Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[CH:23][C:22]=2[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]3[CH:23]=[N:24][O:25][C:21]=3[C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1nccn1-c1ccc(N)cn1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 5-amino-2-(2-methyl-1-imidazolyl)pyridine (0.40 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.58 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.45 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.54 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[6-(2-methyl-1-imidazolyl)-3-pyridyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.59 g, yield 63%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 193–194° C.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[OH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O1CCOCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:44]4[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][OH:38])[CH2:42][CH2:43]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: OCCN1CCNCC1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCN(CCO)CC3)CC2)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and N-(2-hydroxyethyl)piperazine (360 mg, 2.77 mmol) in 1,4-dioxane (15 mL) was refluxed for 3 hrs. The reaction mixture was then cooled to room temperature and the solvent was removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The phases were separated, the organic phase was dried (Na2SO4), and the solvent was removed under vacuum. Recrystallization from CH2Cl2/hexanes gave 2-{4-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-1-piperazinyl}ethanol (134 mg, 72%).
Reaction SMILES: O1CCOCC1.C([O:9][CH:10](OCC)[C:11]1[C:16]([O:17][C:18]2[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1)C.ONS(C1C=CC=CC=1)(=O)=O>O>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([O:26][CH3:27])[N:19]=[C:18]([O:17][C:16]2[C:11]([CH:10]=[O:9])=[N:12][CH:13]=[CH:14][CH:15]=2)[N:23]=1
Reactant: CCOC(OCC)c1ncccc1Oc1nc(OC)cc(OC)n1
Agent: O=S(=O)(NO)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)nc(Oc2cccnc2C=O)n1
Temperature: 82.5 °C
Yield: 170.6 %

Procedure:
To a mixture consisting of 400 ml of dioxane and 400 ml of water, 42.6 g of 3-(4,6-dimethoxy-2-pyrimidinyloxy)-2-pyridinecarboxaldehyde diethylacetal and 22 g of N-hydroxybenzenesulfonamide were added under stirring. The reaction mixture was heated at 80-85° C. for 1 hour so that the reaction was brought to completion. Low-boiling substances were then distilled completion. Low-boiling substances were then distilled out under reduced pressure. The residue was added and extracted with 300 ml of saline and 300 ml of ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, whereby 56.6 g of an oily residue was obtained. The residue was purified by chromatography on a silica gel column (n-hexane/ethyl acetate=1:1) so that 19.2 g of 4,6-dimethoxy-2-(2-formyl-3-pyridyloxy)pyrimidine were obtained (yield: 54%).
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[CH3:60][O:61][C:62]1[CH:63]=[CH:64][C:65]2[CH2:71][CH2:70][CH:69]([N:72]3[CH2:77][CH2:76][O:75][CH2:74][CH2:73]3)[CH2:68][CH2:67][C:66]=2[C:78]=1[NH2:79]>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:79][C:78]2[C:66]3[CH2:67][CH2:68][CH:69]([N:72]4[CH2:73][CH2:74][O:75][CH2:76][CH2:77]4)[CH2:70][CH2:71][C:65]=3[CH:64]=[CH:63][C:62]=2[O:61][CH3:60])=[N:22][CH:23]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: COc1ccc2c(c1N)CCC(N1CCOCC1)CC2
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCC(N1CCOCC1)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with 2-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine to afford 5-Chloro-N*2*-(2-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl)-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine. LC/MS (ESI): 546.26. 1H NMR (400 MHz, DMSO, d6) δ 8.18 (m, 1H), 8.31 (m, 1H), 7.93 (s, 2H), 7.57 (m, 2H), 7.16 (m, 2H), 6.89 (m, 2H), 6.61 (s, 1H), 3.70 (s, 3H), 3.40 (m, 2H), 3.09 (m, 5H), 2.89 (m, 2H), 2.67 (m, 2H), 2.32 (m, 4H), 1.40 (m, 2H).
Reaction SMILES: [CH:1]([N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].ClS(O)(=O)=O.[CH3:19][N:20]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]1[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32]>>[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32].[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5](=[N:4][CH:1]([CH3:3])[CH3:2])[C:24]2[N:20]([CH3:19])[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:23]=2[CH3:25])=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: CC(C)N=C(Cl)c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)Cc1cc(C)c(C(=NC(C)C)c2ccc(Cl)cc2)n1C

Procedure:
The title compound was prepared as in Example X from N-isopropyl 4-chlorobenzimidoyl chloride (10.75 g, 49.8 mmole), chlorosulfonic acid (0.58 g, 5.0 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (8.34 g, 50 mmole), and 70% perchloric acid (7.8 g, 55 mmole) to yield 14.2 g (64%) of a bright yellow solid, m.p. 94°-110° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N+:11]([O-:13])=[O:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:10][N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])Nc1ccccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
2-Chloro-5-chloromethylpyridine (3.24 g) and 2-nitraminopyridine (2.78 g) were dissolved in anhydrous ethanol (50 ml), and triethylamine (4.04 g) was added to the solution. The mixture was stirred at room temperature for a while. Then, it was heated under reflux conditions for 8 hours. The reaction mixture was cooled to room temperature, and poured into ice water. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give pale yellow 1-(2-chloro-5-pyridylmethyl)-2-nitroimino-1,2-dihydropyridine (2.3 g) as the desired compound. mp. 209°-212° C.
Reaction SMILES: [Br-].[Li+].[CH2:3]([Mg]Br)[CH2:4][CH:5]=[CH2:6].[CH2:9]([C:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=1)[CH2:10][CH:11]=[CH2:12]>O1CCCC1.[Cu]I>[CH2:3]([C:13]1([CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCC1=CC(=O)CC1
Reactant: C=CCC[Mg]Br
Agent: [Cu]I
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCC1(CCC=C)CCC(=O)C1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a suspension of copper(I) iodide (2.6 g) and lithium bromide (1.2 g) in tetrahydrofuran (25 mL) was added dropwise a 0.5M tetrahydrofuran solution of 3-butenylmagnesium bromide (26.5 mL) under nitrogen atmosphere at −78° C. over 6 minutes, followed by stirring the reaction mixture at −78° C. for 40 minutes. Then, 5 minutes after addition of boron trifluoride diethyl ether complex (0.554 mL), to the reaction mixture was added 3-(3-butenyl)cyclopent-2-enone (0.6 g) obtained in Step 1. Half an hour later, after addition of boron trifluoride diethyl ether complex (0.250 mL), the reaction mixture was stirred at −78° C. for 2 hours, and further stirred at room temperature overnight after removing a dry-ice/ethanol bath. Then, after addition of saturated aqueous ammonium chloride solution and 28% aqueous ammonia solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with aqueous ammonia solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel to give 3,3-dibut-3-enylcyclopentanone (380 mg).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].O[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC(OC1C=CC(C2C=CC(C(OCCCCCCCC)=O)=CC=2)=CC=1)=O>>[CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][O:4][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC[C@H](C)CO
Agent: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(OC[C@@H](C)CC)cc1

Procedure:
Quantities: (S)-(-)-2-methylbutan-1-ol (5.00 g, 0.057 mol), ethyl 4-hydroxybenzoate (7) (9.47 g, 0.057 mol), DEAD (9.93 g, 0.057 mol), triphenylphosphine (14.95 g, 0.057 mol). The experimental preocedure was as described for the preparation of compound 5. The crude product was purified by column chromatography (10% petrol/dichloromethane) to give a colourless oil.
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=[O:11]>O1CCOCC1>[O:8]=[C:3]1[N:4]=[C:5]([N:9]2[CH2:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][O:1][NH:2]1
Reactant: O=C1CNC(=O)N1
Reactant: O=C1NOCC(=S)N1
Solvent: C1COCCO1
Product: O=C1CN(C2=NC(=O)NOC2)C(=O)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.4 %

Procedure:
To a solution of 1.0 g (0.0075 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione in 50 ml of freshly distilled dry dioxane is added 0.77 g (0.0077 mole) of hydantoin. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 0.6 g (41 percent) of 1-(3,6-dihydro-3-oxo-2H-1,2,4-oxadiazin-5-yl)-2,4-imidazolidinedione.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:26](=S)=[S:27]>C1COCC1>[Br:15][C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]2[C:13]=1[O:14][C:26](=[S:27])[CH:2]=[C:1]2[OH:3]
Reactant: S=C=S
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c2oc(=S)cc(O)c2c1
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
To a suspension of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (75 g, 258 mmol) in THF (350 mL) at −50° C. under nitrogen was added sodium bis(trimethylsilyl)amide (1M in THF) (904 mL, 903.58 mmol) over a 15 min period. The dark solution was allowed to warm to −5-0° C. and stirred for 1 h. Carbon disulfide (24.8 mL, 413 mmol) was added in one portion to the solution at −20° C. The mixture was allowed to warm to RT and stirred for 24 hrs. The reaction mixture was cooled to −50° C., quenched slowly with a 15% aq. sol. H2SO4 (750 mL) (need to trap the H2S formed). The reaction was extracted 3 times with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. This residue was triturated with DCM (500 mL), collected by filtration, washed with ether and dried under vacuum to give methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (33.5 g, 41%) as an yellow solid. The filtrate was evaporated and the resulting dark gum was triturated with ethyl acetate (300 mL) to give a solid which was collected by filtration washed with ether and dried under vacuum to give a second batch of methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (17.5 g, 22%) as a orange solid. Mass Spectrum: [M−H]− 314 for both batches.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH:18]1([C:21]2[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=2)[CH2:20][CH2:19]1.C(OCC)C>ClC>[CH:18]1([C:21]2[CH:25]=[C:24]([NH:26][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:9]([Br:8])=[CH:10][CH:11]=3)[NH:23][N:22]=2)[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: CCl
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
122 mg (loading 1.91 mmol/g, 0.233 mmol) of polystyrene supported N-methylmorpholine were suspended in 4 ml of chloromethane and then treated with 25.6 mg (0.117 mmol) of 4-bromobenzoyl chloride followed by 4.8 mg (0.039 mmol) of 3-cyclopropyl-5-amino-pyrazole. After 48 hours under stirring at room temperature the resin was separated by filtration and washed with 2 ml of dichloromethane. The filtrate was evaporated to dryness, the residue re-dissolved in 4 ml of dichloromethane and 100 mg of polystyrene supported trisamine were added. After 48 hours or stirring at room temperature the resin was filtered, washed with 2 ml of dichloromethane and concentrated to give, after triturating with diethylether, 9.3 mg (78% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:16]([NH2:18])[CH3:17].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH3:17][O:16][NH:18][C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:14]
Reactant: CON
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CONC(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 35.8 %

Procedure:
1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (2.00 g, 9.94 mmol), methoxylamine hydrochloride (1.09 g, 13.02 mmol), EDC.HCl (2.50 g, 13.02 mmol), HOBT (1.99 g, 13.02 mmol) and N-methylmorpholine (2.61 g, 25.8 mmol) were dissolved in anhydrous DMF (20.0 mL) and the resulting reaction mixture was stirred at RT for 5 days. The reaction mixture was evaporated to dryness and the residue was taken up in DCM and washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column eluting with 70% EtOAc/hexanes to afford the title compound (0.82 g, 36%): 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.23 (s, 1H), 3.53 (s, 3H), 1.38 (s, 9H), 1.20 (q, J=4.3 Hz, 2H), 0.85 (q, J=4.3 Hz, 2H). This material is used without further purification.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH:13]([C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:17]=1[NH2:18])([CH3:15])[CH3:14]>C(OCC)(=O)C>[CH:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:16]([CH:13]([CH3:15])[CH3:14])[C:17]=1[N:18]1[C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2][C:1]1=[O:12])([CH3:25])[CH3:24]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)Cc2ccccc2C1=O
Reaction time: 1 h
Yield: 36 %

Procedure:
0.512 g (3.16 mmol) of homophthalic anhydride and 0.42 g (2.37 mmol) of 2,6-diisopropylaniline were mixed, and melted at a temperature of 200° C. for 1 hour. The reactant was dissolved in ethyl acetate, washed with aqueous NaHCO3 solution, with water and then with saturated aqueous sodium chloride, dried over anhydrous MgSO4, and subjected to filtration with a folded filter paper. The filtrate was concentrated and evaporated to dryness. The residue was recrystallized by using a mixture of CH2Cl2 and hexane, to obtain 0.351 g (yield 36%) of the specified substance as light purple leaflets. It showed the following physical properties and analyzed values.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH:37]1([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>[OH-].[Na+].C(#N)C>[CH:44]1([NH:43][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1.[C:27]1([S:33]([NH:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Yield: 73.2 %

Procedure:
Nε -benzyloxycarbonyl-L-lysine (8.41 g, 30 mmole) was dissolved in 1N aqueous sodium hydroxide (30 ml), and dioxane (10 ml) solution of benzene sulfonyl chloride (5 30 g, 30 mmole) was added dropwise to the solution while keeping the pH value thereof to between 10 and 11 with 1N aqueous sodium hydroxide while cooling with ice and stirring. The mixture was further stirred for 1.5 hours at room temperature and then insoluble matter was removed by filtration. The filtrate was washed with two 100 ml portions of diethyl ether. To the water layer, ethyl acetate (150 ml) was added and the solution was adjusted to pH 1.5 with 1N aqueous hydrochloric acid under vigorous stirring. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the oily residue thus obtained was dissolved in acetonitrile (200 ml), and then dicyclohexylamine (5.43 g, 30 mmole) was added thereto with stirring, and thereby Nα -benzenesulfonyl-Nε -benzyloxycarbonyl-L-lysine dicyclohexylamine salt (13.21 g, 73.2%) was obtained.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH3:33])[C:8](=[O:32])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Br)[CH2:24][CH2:23]2)=[N:11][CH:10]=1.C(=O)(O)[O-:44].[Na+]>CN1CCCC1=O>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH3:33])[C:8](=[O:32])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][OH:44])[CH2:24][CH2:23]2)=[N:11][CH:10]=1
Reactant: O=C([O-])O
Reactant: Cc1ccccc1-c1cc(N2CCN(C(=O)CBr)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccccc1-c1cc(N2CCN(C(=O)CO)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 64 %

Procedure:
A mixture of 0.12 g (0.18 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-(4-bromoacetyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide, 1.2 ml 1-methyl-2-pyrrolidone and 0.2 ml half-saturated aqueous sodium bicarbonate solution was stirred at 100° C. over night. After cooling to room temperature and dilution with water the mixture was extracted with five portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate, concentrated and dried in vacuo (0.5 mbar) at 70°. Flash column chromatography afforded 71 mg (64%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([N+:5]([O-:7])=O)([CH3:4])[CH3:3].C(O)(=O)C.[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>C(O)C.[Zn]>[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[N+:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[O-:7])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1ccc(-n2ccnc2)cc1
Temperature: 5 °C

Procedure:
To a suspension of 1,1-dimethylnitroethane (261.2 mg, 2.53 mmol) and zinc (247.0 mg, 3.78 mmol) in ethanol (3.0 ml) was added acetic acid (451.8 mg, 7.52 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 30 minutes. After cooling the mixture to 5° C. again, 4-(1-imidazolyl)benzaldehyde (216.5 mg, 1.26 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (chloroform/methanol=10/1).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[CH2:25][C:26]([NH2:28])=[O:27]>CS(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:25][C:26](=[O:27])[NH2:28])=[O:11])=[CH:7][CH:8]=1
Reactant: NC(=O)CCl
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [K]
Solvent: CS(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: NC(=O)COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
The potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.1 mol) was taken up in a mixture of dimethylsulfoxide (80 mL) and hexamethylphosphoramide (5.37 g, 0.1 mol). 2--Chloroacetamide (13.5 g, 0.3 mol) was added and the reaction mixture was first stirred at room temperature for 24 hours, then heated for 1 hour. The reaction mixture was evaporated, then cooled. The product which separated was taken up in ethyl acetate (150 mL), stirred, filtered and evaporated. The oily residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to give the desired ester, carbamoylmethyl 4-hydroxyphenylacetate, melting at 85°-87° C., in 48.8% yield.