Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][CH2:10][C:11]([NH:13][C@H:14]([C:19]([NH:21][C@@H:22]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:23]([OH:38])[C:24]([N:26]2[CH2:37][CH2:36][CH2:35][C@H:27]2[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17])=[O:12])[CH2:5][CH2:4]1.[CH2:46]([O:53][C:54](Cl)=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:46]([O:53][C:54]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][CH2:10][C:11]([NH:13][C@H:14]([C:19]([NH:21][C@@H:22]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]([OH:38])[C:24]([N:26]2[CH2:37][CH2:36][CH2:35][C@H:27]2[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17])=[O:12])[CH2:5][CH2:4]1)=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COC1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COC1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 47.9 %

Procedure:
Following a procedure similar to that described in Example 30, but using 40 mg (61.2 μmol) of 1-{(2S,3S)-3-[N2 -(4-aminocyclohexyloxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 58) and 0.01 ml (67.3 μmol) of benzyloxycarbonyl chloride, 22 mg of the title compound were obtained as a colorless powder, melting at 109°-114° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:57]=[CH:56][C:34]5[NH:35][C:36]([C@@H:38]6[CH2:42][C@H:41]([CH3:43])[CH2:40][N:39]6[C:44](=[O:55])[C@@H:45]([N:49]([C:51]([O:53][CH3:54])=[O:52])[CH3:50])[CH:46]([CH3:48])[CH3:47])=[N:37][C:33]=5[CH:32]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=O)(C)(C)C.[ClH:58].O1CCOCC1>CO>[ClH:58].[CH3:54][O:53][C:51](=[O:52])[N:49]([CH3:50])[C@H:45]([C:44]([N:39]1[CH2:40][C@@H:41]([CH3:43])[CH2:42][C@H:38]1[C:36]1[NH:35][C:34]2[CH:56]=[CH:57][C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:23]=[CH:24][C:19]([C:17]5[N:18]=[C:14]([C@@H:9]6[CH2:10][C@H:11]([CH3:13])[CH2:12][NH:8]6)[NH:15][CH:16]=5)=[CH:20][CH:21]=4)=[CH:26][CH:27]=3)=[CH:32][C:33]=2[N:37]=1)=[O:55])[CH:46]([CH3:48])[CH3:47]
Reactant: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-{4-[4′-(2-{(2S,4S)-1-[(S)-2-(methoxycarbonyl-methyl-amino)-3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl}-1H-benzoimidazol-5-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (115 mg, 0.1486 mmol) in methanol is added 4M HCl in dioxane (0.632 mL, 2.526 mmol). The reaction mixture is stirred at room temperature for 1 hour and concentrated to dryness. The title product is used as such in the next step.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:21]([S:6][CH2:5][CH:4]([NH2:3])[C:7]([OH:9])=[O:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCBr
Reactant: NC(CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCSCC(N)C(=O)O

Procedure:
16.5 g. (0.42 mole) solid sodium hydroxide are dissolved in 1600 ml. ethanol, mixed with a solution of 25 g. (0.21 mole) D,L-cysteine in 150 ml. ethanol and, after the dropwise addition of 60 ml. (0.25 mole) dodecyl bromide, stirred for 24 hours at ambient temperature. The precipitate is then filtered off with suction, washed with ethanol and dissolved in water. After acidification with 4N hydrochloric acid, the precipitate is filtered off after 2 hours at 5° C. Yield 48.2 g. (81% of theory); m.p. 215°-218° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]1[CH2:17][C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:18][C:19]4[C:20](=O)[CH2:21][CH:22]=[CH:23][C:24]=4[C:5]=3[C:4]=2[C:3]1=[O:26].C(C1C(=O)C(Cl)=C(Cl)C(=[O:32])C=1C#N)#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3](=[O:26])[C:4]2[C:5]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:6]=3[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]=2[C:17]1=[O:32]
Reactant: CN1Cc2c(c3c4c([nH]c3c3[nH]c5ccccc5c23)C(=O)CC=C4)C1=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O

Procedure:
12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of dark yellow crystals which decompose from 310° C. The 12-(2-carboxyethyl)-6,7,12,13-tetrahydro-5,7-dioxoindolo[2,3-a]furano[3,4-c]carbazole used as starting material is prepared as follows: 980 mg (2.39 mmol) 12-(2-Carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole are heated under reflux for 1.5 hours in 200 ml 15% methanolic potassium hydroxide solution. After cooling, the reaction mixture is filtered, the filtrate is acidified with 2N hydrochloric acid and the product which precipitates out is filtered off and washed with water. 12-(2-Carboxyethyl)-6,7,12,13-tetrahydro-5,7-dioxo-indolo[2,3-a]furano[3,4-c]carbazole is obtained as a brownish amorphous powder. The 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole used as starting material is prepared as follows: 500 mg (1.47 mmol) 6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in 50 ml acetonitrile are stirred for 4 days at 20° C. with 1.05 g (14.8 mmol) acrylamide and 0.1 ml DBU. The suspension is evaporated, stirred with 30 ml dichloromethane/methanol (95:5 v/v) and the undissolved crystals are filtered off. 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole is obtained in the form of yellow crystals. The 6,7,12,13-tetrahydro-6-methyl-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole used as starting material is prepared as follows: 1 g (2.93 mmol) 3,4-bis-(indol-3-yl)-N-methyl-maleic acid imide is boiled under reflux for 1 hour with 800 mg (3.52 mmol) DDQ and 560 mg (2.94 mmol) p-toluenesulphonic acid hydrate in 200 ml toluene. Two thirds of the solvent are distilled off and the precipitate is filtered off and stirred with 100 ml 0.1N sodium hydroxide solution. It is filtered, the precipitate is washed with water, then suspended in ethanol and again filtered off. 6,7,12,13-Tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of a yellow amorphous powder; m.p. >350° C. The 3,4-bis-(indol-3-yl)-N-methylmaleic acid imide used as starting material is prepared in the manner described in the literature (see Tetrahedron, 1988, 44, 2887).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22](=[O:24])[N:23]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:29]([NH2:31])[CH3:30]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:25]([NH:31][O:29][CH3:30])=[O:26])[NH:21][C:22](=[O:24])[N:23]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)[nH]c(=O)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(=O)[nH]1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-oxo-2,3-dihydropyrimidine-4-carboxylic acid (Example 173) and methoxylamine hydrochloride.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:11]([CH3:1])[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C

Procedure:
A mixture of Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.17 g) and 20% palladium hydroxide on carbon (0.24 g) in methanol (20 ml) was stirred at room temperature in a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and washed with methanol. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 100:10:1) to give N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 609 mg (71%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].I[CH2:9][CH2:10][CH3:11]>[Ag]=O.CCOCC>[CH2:9]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH2:10][CH3:11]
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCI
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCO[C@H](C)C(=O)OC
Reaction time: 96 h
Yield: 63.1 %

Procedure:
Silver oxide (87.5 g, 0.38 mol) was added to a mixture of (R)-methyl lactate (52.1 g, 0.5 mol) with 1-iodopropane (100 g, 0.59 mol) over 3 hours, followed by allowing the mixture to stand at room temperature for 4 days, adding ether (200 ml) for dilution, filtering the mixture, distilling off ether, washing the residue with 2N-NaOH aqueous solution, drying over anhydrous sodium sulfate, distilling it under reduced pressure to obtain (R)-methyl 2-propoxypropionate (46.1 g, b.p. 33°-34° C./5 mmHg). To this (R)-methyl 2-propoxypropionate (28.2 g) were added water (60 ml) and NaOH (10 g), followed by agitating the mixture at room temperature for 3 hours, pouring the mixture in 6N-hydrochloric acid (80 ml), extracting the resulting organic layer with ether, washing the resulting organic layer with water and distilling off ether to obtain 2-propoxypropionic acid (18.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]1[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:5])=[O:4].[H-].[Na+].[CH3:30]I>C1COCC1.CCOC(C)=O>[CH3:27][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([O:19][CH3:30])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=[C:7]1[Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)Cc2ccccc2)nc1[Si](C)(C)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(Cc1ccccc1)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(tert-butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (160 mg) at r.t. in THF (5 ml) under an argon atmosphere was added NaH (18 mg; 55% dispersion in mineral oil) in one portion. After 1 hour stirring at r.t., MeI (0.04 ml) was added and stirring at r.t. was continued overnight. The mixture was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give 2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (111 mg) as light yellow viscous oil. MS (ISP): 424.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13](O)[CH:12]=1>>[Br:10][C:11]1[CH:17]=[CH:16][C:14]2[N:15]=[C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[O:9][C:13]=2[CH:12]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: Nc1ccc(Br)cc1O
Product: Cc1ccc(-c2nc3ccc(Br)cc3o2)s1

Procedure:
Preparation is carried out analogously to 4.1.a from 5-methylthiophene-2-carboxylic acid and 4-bromo-2-hydroxy-aniline.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([OH:8])[C:16]([F:18])([F:17])[F:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1C(O)C(F)(F)F
Yield: 86.8 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-2-imidazolecarboxaldehyde (100 mg, 0.908 mmol), potassium carbonate (25.1 mg, 0.182 mmol), (trifluoromethyl)trimethylsilane (201 μL, 1.36 mmol) and N,N-dimethylformamide (2.0 mL), the mixture was stirred and reacted at room temperature for 2 hours. Then, slurry purification was performed using diisopropyl ether, to give 1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)imidazole (Compound DI) (142 mg, yield: 87%).
Reaction SMILES: BrC[C:3]1([CH3:17])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([F:16])=[CH:9][CH:4]1[C:5]([O:7]C)=[O:6]>O1CCOCC1.O>[F:16][C:10]1[CH:9]=[C:4]2[C:3]([CH2:17][O:7][C:5]2=[O:6])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=1
Reactant: COC(=O)C1C=C(F)C=C([N+](=O)[O-])C1(C)CBr
Solvent: C1COCCO1
Solvent: O
Product: O=C1OCc2c1cc(F)cc2[N+](=O)[O-]
Yield: 79.2 %

Procedure:
A mixture of methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, 130.5 mmol), NBS (27.8 g, 156.6 mmol) and BPO (3.13 g, 13.1 mmol) in CCl4 (400 mL) was heated to reflux overnight. TLC (petroleum ether/EtOAc=15:1) showed the starting material was consumed completely. Water (200 mL) was added and CCl4 was removed under reduced pressure. The residue was extracted with DCM (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give crude methyl 2-(bromomethyl)-5-fluoro-2-methyl-3-nitrobenzoate (36 g, yield 94%) as a brown oil. A mixture of methyl 2-(bromomethyl)-5-fluoro-2-methyl-3-nitrobenzoate (36 g, 123 mmol) in 1,4-dioxane (250 mL) and water (62.5 mL) was heated to reflux for 4 days. TLC (petroleum ether/EtOAc=15:1) showed the starting material was consumed completely. Dioxane was removed under reduced pressure. The residue was extracted with EtOAc (300 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, concentrated to give crude product. The crude product was purified by gel chromatography (petroleum ether to petroleum ether/EtOAc=5:1) to give 6-fluoro-4-nitroisobenzofuran-1(3H)-one (19.2 g, yield 79%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.74 (s, 2H), 7.97-7.98 (dd, 1H), 8.24-8.27 (dd, 1H); LC-MS (ESI) m/z: 198 (M+1)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:19][CH:20]=1)=[O:3]
Reactant: Nc1ccc(OCCn2ccnc2)cc1
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Methyl chloroformate (0.5 g) was added to a stirred solution of 1-[2-(4-aminophenoxy)ethyl]imidazole (1.0 g) in chloroform (50 ml) and the mixture was stirred at room temperature for 2 hours and then evaporated. The residue was dissolved in water and made basic by the addition of sodium bicarbonate. The resulting precipitate was filtered off, washed with water and crystallised from methanol/water to give 1-[2-(4-methoxycarbonylaminophenoxy)ethyl]imidazole (1.13 g), m.p. 152°-153° C., Found: C, 59.77; H, 5.81; N, 15.92. C13H15N3O3 requires: C, 59.76; H, 5.79; N, 16.08%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>>[C:11]1([CH3:12])[CH:10]=[CH:9][C:8]([S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][N:1]=[N+:2]=[N-:3])(=[O:6])=[O:7])=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-])cc1
Yield: 19 %

Procedure:
Sodium azide and tetraethylene glycol ditosylate were reacted according Example 7 p to yield 0.7 g (19%) of 8 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H), 3.38 (t, J=5.2 Hz, 2H), 3.55-3.70 (m, 12H), 4.16 (t, J=5.2 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 21.6, 50.7, 68.7, 68.8, 69.2, 70.0, 70.6-70.7, 127.9, 129.8, 133.1, 144.7 MS ESI (m/z): [M+H]+ calcd. for C15H24O6N3S, 374.2. found 374.2
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1)(=[O:25])=[O:24]
Reactant: Clc1ccc(OC2CCNCC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
To a solution 2-(4-piperidinyloxy) -5-chloropyridine(12.9 g, 0.06 mol) and Et3N (25.4 ml, 0.182 mol) in dry dichloromethane (400 ml) at 0° C. and under Argon, was added methanesulfonyl chloride (5.3 ml, 0.067 mol) in dry dichloromethane (100 ml), dropwise. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with dichloromethane (250 ml), then washed with water (×3) then brine. The organic layers were dried with Na2SO4 and evaporated in vacuo. The residue was triturated and washed with diethylether to give 2-(N-methanesulfonyl-4-piperidinyloxy)-5-chloropyridine (15.1 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:8])[CH2:4][C:5]([OH:7])=[O:6].[C:9]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1CCCC1.Cl>[OH-].[Na+]>[CH2:9]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([NH:1][CH2:2][CH:3]([OH:8])[CH2:4][C:5]([OH:7])=[O:6])=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC(O)CC(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1OC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCC(O)CC(=O)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18.1 g of 4-amino-3-hydroxy-butyric acid are dissolved in 176 ml of 2 N sodium hydroxide. To this there are added within 2 minutes 14.0 g of 3-benzoyloxy-4-methoxybenzoylchloride and subsequently 30 ml of tetrahydrofuran. The mixture is stirred intensively at room temperature for 2 hours, then treated with ice and acidified with concentrated hydrochloric acid. The separated solid is filtered off and washed with water. After drying, the filter cake is boiled in ethyl acetate and the insoluble portion is recrystallised from tetrahydrofuran/n-hexane (3.6:1). There is obtained 4-[(3-benzyloxy-4-methoxybenzoyl)amino]-3-hydroxy-butyric acid of melting point 158°-160° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([NH:14][C:15](=[O:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].[C:18](Cl)(=[O:20])[CH3:19]>ClC(Cl)C>[C:18]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([NH:14][C:15](=[O:17])[CH3:16])([CH3:5])[CH3:7])=[CH:13][CH:12]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)NC(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Aluminum chloride (41.5 g) was portionwise added to a solution (75 ml) of N-(1-methyl-1-phenylethyl)acetamide (25 g) and acetyl chloride (16.6 g) in dichloroethane under ice-cooling. The mixture was stirred at said temperature for 1 hour and then at 50°-60° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure to give crystals which were then recrystallized from ethyl acetate-isopropyl ether to give 20.4 g of N-(1-(4-acetylphenyl)-1-methylethyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:21]([NH:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:19]=2)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.69) (0.40 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.39 g, 1.5 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.103 g) which was subsequently deprotected.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12]
Reactant: C=C1CC(=O)O1
Reactant: CNCC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)CC=Cc1ccccc1

Procedure:
0.736 g (5.0 mmol) of methyl-(3-phenyl-2-propene-1-yl)amine, 0.386 ml (5.0 mmol) of ketene dimer and 0.07 ml (0.50 mmol) of triethylamine were heated at 70° C. under stirring in 5 ml of toluene overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the thin-layer silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 83 %

Procedure:
2,4-Dihydroxybenzoic acid was reacted with sodium hydride and benzyl bromide in dimethylformamide (DMF) to give a compound protected with benzyl groups at hydroxyl and carboxylic acids moieties in a 91% yield. The benzyl group was removed from the carboxylic acid moiety by refluxing it with 2 N sodium hydroxide in dioxane, followed by acidifying the mixture, to give 2,4-dibenzyloxybenzoic acid in 83% yield.