Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC1C=CC(S([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=O)=O)=CC=1C.Cl[C:19]1[CH:20]=[CH:21][C:22]([F:29])=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:24]=1.[CH3:30][N:31]1C(=O)CCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:31][CH2:30][C:19]1[CH:20]=[CH:21][C:22]([F:29])=[C:23]([S:25]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:27])=[O:26])[CH:24]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1F
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1CN
Reactant: CN1CCCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cc(CN)ccc1F
Temperature: 120 °C
Reaction time: 15 h

Procedure:
5-Aminomethyl-N-tert-butyl-2-fluoro-benzenesulfonamide was synthesized in a manner analogous to 4-Aminomethyl-N-tert-butyl-3-methyl-benzenesulfonamide in Example 4, using 5-chloro-2-fluorobenzene-1-sulfonyl chloride in place of 4-bromo-3-methylbenzene-1-sulfonyl chloride. In the second step NMP was used as the solvent, Pd(dppf)Cl2 alone was used as catalyst and the reaction mixture was stirred at 120° C. for 15 hours.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30]>>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)=[N:26][C:25]=1[CH2:24][N:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc2cc(CC(Oc3ccccc3)C(=O)O)ccc21

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl methyl]-1H-indol-5-yl}-2-phenoxy-propionic acid as colorless solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.[CH3:19][C:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.CN(C1C=CC=CN=1)C>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:7][N:6]1[C:23]([C:20]1([CH3:19])[CH2:22][CH2:21]1)=[O:24])=[O:11]
Reactant: CC1(C(=O)Cl)CC1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)C1(C)CC1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a suspension of hydroxyproline methyl ester hydrochloride (36.3 g, 200 mol), triethylamine (65.8 g, 650 mmol) and dimethylaminopyridine (1.25 g, 10 mmol) in dichloromethane (800 mL) was added at 0° C. the 1-methyl-cyclopropanecarbonyl chloride (24.9 g, 210 mmol) over 0.5 h. After additional stirring for 2 h, methanesulfonyl chloride (28.64 g, 250 mmol; note 7) was added over 0.5 h and stirring at 0° C. was continued for 1 h. The cold reaction mixture was transferred into a separatory funnel and washed with 1 M HCl (400 mL) and 10% brine (400 mL). The aqueous layers were extracted with dichloromethane (400 mL) and the combined organic layers were dried over Na2SO4. Filtration and evaporation of the solvent (35-45° C./≧10 mbar) afforded crude, crystalline product (63.8 g) which was dissolved in isobutyl acetate (250 mL) at ˜70° C. After seeding at ˜50° C., crystallization was completed by cooling to room temperature and stirring at −20° C. overnight. Filtration and washing with cold isobutyl acetate gave after drying (50° C./10 mbar/3 h) the title product (57.5 g, 94.2%) as a white, crystalline powder, mp. 102-103° C. [α]D20=−10.3 (c 1.0; CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.50-0.70 (m, 2H), 0.90 (m, 1H), 1.10 (m, 1H), 1.34 (s, 3H), 2.23 (m, 1H), 2.59 (m, 1H), 3.06 (s, 3H), 3.74 (s, 3H), 3.95 (d, 1H), 4.25 (d, 1H), 4.63 (br t, 1H), 5.35 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4]([CH3:9])[N:3]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(O)cc(C)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(C)n1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
2,6-dimethyl-4-hydroxypyridine (1 g) was added to phosphoryl chloride (5 mL). The solution was stirred at 100° C. for six hours. The reaction mixture was partitioned by adding water, a 5 N aqueous sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.15 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si](C)(C)C)[CH:20]=4)[CH2:16][C:15](=[O:31])[NH:14][C:13]=3[CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO.C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([C:17]2[CH2:16][C:15](=[O:31])[NH:14][C:13]3[CH:32]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:10]=[CH:11][C:12]=3[N:18]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Yield: 58.9 %

Procedure:
Prepared from 8-phenylethynyl-4-(3-trimethylsilanylethynyl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (63 mg, 0.146 mmol) by treatment with 1N NaOH (3drops ) in MeOH (3 mL) and THF (0.5 mL) at 23° C. for 2 h. Obtained as a brown solid (31 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C([O:32]C(Cl)=O)C.C([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)(=O)C1C=CC=CC=1>O1CCCC1>[CH:47]1([NH:48][C:20](=[O:22])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([OH:32])=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:49][CH2:50][CH2:44][CH2:45][CH2:46]1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NC1CCCCC1
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
N-(t-butyloxycarbonyl)-4-nitro-D,L-phenylalanine (0.95 g) and triethylamine (0.4 ml) were dissolved in dry tetrahydrofuran (15 ml), and ethylchorocarbonate (0.33 g) was added under ice-cooling to the resultant solution, followed by stirring for 20 minutes. 4-benzoylaniline (0.6 g) was added to the solution and the mixture was further stirred at room temperature for 12 hours. According to a conventional post-treatment, 0.98 g of N-(t-butyloxycarbonyl)-4-nitro-D,L-phenylalanine 4-benzoylanilide (I) was obtained. To the above compound (I) (0.37 g) was added 4N-hydrogen chloride/dioxane solution (1.5 ml) and the mixture was stirred at room temperature for 1 hour. The solid precipitated by addition of ethyl ether (10 ml) into this solution was collected by filtration to give 0.33 g of 4-nitro-D,L-phenylalanine 4-benzoylanilide hydrochloride (II). Trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid (0.2 g) and triethylamine (0.2 ml) were dissolved in dry tetrahydrofuran (15 ml) and ethyl chlorocarbonate (0.09 g) was added to the solution under ice-cooling, followed by stirring for 20 minutes. To this solution was added the above compound (II) (0.33 g) and the mixture as stirred at room temperature for 12 hours. According to a conventional post-treatment, 0.29 g of N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-nitro-D,L-phenylalanine 4-benzoylanilide (III) was obtained. The above compound (III) (0.29 g) was dissolved in 4N-hydrogen chloride/dioxane solution (1 ml), the solution was stirred at room temperature for 1 hour and then ether (8 ml) was added. The crystalline substance precipitated was collected by filtration and subjected to a conventional post-treatment, whereby 0.24 g of N-(trans-4-aminomethylcyclohexylcarbonyl)-4-nitro-D,L-phenylalanine 4-benzoylanilide hydrochloride was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1.[H-].[Na+].I[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH3:35])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: CI
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(CO)c3)C(C)(C)C2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1cccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(hydroxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-34) (559 mg, 1.32 mmol) in anhydrous dimethylformamide (10 mL) at 0° C., was added sodium hydride (53 mg, 1.32 mmol), followed by iodomethane (99 ul, 1.58 mmol). The reaction was allowed to warm to room temperature and stirred for about 4 hours. The resulting mixture was diluted with ethyl acetate (40 mL) and ice water (10 mL), The organic phase was collected, dried over anhydrous MgSO4, filtered and then concentrated on the rotovap. The residue was purified by reverse phase HPLC (gradient 10% to 100% methanol/water) and further purified by column chromatography (60% EtOAc in hexane). Yield 36%, colorless gel. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.25 (s, 3H), 4.37 (s, 2H), 4.55 (s, 2H), 5.18 (s, 2H), 7.19 (t, 1H) 7.30 (d, 2H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 438 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[Cl:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[ClH:15].[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[CH3:21]
Reactant: c1ccn(Nc2ccncc2)c1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccncc1)n1cccc1
Product: Cl
Temperature: 0 °C
Yield: 46.3 %

Procedure:
A solution of N-(1H-pyrrol-1-yl)-4-pyridinamine (5 g) in 25 ml of dimethylformamide was slowly added to a suspension of sodium hydride (60% oil dispersion, 1.4 g, washed with hexane) in 5 ml of dimethylformamide. After the anion formation, the mixture was cooled with an ice-salt bath, and a solution of ethyl chloroacetate (4.2 g) in 5 ml of dimethylformamide was slowly added. After thirty minutes, the mixture was stirred with ice water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 8 g of oil. This oil was purified by HPLC (silica, ethyl acetate) to give 4.1 g of solid, mp 92°-95°. This material was converted to the hydrochloride salt and recrystallized twice from isopropanol and once from ethanol to give 2.6 g of crystals, d 240°-241°.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=[CH:6][N:5]=1.[SH:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=2[N:22]=1.O.[OH-].[Na+]>C(O)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:18]([S:17][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[N:7]=[CH:6][N:5]=3)=[N:19][C:20]=2[CH:26]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1c(CCl)ncnc1N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3ncnc(N4CCCCC4)c3C)nc2c1

Procedure:
A mixture of 4-chloromethyl-5-methyl-6-piperidino pyrimidine hydrochloride (4.63 g) and 2-mercapto-5-methoxybenzimidazole (3.18 g) in ethanol (180 ml) were heated at 50° for 5 hours. The solution was stripped to a residual glass, to which water was added, the pH raised to 13 (NaOH), and extracted with chloroform. Extracts were dried (K2CO3) and stripped to a residual glass which crystallised from ethyl acetate to give 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, 5.67 g, m.p. 94°-96°.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O.CN(C)C=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([Cl:25])=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.61 g (5.7 mmol) of 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (60 mL), and 3.5 mL (42 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (60 mL), and 0.71 g (6.3 mmol) of 1,3-cyclohexanedione and 0.97 mL (6.9 mmol) of triethylamine were added to the above solution. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 2.13 g of the title compound was obtained as a light yellow solid (yield: quantitative).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH2:15][CH3:16])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:13]([N:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]1=[O:1])([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)Br
Reactant: COC(=O)c1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(C)n1ccc(C(=O)OC)cc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of methyl 2-hydroxyisonicotinate (306 mg, 2 mmol) in N,N-dimethylformamide (20 mL) was added 2-bromobutane (330 mg, 2.4 mmol) and cesium carbonate (652 mg, 2 mmol), then stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography with dichloromethane/methanol=40:1 to give methyl 1-sec-butyl-2-oxo-1,2-dihydropyridine-4-carboxylate (334 mg, 80%). LRMS (M+H+) m/z: calcd 209.11. found 209.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O.C1COCC1.CO>[C:1]([C:5]1[NH:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)O)[nH]1
Temperature: 75 °C
Yield: 64.3 %

Procedure:
A solution of LiOH monohydrate (0.083 g, 2.0 mmol) in water (1 mL) was added to a solution of methyl 5-tert-butyl-3-nitro-1H-pyrrole-2-carboxylate (0.150 mL, 0.66 mmol) in THF:MeOH (3:1, 3 mL) and the resulting mixture heated at 75° C. for 5 hours. The reaction was cooled down to room temperature and acidified with 1N aqueous HCl, extracted with ethyl acetate. The combined organic layers were dried, the solvent eliminated under vacuum and the crude product recrystallized from dichloromethane:hexane to afford 90 mg of expected 5-tert-butyl-3-nitro-1H-pyrrole-2-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:36][CH:37]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1cccc(-c2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)c1)S(C)(=O)=O

Procedure:
N-Methyl-N-(3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (71.0 mg, 0.263 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.018 g, 15%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.31 (d, J=6.4 Hz, 1H), 8.13 (s, 3H), 7.93 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H), 7.56-7.46 (m, 3H), 7.46 (d, J=8.9 Hz, 1H), 6.98-6.90 (m, 3H), 6.68 (s, 1H), 4.11 (t, J=6.0 Hz, 2H), 3.41 (s, 3H), 2.96-2.88 (m, 5H), 2.64 (br s, 4H), 1.87-1.77 (m, 4H). MS=507 (MH)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:44][N:45]1[C:49](=[O:50])[C:48]2([CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([CH3:58])[C:52]([CH3:60])([CH3:59])[CH2:51]2)[NH:47][C:46]1=[O:61])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:43])[CH2:25][N:26]3[C:30](=[O:31])[C:29]4([CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([CH3:39])[C:33]([CH3:41])([CH3:40])[CH2:32]4)[NH:28][C:27]3=[O:42])=[CH:18][CH:17]=2)([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[CH2:62](Br)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73]>CN(C)C=O>[CH2:62]([O:43][CH:24]([CH2:25][N:26]1[C:30](=[O:31])[C:29]2([CH2:36][C:35]([CH3:37])([CH3:38])[N:34]([CH3:39])[C:33]([CH3:40])([CH3:41])[CH2:32]2)[NH:28][C:27]1=[O:42])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:4]([O:3][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:13][CH2:10][CH2:9][CH2:8][CH2:7][CH2:12][CH3:11])[CH2:44][N:45]3[C:49](=[O:50])[C:48]4([CH2:55][C:54]([CH3:57])([CH3:56])[N:53]([CH3:58])[C:52]([CH3:60])([CH3:59])[CH2:51]4)[NH:47][C:46]3=[O:61])=[CH:12][CH:11]=2)([CH3:15])[CH3:14])=[CH:17][CH:18]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73]
Reactant: CCCCCCCCCCCCBr
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)N(C)C(C)(C)C5)C4=O)cc3)cc1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOC(COc1ccc(C(C)(C)c2ccc(OCC(CN3C(=O)NC4(CC(C)(C)N(C)C(C)(C)C4)C3=O)OCCCCCCCCCCCC)cc2)cc1)CN1C(=O)NC2(CC(C)(C)N(C)C(C)(C)C2)C1=O
Reaction time: 2 h

Procedure:
1.5 g of sodium hydride was added, with stirring, to a solution of 8.2 g of 2,2-bis{4-[2-hydroxy-3-(7,7,8,9,9-pentamethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane, prepared as described in Example 1, in 150 ml of N,N-dimethylformamide, and the mixture was stirred at 50°-60° C. for 2 hours. 10.0 g of n-dodecyl bromide were then added dropwise to the mixture and the whole mixture was heated at 50°-60° C. for two hours and then at 70°-80° C. for a further 4 hours, stirring all the time. After completion of the reaction, the reaction mixture was condensed by evaporation under reduced pressure and then 200 ml of benzene were added to the resulting residue. This solution was then washed with, in turn, a 2% w/w aqueous solution of sodium carbonate and water. The washed solution was dried over anhydrous potassium carbonate and then the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 32:4:5:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine, giving the desired Compound No. 34 as a colourless, viscous liquid, having an Rf value of 0.53 on thin-layer chromatography on silica gel using a 20:2:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine as developing solvent.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[S:19][C:18]([C:20](=O)[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1.Cl.[O:26]([NH2:29])[CH2:27][CH3:28].N1C=CC=[CH:32][CH:31]=1>>[CH2:31]([O:23][C:21](=[O:22])/[C:20](=[N:29]/[O:26][CH2:27][CH3:28])/[C:18]1[S:19][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1)[CH3:32]
Reactant: CCON
Reactant: c1ccncc1
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: Cl
Product: CCO/N=C(/C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
As described in example 305, 5-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxo-2-thiopheneacetic acid (0.34 g) was combined with ethoxylamine hydrochloride (0.130 g) in pyridine (5 mL) and stirred for 10 days at room temperature. The rnixmre of isomers, obtained after work up of the reaction in the usual manner, were separated by flash chromatography over silica gel (70 g: dichlorornethane-hexane; 4:1 ). Fractions containing the less polar isomer were evaporated to give 0.151 g of (Z)-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid ethyl ester, mp 114°-115.5° C.
Reaction SMILES: C(C1OC1)Cl.[CH2:6]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=O)[CH:7]1[O:9][CH2:8]1.[OH2:23].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:32]O>C(O)C.O>[CH2:6]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=[N:32][OH:23])[CH:7]1[O:9][CH2:8]1
Reactant: O
Reactant: O=Cc1c(OCC2CO2)ccc2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCC1CO1
Product: ON=Cc1c(OCC2CO2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
As shown in Chemical Formula 2, an ethanol solution in which 5.03 g (22.0 mmol) of 2-(glycidyloxy)-1-naphthoaldehyde (3) was thoroughly dissolved in 110 mL of ethanol was prepared. Separately, an aqueous solution in which 4.48 g (32.9 mmol) of sodium acetate trihydrate and 2.29 g (32.9 mmol) of hydroxylamine hydrochloride were dissolved in 110 mL of water was prepared. The aqueous solution was added to the ethanol solution and the resultant reaction mixture was stirred at room temperature for 4 hours to effect the reaction. Then, water was added to the reaction mixture and the resultant precipitate was recovered by filtration and was vacuum-dried to obtain 5.36 g (yield: 100%) of 2-(glycidyloxy)-1-naphthoaldehyde oxime (4) as a white powder.