Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18]Cl)[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(#N)C>[CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CCCCl)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCn2c(=O)c(C)cn(Cc3ccccc3)c2=O)CC1
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of 1-benzyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (550 mg, 1.87 mmol), prepared as in Example 19, 1-(2-methoxyphenyl)piperazine (367 g, 1.87 mmol), sodium iodide (623 g, 3.75 mmol), potassium carbonate (260 mg, 1.81 mmol) and acetonitrile (50 mL) was stirred 8 hours at reflux. The reaction mixture then was poured into water (200 mL) and extracted with methylene chloride (3×100 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to give 1-benzyl-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione (800 mg, 1.78 mmol) as an oil. The free base was recrystallized from a solution of hydrochloric acid in alcohol to give 1-benzyl-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propy1}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 195°-198° C. Anal.: Calcd. for C26H32N4O3.(HCl)2 : C, 59.88; H, 6.57; N, 10.74%; Found: C, 59.71; H, 6.64; N, 10.73%.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:45][CH:44]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[CH:45][CH:44]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(OCc4ccccc4)cc3)cc12

Procedure:
25.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.1 g of N-[6-chloro-5-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and the resulting mixture is allowed to return to room temperature and 100 cm3 of ethyl acetate are added; the organic phase is washed with 2×100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 30 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed with 2×20 cm3 of diisopropyl ether. After drying under reduced pressure (90 Pa; 50° C.), 1.3 g of N-[6-chloro-5-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide are obtained in the form of white crystals melting at 230° C.
Reaction SMILES: S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[C:42]([O:46][C:47](=[O:63])[CH2:48][N:49]=[C:50]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([CH3:45])([CH3:44])[CH3:43].Br[CH2:65][C:66]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[CH:68][C:67]=1[F:74]>ClCCl.CCOCC>[C:42]([O:46][C:47](=[O:63])[CH:48]([N:49]=[C:50]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[CH2:65][C:66]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[CH:68][C:67]=1[F:74])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)c(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(F)c(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Tetrabutylammonium sulfate (156.2 mg, 0.46 mmol) was added to a two-phase mixture consisting of 10% NaOH (2.5 mL), t-butylglycinate Schiff base 3 (142.7 mg, 0.48 mmol), and 2-fluoro-5-methoxybenzyl bromide 35 (100 mg, 0.46 mmol) in dichloromethane (2.0 mL). After 5 h of vigorous stirring at ambient temperature, the reaction mixture was diluted with ether (10 mL) and the layers were separated. The organic layer was washed with water (3×3.0 mL), dried over sodium sulfate, filtered, and evaporated in vacuo. A crude yellow oil of 40 was obtained in 90% yield. The pure product 40 was made as a residue in 83% (149 mg).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:20])[C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)C.O1CCCC1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:20])[C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(C(O)C#Cc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(C(O)C#Cc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
To 185 g of 1-(4-diethoxymethylphenyl)-3-phenyl-prop-2-yn-1-ol in 1.8 liters of a 9:1 mixture of tetrahydrofuran and water were added 30 g of p-toluenesulfonic acid pyridinium salt. After stirring at 20° C. for 15 hours, 500 ml of a saturated aqueous solution of sodium bicarbonate were added. The organic layer was separated, and after drying over magnesium sulfate, the drying agent was separated, and ethyl acetate was distilled off at 40° C. and 2.7×103Pa to yield 131 g of 1-(4-formylphenyl)-3-phenylprop-2-yn-1-ol in the form of a yellow oil. The resulting oil was stirred together with 57.9 g of hydroxylamine hydrochloride and 44 g of sodium carbonate in 1.1 liters of tetrahydrofuran/water 4:1 at 20° C. for 15 hours. Then 500 ml of a saturated aqueous solution of sodium chloride were added. The reaction mixture was shaken with ethyl acetate. After drying the organic layer over magnesium sulfate, the drying agent was separated by filtration at 40° C. and 2.7×103Pa to yield 153 g of the oxime 1-(4-hydroxyiminomethylphenyl)-3-phenyl-prop-2-yn-1-ol, syn/anti-mixture, in the form of a colorless solid.
Reaction SMILES: [NH2:1][C:2](=[O:65])[C@@H:3]([NH:25][C:26](=[O:64])[C@@H:27]([NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]1[CH:55]=[CH:54][C:37]([CH2:38][C@@H:39]([C:48]([O:50]CC=C)=[O:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:36][CH:35]=1)=[O:32])[CH2:4][S:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[NH2:1][C:2](=[O:65])[C@@H:3]([NH:25][C:26](=[O:64])[C@@H:27]([NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]1[CH:55]=[CH:54][C:37]([CH2:38][C@@H:39]([C:48]([OH:50])=[O:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:36][CH:35]=1)=[O:32])[CH2:4][S:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
4.14 g (4.55 mmol) of the compound from example 3A was dissolved in 90 ml tetrahydrofuran. 3.17 ml (22.8 mmol) triethylamine, 0.86 ml (22.8 mmol) formic acid and 0.526 g (0.455 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 100 ml water, and twice extracted with approx. 100 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 500 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.62 g raw product of 94.5% purity. The product was further purified by preparative RP-HPLC on a C18 with a water/methanol gradient to yield 2.35 g (2.70 mmol, 59% of theory) pure product.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([CH3:23])[C@H:8]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)(=O)=O.[H-].[Na+]>C1COCC1>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C@@H:8]([N:14]([CH3:15])[C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:7]([CH3:23])[CH2:6][O:5][C@H:13]1[CH2:12][CH2:11][O:10][CH2:9]1
Reactant: C[C@H](COS(C)(=O)=O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CO[C@H]1CCOC1)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 2.16a in THF (6 mL) was added NaH (120 mg, 60% in mineral oil, 3 mmol, 8 equiv.) at 0° C. The mixture was stirred at room temperature for 30 minutes. After cooled down to 0° C. in an ice bath, to the solution was added (2S,3S)-3-((tert-butoxycarbonyl)(methyl)amino)-3-(furan-2-yl)-2-methylpropyl methanesulfonate in THF (2 mL) was added and the resulting mixture was heated to reflux for 16 hours. The reaction was quenched at room temperature by addition of saturated aqueous NH4Cl solution. The mixture was neutralized to pH=7 by addition of 0.5 M KHSO4 aq solution. The aqueous layer was extracted EtOAc. The combined organic layer was washed brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane, 15-50%) to give product 2.16b (50 mg, 39% yield). MS (m/z): 340 [M+1]. 1H NMR (CDCl3, 400 MHz) 7.36 (dd, J=1.96, 0.78 Hz, 1H) 6.32 (dd, J=3.33, 1.76 Hz, 1H) 6.17-6.25 (br. d., 1H) 5.08-5.21 (br. dd, 1H) 3.92 (br. s., 1H) 3.76-3.86 (m, 2H) 3.66-3.76 (m, 2H) 3.27 (br. s., 1H) 3.08 (br. s., 1H) 2.71 (s, 3H) 2.32-2.45 (m, 1H) 1.74-1.91 (m, 2H) 1.58 (s, 1H) 1.41-1.53 (m, 9H) 1.03 (d, J=6.65 Hz, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:24]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCCCC(=N)NO
Solvent: Cc1ccccc1
Product: CCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.70 g (3.39 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.59 g (3.69 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under an inert atmosphere. To the thickened reaction mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-hexanimidamide (compound of Example 38; 0.9 g, 6.9 mmol) diluted with 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mass was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After the completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude material, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.ClCl>O1CCCC1.ClCCl.CO>[C:31]([NH:1][CH2:2][CH:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cc(C(=O)NC(CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: O=C(Cl)c1ccccc1
Agent: ClCl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NC(CNC(=O)c2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 65 %

Procedure:
Prepared analogously to Example 125 from N-[2-amino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, benzoyl chloride, and triethylamine in tetrahydrofuran. Yield: 65%; Rf value: 0.32 (silica gel; dichloromethane/methanol=19:1); C29H28ClN5O3 (530.03); mass spectrum: (M+H)+=530/532 (chlorine isotope) and (M−H)-=528/530 (chlorine isotope).
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C@H:8]2[O:12][CH:11]([OH:13])[C@H:10]([OH:14])[C@@H:9]2[OH:15])[CH:4]=1)[CH3:2].C(O[C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1>[C:3]([O:15][C@H:9]1[C@@H:10]([O:14][C:11](=[O:12])[CH3:10])[CH:11]([O:13][C:20](=[O:22])[CH3:21])[O:12][C@@H:8]1[C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[O:7][N:6]=1)(=[O:7])[CH3:1]
Reactant: CCc1cc([C@H]2OC(O)[C@H](O)[C@@H]2O)no1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1cc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
(3R,4S,5R)-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-2,3,4-triol isomer 1 (150 mg) was dissolved in pyridine (4 ml) and the mixture treated with acetic anhydride (0.983 ml). The resulting solution was stirred at 22° C. for 18 h. The mixture was concentrated in vacuo to afford a brown oil. Purification by chromatography on silica gel (Varian Bondelut SiO2 cartridge), eluting with (i) dichloromethane, (ii) ether (iii) ethyl acetate, afforded the title compound as a pale yellow solid (142 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:4].[CH3:16]I.O>O1CCCC1>[CH2:3]([O:5][CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:4]
Reactant: CCOCCNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxyethylamine (502 mg) in water (4 ml) was added 1,4-dioxane (10 ml), and an aqueous solution of 1N sodium hydroxide (6 ml) and di-tert-butyl dicarbonate (1.4 g) were sequentially added thereto on an ice bath. The solution was stirred overnight while warming to room temperature. Water was added thereto, the solution was extracted with diethyl ether, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo to provide tert-butyl (2-ethoxyethyl)carbamate (1.1 g). To a suspension of 60% sodium hydride (253 mg) in tetrahydrofuran (2 ml) was added dropwise a solution of tert-butyl (2-ethoxyethyl)carbamate (1.1 g) in tetrahydrofuran (8 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then methyl iodide (0.7 ml) was added thereto on an ice bath, and the solution was stirred overnight while warming to room temperature. Water was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (1.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:21]([O-])=O)[CH:8]=2)[O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:24])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CO
Agent: [Pd]
Solvent: CO
Product: CC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)=C1CO

Procedure:
A solution of 1 g of 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-nitro-3-chromene in 25 ml of methanol is hydrogenated on 0.5 g of 5% Pd-C at 20° C. and at 1 bar until hydrogenation is complete. The mixture is filtered, evaporated and 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromene is obtained.
Reaction SMILES: C1(CCO)CC1.OC1C=CC(C=O)=CC=1.[OH:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])[CH2:19][CH2:18]2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](O)CC1
Agent: O=Cc1ccc(O)cc1
Agent: OCCC1CC1
Product: CON(C)C(=O)[C@H]1CC[C@H](Oc2ccc(Cl)cc2)CC1

Procedure:
Instead of 2-cyclopropylethanol and 4-hydroxybenzaldehyde, the compound (850 mg) obtained in step (1) above and p-chlorophenol (700 mg) were respectively used and treated by the same technique as in Reference Example 11-1 to give trans-4-(4-chlorophenoxy)-N-methoxy-N-methylcyclohexanecarboxamide as a colorless solid (458 mg).
Reaction SMILES: Cl.[C:2]1([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21](Cl)=[N:22][CH:23]=1.O1CCOCC1.C(N(CC)CC)C>O>[Br:17][C:18]1[CH:19]=[N:20][C:21]([N:14]2[CH2:15][CH2:16][N:11]([S:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])[CH2:12][CH2:13]2)=[N:22][CH:23]=1
Reactant: Clc1ncc(Br)cn1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
A 250 mL round-bottomed flask was charged with 1-(phenylsulfonyl)piperazine hydrochloride (4.08 g, 15.51 mmol, Example 15, step 1), 5-bromo-2-chloropyrimidine (2.50 g, 12.92 mmol, Sigma-Aldrich, St. Louis, Mo.), and 20 mL of dioxane. To this was added triethylamine (4.50 mL, 32.3 mmol). After stirring at room temperature for 3 h, the mixture was diluted with water (50 mL) and the resulting precipitate was collected by filtration to give 5-bromo-2-(4-(phenylsulfonyl)-1-piperazinyl)pyrimidine (2.50 g) as a white solid.
Reaction SMILES: C(OC([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Oc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1Oc1ccc(-c2cccc(CNC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
3.1 g (6.7 mmol) of ethyl 2-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yloxy}benzoate are placed in 50 ml of dichloromethane and 2.6 ml of trifluoroacetic acid. After stirring at room temperature for 8 hours, the reaction medium is concentrated, placed in water, brought to pH 8 with aqueous 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. 2.3 g of ethyl 2-(3′-methylaminomethylbiphenyl-4-yloxy)benzoate are obtained in the form of an orange-colored oil, in a yield of 95%.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Product: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 60 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide (0.1 g, 0.476 mmol) gave (R)-N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.1 g, 60%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.39-6.36 (m, 1H), 4.23-4.19 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: C([NH:11][C@H:12]([C:20]([CH:22]1[C:29]2([NH2:31])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:32][C:23]1([C:33]([O:35][CH3:36])=[O:34])[CH2:24]3)[CH2:28]2)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.[BrH:37]>C(O)(=O)C>[BrH:37].[NH2:11][C@H:12]([C:20]([CH:22]1[C:29]2([NH2:31])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:32][C:23]1([C:33]([O:35][CH3:36])=[O:34])[CH2:24]3)[CH2:28]2)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C2
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@@H](N)Cc1ccccc1)C2
Reaction time: 1 h

Procedure:
To 3.58 grams of methyl carbobenzoxy-L-phenylalanyl-3-amino-1-adamantanecarboxylate dissolved in 10 ml of acetic acid is added 15 ml of a 5 M solution of hydrogen bromide in acetic acid, and the reaction mixture is allowed to stand for one hour at room temperature. The solvent is removed by distillation under vacuum and the residue is shaken with two 100 ml portions of hexane, then 100 ml of ether, to give methyl L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrobromide which has the following structural formula ##STR14##