Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]ncc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indazole-5-carboxylic acid (ABCR) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.7 (dd, J=7.9, 4.8 Hz, 1H), 7.8 (d, J=8.7 Hz, 1H), 8.2 (dd, J=8.7, 1.6 Hz, 1H), 8.4 (s, 1H) 8.5 (dt, J=7.9, 1.8 Hz, 1H), 8.7 (s, 1H) 8.8 (dd, J=4.8, 1.6 Hz, 1H), 9.3 (d, J=2.0 Hz, 1H), 13.6 (s, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CCN(CC)CC>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: NCc1ccccn1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NCc1ccccn1)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
By the method described in Example 18, the title compound of Example 2 in CH2Cl 2 with molecular sieves #5A and Et3N was reacted with 2-(aminomethyl)pyridine to generate the free base of the title product. This material was converted to the title compound by the method described in Example 40.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[N:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl.C(OC(=O)C)C>[N:19]1[CH:24]=[CH:23][C:22]([NH:25][C:16]([C:3]2[CH:4]=[N:5][N:6]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[C:2]=2[CH3:1])=[O:17])=[CH:21][N:20]=1
Reactant: Cc1c(C(=O)Cl)cnn1C(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccnnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccnnc2)cnn1C(C(F)(F)F)C(F)(F)F
Temperature: 22.5 °C
Reaction time: 68 h
Yield: 33.5 %

Procedure:
A solution of 398 mg 5-methyl-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyrazole-4-carbonyl chloride in 10 ml CH2Cl2 was added dropwise to a solution of 185 mg pyridazin-4-amine and 750 mg triethylamine in 30 ml CH2Cl2 at 0° C. The mixture was stirred at 20-25° C. for about 68 h, diluted with 25 ml ethylacetate, washed with 3×15 ml sat. aq. NH4Cl solution, dried over MgSO4 and evaporated. Purification by flash chromatography (CH2Cl2/MeOH) gave 160 mg of the title compound (90% purity). HPLC-MS (Method 1): RT 2.278 min, m/z [MH]+ 354.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([OH:21])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=CC=CC=1.CO[CH:31](OC)[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=1[O:40][CH3:41].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:21][CH:31]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])[N:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Reactant: COC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzoyl-β-phenyl isoserine methyl ester (3A, 0.5 g, 1.67 mM) is dissolved in dry THF (10 mL) and benzene (10 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (4, 0.420 g, 1.98 mM) and pyridinium p-toluenesulfonate (12 mg) and the solution warmed to reflux. After 30 minutes the reaction is cooled to RT and allowed to stand overnight. It is then again warmed to slowly distill off 1/2 of the solvent over 1 hr. TLC shows the reaction to be finished at this point. The reaction is concentrated in vacuo and the residue chromatographed over 50 g silica gel packed in (5-95) methanol-toluene. The column is eluted with methanol-toluene (5-95). Fractions of 12 mL are collected. The product elutes as a mixture. Thus, fractions containing both 5Aa & 5Ab are recombined and evaporated. The residue (0.90 g) is rechromatographed over silica gel (100 g) The column is eluted with ethyl acetate-toluene (500 mL of 15-85 and 500 mL of 20-80). Fractions of 20 mL are collected and analyzed by TLC. The fractions containing each 5Aa & 5Ab are combined and evaporated under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[F:44][C:43]([F:45])([F:46])[O:42][C:39]1[CH:38]=[CH:37][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:41][CH:40]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of 1-isocyanato-4-trifluoromethoxy-benzene (52.0 mg, 0.26 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-trifluoromethoxy-phenyl)-amide as a white solid. (Yield 82 mg, 66.7%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH2:16][OH:17])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].O>ClCCl.CN(C)C1C=CN=CC=1>[C:31]([O:17][CH2:16][CH2:15][N:7]([C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1)[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CSCC(C)C(=O)N(CCO)c1cn(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CSCC(C)C(=O)N(CCOC(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(2-hydroxyethyl)-2-methyl-3-(methylthio)propanamide (0.045 g, 0.127 mmol) in dichloromethane (1.27 ml) was added N,N-dimethylpyridin-4-amine (0.023 g, 0.190 mmol) and triethylamine (0.019 g, 0.190 mmol) followed by acetyl chloride (0.015 g, 0.190 mmol). The reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane. The combined organic phases were concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give 2-(N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamido)ethyl acetate as a yellow oil (0.015 g, 0.034 mmol, 26.8%): IR (thin film) 1739, 1669 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.3 Hz, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.47 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 4.50-3.40 (m, 4H), 2.84 (dd, J=12.7, 8.9 Hz, 1H), 2.78-2.63 (m, 1H), 2.46 (dd, J=12.7, 5.4 Hz, 1H), 2.03 (s, 3H), 2.01 (s, 3H), 1.16 (d, J=6.6 Hz, 3H); ESIMS m/z 398 ([M+H]+).
Reaction SMILES: [CH2:1]([S:4]([CH2:7][C:8](O)=O)(=[O:6])=[O:5])[CH2:2][CH3:3].[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C=O.[C:20](=O)=O>O.O1CCOCC1>[CH2:1]([S:4]([C:7](=[CH2:8])[CH2:20][N:15]1[CH2:16][CH2:17][CH:12]([OH:11])[CH2:13][CH2:14]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)CC(=O)O
Reactant: OC1CCNCC1
Reactant: O=C=O
Agent: C=O
Solvent: C1COCCO1
Solvent: O
Product: C=C(CN1CCC(O)CC1)S(=O)(=O)CCC
Temperature: 57 °C
Reaction time: 0.17 h

Procedure:
In a 1 l. 3-neck round bottom flask, under a nitrogen atmosphere, 13 g. (0.078 mole) of n-propylsulfonylacetic acid was dissolved in 75 ml. of dioxane. There was then added with good stirring a solution of 7.89 g. (0.078 mole) of 4-hydroxypiperidine in 75 ml. of dioxane and 5 ml. of water (obtained by warming to 40° C.). The almost clear solution was kept at 30° C. and over a 10 minute period 12.7 g. of a 37% aqueous formaldehyde solution (0.156 mole) was dripped in. After complete addition there was gradual warming of the reaction mixture to 50° C. with carbon dioxide evolution. The temperature rose to 57° C. with vigorous gas evolution; and the reaction mixture was maintained at 57° C. for 4 hours, followed by stirring for 12 hours at 20°-25° C. The solvents were removed in vacuo; the residual oil was taken up in methylene chloride, washed well with water, dried over anhydrous sodium sulfate, again concentrated, then taken up in ether (120 m.), washed twice with 10 ml. of water, dried over anhydrous sodium sulfate; and the solvent was removed to leave 7 g. of the product as an oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1.O>O1CCOCC1.C/C(/O)=C/C(C)=O.C1CC=CCCC=C1.[Rh]>[C:1]1([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C=CCCC1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: CC(=O)/C=C(/C)O
Solvent: O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Product: c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 25-mL three-neck flask were added Rh(acac)(cod) (6.8 mg, 21.8 μmol) and PhB(OH)2 (445 mg, 3.65 mmol), and the atmosphere in the system was substituted with argon. The mixture was added with 3.6 mL of a solution of each ligand (21.8 μmol) in anhydrous dioxane and 2-cyclohexenone (0.073 mL, 0.73 mmol). The mixture was stirred at room temperature for 15 minutes, and added with water (0.18 mL). The reaction mixture was stirred at 100° C. for 3 hours, then added with 9 mL of water, and extracted twice with 9 mL of diethyl ether. The organic layers were combined, washed with 9 mL of saturated sodium chloride solution, and concentrated in an evaporator. The residue was treated by silica gel column chromatography (toluene:ethyl acetate=2:1) to obtain 3-phenylcyclohexane as colorless oil. The resulting optically active 3-phenylcyclohexanone in an amount of 2 mg was dissolved in 1 mL of a mixture of n-heptane and 2-propanol (99:2). This solution was analyzed by HPLC under the following conditions.
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:23]([O-:26])(=O)[CH3:24].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>O>[C:28]([O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:26])[CH3:24])=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: Oc1ccc(P(c2ccccc2)c2ccc(O)cc2)cc1
Agent: Br
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1ccc(P(c2ccccc2)c2ccc(OC(C)=O)cc2)cc1

Procedure:
A mixture of 18.76 g (0.05 mol) of bis(4-hydroxyphenyl)phenylphosphine hydrobromide, 9.1 g (0.11 mol) of sodium acetate and 61 ml of acetic anhydride was heated at reflux for 4 hr and cooled. The mixture was poured onto a mixture of ice and water and the resultant solid was collected and recrystallized from methanol. The yield of bis(4-acetoxyphenyl)phenylphosphine was 4.9 g (25.9% of theory); mp=118°-20° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](=[CH:18]\[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)/[C:9]([NH:11][C:12]2[S:13][C:14]([Cl:17])=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CCOCC>[Cl:17][C:14]1[S:13][C:12]([NH:11][C:9](=[O:10])/[C:8](/[C:5]2[CH:6]=[N:7][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][CH:4]=2)=[CH:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:16][CH:15]=1
Reactant: Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of (E)-2-(6-aminopyridin-3-yl)-N-(5-chlorothiazol-2-yl)-3-cyclopentylacrylamide (EXAMPLE 75, 50 mg, 143 μmol) in anhydrous CH2Cl2 (3 mL) was treated with pyridine (570 μL, 7.1 mmol) and MsCl (170 μL, 2.2 mmol). After stirring for 3 d at 20° C., the reaction mixture was diluted with Et2O (40 mL), before being extracted with 1M NaOH-saturated aqueous NaHCO3 (1:1, 2×15 mL). The combined aqueous extracts were neutralised with 2M HCl, before being extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (1:1 IH-EtOAc) furnished the title compound: RTA=3.73 min; m/z (ES+)=427.2 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[CH3:30][C:31]1[C:36]([N+:37]([O-])=O)=[CH:35][N:34]=[C:33]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=1>>[NH2:37][C:36]1[C:31]([CH3:30])=[CH:32][C:33]([N:40]([CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:24]=[CH:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:21][CH2:22]2)[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[N:34][CH:35]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ncc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Product: Cc1cc(N(CC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)C(=O)OC(C)(C)C)ncc1N

Procedure:
The title compound was synthesized by procedure analogous to Step 2 and 3 of Example 28 from 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and tert-butyl (4-methyl-5-nitropyridin-2-yl)carbamate from Step 1 of this example.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N+:7]=1[O-:14].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[C:11]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([CH3:13])=[CH:8][N+:7]=1[O-:14]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 ml of fuming nitric acid (d =1.5) were added dropwise while cooling to 210 ml of concentrated sulfuric acid. 96.5 g of 2.3.5-trimethylpyridine 1-oxide were subsequently added portionwise at 0-5° , whereupon the mixture was stirred at room temperature for 1 hour, then heated to 90° within 3 hours and left at this temperature overnight. After cooling the solution was poured on to 1.5 kg of ice. whereupon the mixture was adjusted to pH 3 with concentrated sodium hydroxide solution and extracted three times with 500 ml of methylene chloride. The combined organic phases were washed with 1 1 of water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ether/petroleum ether and there was obtained 2,3,5-trimethyl-4-nitropyridine 1-oxide of melting point 76-78° .
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl-].C[Al+]C.[CH3:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][N:12]=1.O>ClCCl.CCCCCC>[CH3:2][N:3]([O:4][CH3:5])[C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH3:10])=[N:12][CH:13]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: CNOC
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)nc1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (710 mg, 7.28 mmol) was suspended in dichloromethane (50 mL). To this, dimethylaluminum chloride (a 1.04 mol/L solution in hexane, 7.00 mL, 7.28 mmol) was slowly added under a nitrogen atmosphere at 0° C. and the mixture was stirred at the same temperature for 1 hour. To this, methyl 6-methylnicotinate (1.00 g, 6.62 mmol) was added, and (7.00 mg, 1.88 mmol) was added at room temperature. Then, water was added to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 6-methylnicotinic acid N,O-dimethylhydroxylamide (737 mg, yield: 62%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH:14]=[CH2:13]
Reactant: Oc1ccccc1C1CCCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C1CCCC1
Reaction time: 26 h
Yield: 97.7 %

Procedure:
486.7 g (3.0 mol) of 2-cyclopentylphenol, 472 g (3.9 mol) of allyl bromide and 830 g (6.0 mol) of potassium carbonate are heated under reflux in 2.5 l of acetone while stirring vigorously for 26 h. The cooled reaction mixture is filtered, and the filtrate is concentrated in vacuo. The residue is taken up in petroleum ether, and the solution is washed three times with 2N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo, and the residue is finally distilled in vacuo. 593 g (97% of theory) of 2-cyclopentylphenyl allyl ether are obtained.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22].[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30](C(O)=O)=[C:29]([O:37][CH3:38])[CH:28]=1>>[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25])[CH2:11]2)=[O:7])=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Reactant: CCCN=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CCCNC(=O)NCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.10 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.42 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.82 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(4-(3-n-propylureido)butyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:12])[CH2:8][CH:9]([OH:11])[CH3:10].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>C(Cl)Cl>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:7][CH2:8][CH:9]([CH3:10])[OH:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Pyridine (9.0 ml, 111 mmol) was added to a solution of 1,3-butanediol (5.07 g, 56.3 mmol) in anhydrous methylene chloride (20 ml) at room temperature. After ice-cooling, p-toluenesulfonyl chloride (15.9 g, 83.4 mmol) was added thereto, the mixture was stirred at room temperature overnight, then water (60 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with 1 N hydrochloric acid (30 ml) and saturated brine (30 ml) successively and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=3/1) to give 7.72 g (57%) of the target compound.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:22]([NH2:39])=[N:23][CH:24]=[C:25]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[CH:31]=2)[CH:26]=1>C(Cl)Cl>[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:22]([NH2:39])=[N:23][CH:24]=[C:25]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:33][CH2:34][N+:35]([CH3:38])([O-:9])[CH2:36][CH2:37]3)[CH:31]=2)[CH:26]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Solvent: ClCCl
Product: C[N+]1([O-])CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Reaction time: 0.08 h

Procedure:
3-Chlorobenzenecarboperoxoic acid (0.046 g) was added to 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.100 g) in DCM (10 ml). The resulting solution was stirred for 5 minutes. The resultant precipitate was collected by filtration, washed with DCM (2 ml) and dried under vacuum. The residue was purified by SCX ion exchange chromatography (elution with 7M methanolic ammonia) and there was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-1-oxido-piperidin-1-ium-4-yl)pyrazol-4-yl]pyridin-2-amine (0.026 g); Mass Spectrum: M+H+ 391.29; RT 1.18 min; NMR Spectrum: (DMSOd6) 8.49 (d, 1H), 8.41 (d, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.78 (dd, 1H), 7.73 (dd, 1H), 7.57 (br s, 2H), 7.38 (m, 2H), 4.26 (tt, 1H), 3.46 (m, 2H), 3.11 (s, 3H), 3.06 (m, 2H), 2.68 (m, 2H), 1.90 (br m, 2H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=[O:9].N1C=CC=CC=1.[SH:17][C:18]([CH3:24])([CH3:23])[CH2:19][CH:20](O)[CH3:21]>C(OCC)C>[CH:8]([O:10][CH:20]([CH2:19][C:18]([SH:17])([CH3:24])[CH3:23])[CH3:21])=[O:9]
Reactant: O=CO
Reactant: CC(O)CC(C)(C)S
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(CC(C)(C)S)OC=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of 12.3 g of acetic anhydride and 6.2 g of formic acid was heated at 40°C for 1 hour. After cooling to 20°C 1 g of pyridine was added and subsequently, with stirring, 15 g of 4-mercapto-4-methylpentan-2-ol in the course of 10 minutes. The temperature of the reaction mixture slowly rose to 28°C. After standing overnight it was dissolved in diethylether, washed five times with 3% aqueous NaHCO3 solution and then with aqueous NaCl solution to neutral. The ethereal solution was dried over Na2SO4 and concentrated. Distillation of the residue yielded 10.5 g (58%) of 4-mercapto-4-methylpent-2-yl formate, b.p. 30°-32°C/1 mm, nD20 1.4564.