Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])=[O:16])=[CH:13][CH:12]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1

Procedure:
Compounds of the invention having the formula ##STR19## can be prepared as follows. Benzaldehyde and 4-methoxybenzaldehyde are reacted to yield 4-methoxybenzoin, which is converted to the hemisuccinate by reaction with succinic anhydride. The latter is reacted with urea and acetic acid to yield the intermediate 4-(4-methoxyphenyl)-5-phenyl-2-oxazole-propionic acid. ##STR20## The latter intermediate is demethylated with hydrogen bromide and esterified with methanol to yield the corresponding hydroxy methyl ester intermediate, which is then reacted with an appropriate haloalky-A compound, where A is as defined hereinbefore and hal is halo, to yield the desired final product as the methyl ester. ##STR21## The ester can be hydrolyzed by conventional methods to yield the desired final product in its free carboxylic acid form.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[O:17])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)nc(NCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccnc(NCc2ccccc2)c1)c1ccc(O)cc1

Procedure:
Rf value: 0.58 (silica gel; methylene chloride/methanol=9:1) by hydrogenation of 4-[(2-benzylamino-6-chloro-4-pyridyl)aminocarbonyl]-1-benzyloxy-benzene at ambient temperature.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([OH:10])[CH:9]=1.Cl[CH:15]([CH3:18])[CH:16]=[CH2:17].[OH-].[Na+]>CS(C)=O>[CH3:17][CH:16]([O:10][C:8]1[CH:9]=[C:4]([CH3:3])[CH:5]=[CH:6][C:7]=1[N+:11]([O-:13])=[O:12])[CH:15]=[CH2:18]
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CC(C)Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CC(C)Oc1cc(C)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
24 g of sodium hydride was added in portions to a stirred mixture of 153 g of 5-methyl-2-nitrophenol and 500 ml of DMSO. Then 135.7 g of 3-chloro-1-butene was added drop-by-drop (over 5 minutes) to the stirred mixture, which then was stirred at reflux (79°-81° C.) for 24 hours. Then the mixture was made basic with 50% aqueous sodium hydroxide, poured over ice water and extracted with methylene chloride. The extract was washed with cold water, dried (MgSO4), filtered and stripped of solvent, to give 1-(1-methyl-2-propenyloxy)-5-methyl-2-nitrobenzene (1A), as a dark-colored syrup.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1>C(#N)C>[N:11]1([C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])[CH2:14][CH2:13][CH2:12]1
Reactant: C1CNC1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CC#N
Product: O=C(c1ccc(O)cc1)N1CCC1
Temperature: 50 °C
Yield: 0.1 %

Procedure:
1,1-Carbonyldiimidazole (95.57 mmol; 16.57 g) was charged to a 250 mL round bottomed flask purged with nitrogen, acetonitrile (72 mL) was added, to form a mobile white slurry. 4-Hydroxybenzoic acid (86.88 mol; 12.00 g) was added in portions over 30 minutes to give clear yellow solution, which then became a slurry after approximately 15 minutes. The slurry was heated to 50° C. and azetidine (104.25 mol; 5.95 g) in acetonitrile (10 mL) was added drop wise over 10 minutes. Further azetidine (17.38 mmol; 992.08 mg) was added in acetonitrile (12 mL) and the reaction mixture was heated to 50° C. for a further hour. The precipitated product (10 g, 65% yield) was isolated by filtration and washed with acetonitrile (15 mL) and then dried in a vacuum oven at 40° C.
Reaction SMILES: [CH:1](=[N:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:14].[Na+].OOS([O-])=O.[K+].O1CN1>O.CC(C)=O>[C:9]([N:8]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(C)(C)N=Cc1ccccc1
Agent: C1NO1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)N1OC1c1ccccc1

Procedure:
13.2 gm (0.082 moles) of the N-benzylidene-t-butylamine prepared as in Example 1 was added to a 600 ml beaker containing 28.8 gm of sodium bicarbonate (0.3428 moles) in a solution consisting of 50 ml water and 50 ml acetone. The mixture was stirred vigorously with a mechanical paddle stirrer. While stirring, 60 gm (0.098 moles) of Oxone® was added portion wise over a 3 to 5 minute period. The resulting three-phase mixture was initially bluish in color and eventually faded to a pale yellow color as the reaction proceeded. The reaction was stirred at ambient temperature for one hour and followed by GC analysis as described in Example 1. The GC analysis revealed only a trace of the starting material (very tiny peak at 3.72 minutes) and predominant conversion to the oxaziridine, a peak having a retention time of 4.45 minutes. The mixture was diluted with 300 ml of water to dissolve any salts therein. The 2-phase mixture was extracted with 100 ml of hexane. The hexane layer was separated and concentrated under vacuum to remove all solvent. The resulting, almost clear liquid, 2-t-butyl-3-phenyl oxaziridine product weighed 13.74 gm (94.7% crude yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C(N)=O)ccc2c1=O
Yield: 95.5 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (0.70 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt (0.46 g, 3 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.67 g, 95.7%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:17])([OH:16])[CH3:15])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:40]=[CH:41][C:32]([CH2:31][O:16][C:14]([CH3:15])([CH3:17])[CH:13]([N:12]2[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:33][CH:34]=1
Reactant: CC(C)(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COC(C)(C)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Yield: 12 %

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol and methyl 4-(bromomethyl)benzoate (commercially available) to give the desired compound as a white solid (12%). MS (Turbo Spray): m/z=567.3 [M+H].
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:59])[CH2:43][N:44](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:38][C:37]=1[NH:60][S:61]([CH3:64])(=[O:63])=[O:62])C1C=CC=CC=1>>[OH:59][CH:42]([C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[C:37]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:38]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35–1.60 (m, 2 H), 1.90–2.10 (m, 2 H), 2.06 (s, 3 H), 2.50–3.00 (m, 5 H), 3.16 (s, 3 H), 3.55–3.70 (m, 2 H), 4.65–4.80 (m, 1 H), 6.00 (brs, 1 H), 6.70–7.25 (m, 7 H), 7.58 (d, J=9.0 Hz, 2 H), 7.68 (d, J=9.0 Hz, 2 H), 10.39 (s, 1 H); MS (ES) m/z: 618.1 (MH+); HRMS Calcd. for C28H36N5O7S2 (MH+): 618.2056. Found: 618.2036.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: COc1cccc(C(=O)Cl)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(OC)c3)CC2)ccc1Cl
Yield: 65 %

Procedure:
The title compound (26 mg, 65%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-methoxybenzoyl chloride. MS: 403.4 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[OH:46].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[C:7]=4[C:8]=3[CH:9]=2)[CH:34]=[CH:33][C:32]=1[OH:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(O)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.6 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.5 mg, 0.12 mmol) in toluene/ethanol (1:1, 8 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Methoxy-4-[6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenol as brown solid in 60% yield.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[O:13]=[CH:14][C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])[OH:16]>>[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10].[O:13]=[CH:14][C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])[OH:16]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The results reported in Table 3 demonstrate that ascorbic acid can be synthesized from glucose in one step. This is very advantageous in that using D-glucose instead of D-sorbitol as the starting material in the synthesis of vitamin-C eliminates the hydrogenation step, and its associated costs, necessary to produce D-sorbitol from D-glucose.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[C:6]([OH:12])[CH:5]=1.Cl[CH2:15][C:16]([CH3:18])=[CH2:17]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH2:17][C:16]([CH3:18])=[CH2:15])[C:7]([Br:11])=[C:6]([OH:12])[CH:5]=1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Reactant: C=C(C)CCl
Solvent: CO
Product: C=C(C)COc1cc(C(=O)OC)cc(O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Na pieces (41.4 g, 1.82 mol) were added slowly to MeOH (3 L). The resulting mixture was stirred at room temperature for 30 min and then 4-bromo-3,5-dihydroxy-benzoic acid methyl ester (197a) (450 g, 1.82 mol) was added portion wise. The mixture was warmed to 60° C. 3-Chloro-2-methyl-propene (202.5 mL, 2 mol) was added drop wise. The mixture was refluxed for 6 h. TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (75 g, 13.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.06(s, 1H), 5.72(s, 1H), 5.11(s, 1H), 4.96(s, 1H), 4.47(s, 2H), 3.84(s, 3H), 1.79(s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[O:3]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)OC(C=Cc2ccc(F)cc2)=CC1=O
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) and 4-fluorobenzaldehyde (1.6 g, 13.2 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 50° C. for four hours. After the reaction solution was cooled to room temperature and diluted with saturated aqueous sodium chloride (200 mL) and water (200 mL), the aqueous solution was extracted with diethyl ether (2×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a dark yellow crystalline solid. The crude product was recrystallized from hexane to give light yellow crystals (1.8 g, 45% yield), m.p. 55°-57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=1
Reactant: CCOC(=O)Cc1nc(-c2ccccc2Cl)oc1-c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccccc2Cl)oc1-c1ccsc1
Yield: 88.3 %

Procedure:
3.5 g of ethyl 2-[2-(2-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate, 75 ml of methanol, 7.5 g of water and 1.4 g of potassium hydroxide are treated in the same manner as described in Example 8. 2.84 g of 2-[2-(2-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid are thereby obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=2)[N:33]([CH3:41])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=4)[N:33]([CH3:41])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cc1ccc2c(c1)c(C(=O)CCCCCBr)cn2C
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(C)c3ccc(C)cc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(1,5-dimethyl-1 H-indol-3-yl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(1,5-dimethyl-1H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.Br[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:22][CH2:21][CH2:20][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: BrCCCc1ccccc1
Product: O=C(N[C@H]1CCN(CCCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 21.4 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.38 g) and 3-bromopropylbenzene (0.37 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(3-phenylpropyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.12 g), melting point 118-120° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:13]([NH:25][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
18 g of glucose were stirred in 50 ml of ethanol at 70° C., 18.5 g of dodecylamine were then added, the mixture was heated again until a clear solution was obtained, the solution was allowed to cool to room temperature and, after 20 hours, the crystals which had precipitated were filtered off with suction. The product was washed with ethanol and ether and dried in vacuo.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>ClCCl>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 30 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 1-tetradecanol (96.3 grams, 449 millimoles (mmol), pyridine (40 milliliters), and dichloromethane (1000 milliliters) was heated to 30° C. 4-Nitrobenzoyl chloride (100 grams, 539 mmol) was added in portions over a twenty minute period. The reaction mixture was heated to reflux for sixteen hours. The reaction mixture was then washed twice with water (2×500 milliliters). The organic layer was concentrated under reduced pressure to a yellow solid. One thousand (1000) milliliters of hexane was added, and the mixture was heated to reflux. The mixture was cooled and concentrated to yield a yellow solid that was filtered. The yellow solid was recrystallized twice from ethanol to obtain 77.0 grams of tetradecyl 4-nitrobenzoate as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:45]=[CH:44][C:13]2[N:14]([CH2:33][CH2:34][CH2:35][CH2:36][O:37]C(=O)C(C)(C)C)[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH:29]4[CH2:31][CH2:30]4)[C:19]3=[O:32])=[N:16][C:12]=2[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:45]=[CH:44][C:13]2[N:14]([CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH:29]4[CH2:31][CH2:30]4)[C:19]3=[O:32])=[N:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCOC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCO
Temperature: 75 °C
Yield: 63.2 %

Procedure:
To a solution of 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (110 mg, 0.178 mmol) in methanol (5 mL) and water (1.5 mL) was added 1M NaOH (356 μL, 0.356 mmol). The resulting mixture was heated at 70-80° C. for 2 hrs. The solution was neutralized with 1M HCl, methanol was removed in vacuo and the aqueous residue extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and dried (MgSO4). Purification by flash chromatography (eluent 2%, 5% methanol in DCM) afforded [2-(3-Cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(4-hydroxy-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (60 mg, 63%) as a white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([NH:36]N)[C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:29]=2[O:28]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.1 (M+H)+