3:12])[C:17](=[O:18])[CH:16]=2)=[O:19])[CH:7]=[CH:6][CH:5]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CN1C(=O)C=C(c2cccc(C(F)(F)F)c2)C1=O

Procedure:
An 80.6 g portion of 3-aminobenzotrifluoride was reacted with 55.6 g of N-methylmaleimide as described in Example 6, giving 2-(m-trifluoromethylphenyl)-N-methylmaleimide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH2:36][CH3:37])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:36][CH3:37])=[O:11]
Reactant: CCC(CN)c1cccc(OC)c1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC(CNC(=O)Cc1c(Cl)cncc1Cl)c1cccc(OC)c1
Yield: 96.7 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10 mmoles), carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and 2-(3-methoxy-phenyl)-butylamine (1.79 g, 10 mmoles), obtained as described in example 25, 3.55 g of the title compound were obtained (yield: 96.7%). m.p.: 104-105° C.
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6]N=C=NCC.[CH3:13][C:14]1[NH:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]([OH:41])=O)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[N:15]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(N)C#C>ClCCl.CN(C)C=O>[CH3:13][C:14]1[NH:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]([NH:3][CH2:4][C:5]#[CH:6])=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[N:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)O)CCOCC4)c3)cc2)c(=O)[nH]1
Agent: C#CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCNC(=O)C1(c2cccc(Sc3ccc(-n4nc(C)[nH]c4=O)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCL HCl) (1.0 mmol) is added to a mixture of 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxylic acid (1.0 mmol) (example 15), 1-hydroxybenzotriazole (1.0 mmol), N-methylmorpholine (1.65 mmol) and propargylamine (1.0 mmol) in dichloromethane-dimethylformamide (1:1) at 0° C. The solution is stirred overnight at room temperature, washed with water and the aqueous layer is extracted with dichloromethane. The combined organic extracts are dried with sodium sulphate, filtered and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography over silica gel to yield the title product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:35]=[C:23]1[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][C:9]=2[NH:22]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K67) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (10 mg).