Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[CH:16]=[C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=[CH:13][C:12]=2[CH:11]=[CH:10]1>ClCCl>[Cl:1][C:11]1[C:12]2[CH:13]=[N:14][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:17]=2[NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2[nH]cc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.4 %

Procedure:
N-Chlorosuccinimide (514 mg) was added to a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridin-6-carboxylate (800 mg) in dichloromethane (16 ml) at room temperature and the mixture was stirred at the room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulted residue was dissolved in tetrahydrofuran. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo to give a crude product of tert-butyl 3-chloro-1H-pyrrolo[3,2-c]pyridin-6-carboxylate (1.06 g) as an orange powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16].C1(O)C=CC=CC=1>COCCOC>[Cl:16][CH2:15][CH2:14][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: ClCCCBr
Reactant: CSc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: COCCOC
Product: CSc1ccc(OCCCCl)cc1
Yield: 32 %

Procedure:
A solution of 4-(methylthio)phenol (10.0 g, 0.071 mole) in 150 ml. of 1,2-dimethoxyethane is added to a slurry of a 57% dispersion of sodium hydride (3.0 g., 0.071 mole) in mineral oil (previously washed with hexane to remove the mineral oil) in 100 ml. of 1,2-dimethoxyethane. After the initial reaction is complete, 1-bromo-3-chloropropane (12.63 g., 0.08 mole) is added in one portion. The resulting mixture is stirred and refluxed for a period of 68 hrs., cooled and then concentrated under reduced pressure. Residual material (oil) is dissolved in ether and washed with water. The ether solution (after drying over magnesium sulfate) is concentrated under reduced pressure to provide 14.6 g. of an oil containing approximately 25% starting phenol according to NMR spectra. Distillation of the oil under reduced pressure affords, after a forerun of 4-(methylmercapto)phenol, 5.0 g. (32% yield) of 1-chloro-3-[4-(methylthio)phenoxy]propane, b.p. 150°-152° C. at 27 mm Hg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:20](Cl)(=[O:31])[O:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:20]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[O:31])[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl piperidin-4-ylcarbamate (2.0 g, 9.99 mmol) in DCM (40 ml) was treated with sodium bicarbonate solution (50 ml, 9.99 mmol) followed by a solution of 3,5-dichlorobenzyl carbonochloridate (2.392 g, 9.99 mmol) in DCM (10 ml). The reaction mixture was stirred vigorously at RT until gas evolution ceased. The organic layer was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure, yielding the title compound as colourless oil that solidified on standing;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[NH:5][C:6](=O)[C:7]=1[N+:8]([O-:10])=[O:9].O(Cl)[Cl:19].P(Cl)(Cl)(Cl)=O>C(N(CC)C1C=CC=CC=1)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:19])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: ClOCl
Reactant: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 72 %

Procedure:
The title compound of Example 23 (10.0 g, 38.37 mmol) was heated to reflux in phosphorus oxychloride oxychloride (200 ml) and N,N-diethylaniline (3-4 drops) for 5 hours under nitrogen. The solution was then cooled to room temperature, concentrated to dryness, and the syrup was dissolved in cold (~-10° C.) methylene chloride (200 ml). The organic layer was treated with saturated aqueous sodium bicarbonate (100 ml) with vigorous stirring, and the temperature was kept below 5° C. as solid sodium bicarbonate was added portionwise to elevate the pH to between 5 and 7. The layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic layers were filtered over phase-separator paper, concentrated and dried under vacuum to give the title compound (7.71 g, 72%) as a yellow-white solid sufficiently pure to employ in the next step. Recrystallisation of the solid from hexane/methylene chloride provided an analytical sample, m.p. 166°-169° C.; 1H-NMR (DMSO-d6) δ 1.09 (d, J=6.9 Hz, 6H, (CH3)2CH), 2.79 (m, J=6.9 Hz, 1H, (CH3)2CH), 11.61 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[O:18])[C:15]([OH:16])=[C:10]2[CH:9]=[N:8]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C)C=O>[CH2:30]([O:16][C:15]1[C:14]([C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[O:18])=[CH:13][N:12]=[C:11]2[N:7]([CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:8]=[CH:9][C:10]=12)[CH3:31]
Reactant: O=C(c1cccs1)c1cnc2c(cnn2Cc2ccco2)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(C(=O)c2cccs2)cnc2c1cnn2Cc1ccco1

Procedure:
3.3 g. of [1-(2-furanylmethyl)-4-hydroxy-1H-pyrazolo[ 3,4-b]pyridine-5-yl]-2-thienylmethanone (0.01 mol.), 1.5 g. of potassium carbonate (0.011 mol.) and 3.1 g. of ethyl iodide (0.02 mol.) are stirred together in 20 ml. of dimethylformamide at 70° for 12 hours. After this time, the inorganic precipitate is filtered off and the filtrate treated with about 10 ml. of water. The product, [4-Ethoxy-1-(2-furanylmethyl)-1H-pyrazolo[ 3,4-b]pyridin-5-yl]-2-thienylmethanone, crystallizes on standing, yield 3 g. (86%); m.p. 85°-87° (methanol).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][C@@H:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1>O>[Si:10]([O:19][C@@H:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@H](O)CN1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.02 g of imidazole and 1.58 g of t-butyldimethylchlorosilane were added to a dimethylformamide (5 ml) solution of 1.01 g of (S)-4-hydroxy-2-pyrrolidone, and stirred overnight at room temperature. Water was added to the reaction liquid, and stirred with cooling with ice.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl.O>O1CCCC1>[Cl:26][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Cl)cnc21
Reaction time: 1 h
Yield: 114.3 %

Procedure:
To 5-bromo-1-triisopropylsilyl-7-azaindole (2, 1.60 g, 4.53 mmol, prepared as described in Example 4) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at −78° C., was added tert-butyllithium (1.70 M in hexane, 6.12 mL). The reaction was stirred for 1 hour, followed by addition of hexachloroethane (1.29 g, 5.43 mmol). The reaction was stirred for 3 hours, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude compound (5, 1.60 g). MS (ESI)[M+H+]+=309.3.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH3:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH3:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(N)c1ccccc1N(C)S(C)(=O)=O
Product: CC(Nc1cccn2nc(Cl)nc12)c1ccccc1N(C)S(C)(=O)=O

Procedure:
N-{2-[1-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-ethyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (350.0 mg, 1.506 mmol) and N-[2-(1-amino-ethyl)-phenyl]-N-methyl-methanesulfonamide (380.0 mg, 1.664 mmol) in a manner analogous to Example 2d. Product isolated as a yellow foam (0.315 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83-7.79 (m, 1H), 7.62-7.25 (m, 4H), 6.85-6.71 (m, 1H), 6.61-6.43 (m, 1H), 5.42-6.13 (m, 2H), 3.35-3.26 (m, 3H), 3.08-3.00 (m, 3H), 1.70-1.53 (m, 3H). MS=402 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[C:21]([C:22]2[CH:23]=[N:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>CN1CCCC1=O>[C:27]([N:25]1[CH:26]=[C:22]([C:21]2[C:16]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:23]=[N:24]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ncccc2-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
In 4 separate microwave vessels were added equal amounts of the following (total/4): dissolved 4-aminophenol (0.054 g, 0.498 mmol) in 1-methyl-2-pyrrolidinone (4.7 mL), added cesium carbonate (0.309 g, 0.948 mmol). Each mixture was stirred at 20° C. for 5 minutes, after which was added 2-chloro-3-(1-trityl-1-H-pyrazol-4-yl)pyridine (0.200 g, 0.474 mmol) and heated to 200° C. in the microwave for 6 minutes. The solutions were combined and extracted into EtOAc, washed 1×H2O, 1×NaCl, dried with Mg2SO44, filtered through fritted funnel, and concentrated. The crude residue was purified by silica gel chromatography using 25-70% EtOAc/Hexanes. The product fraction were concentrated to yield 4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine as brown oil. MS m/z=495 [M+1]+. Calc'd for C33H26N4O: 494.59.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CC1c2ccccc2C(=O)N1Cc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(3-Oxo-2,3-dihydro-1H-isoindol-1-yl)-acetic acid (100 mg, 0.52 mmol) was dissolved in 2 mL dry DMF and stirred under N2 at 0° C. NaH (44 mg, 1.1 mmol) was added and stirring continued for 0.5 h. Benzyl bromide (0.13 mL, 1.1 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. The mixture was diluted with EtOAc. The organic phase was washed with 2×10 mL aq LiCl and 10 mL brine, then dried (MgSO4), filtered and evaporated. The title compound was purified by silica gel chromatography (102 mg, 53%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([Br:13])=[CH:15][CH:16]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(Br)cc1
Product: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
1H-Benzo[d][1,3]oxazine-2,4-dione (A) (3.26 g, 20.0 mmol) and 4-bromo-aniline (H) (3.23 g, 18.8 mmol) were mixed together as a neat mixture (both solids), and the reaction mixture was stirred at 130° C. for 4 hours, and then cooled to room temperature. The crude compound was purified by the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 2-amino-N-(4-bromo-phenyl)-benzamide (J) as white solid. Yield: 4.35 g (75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.[I:12]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[I:12]
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2[nH]nc(I)c2cc1Br
Temperature: 70 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
To a solution of 10.0 g of 5-bromo-6-fluoro-1H-indazole in 150 mL of N,N-dimethylformamide was added 10.5 g of N-iodosuccinimide at room temperature, and stirred at 70° C. for 2 days. Then the solution was diluted with ethyl acetate, washed successively with aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crystals precipitated by adding diethyl ether to the residue were collected by filtration. The filtrate was further concentrated and purified and separated by silica gel column chromatographsy (ethyl acetate:n-hexane=1:10-1:5) and combined with the previous crystals, to afford 14.5 g of the title compound as colorless crystals.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][CH:8]([CH3:11])[CH:9]=[O:10].Cl>>[OH:10][C@@H:9]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[CH:8]([CH3:11])[CH3:7]
Reactant: COP([O-])OC
Reactant: CC(C)C=O
Agent: Cl
Product: COP(=O)(OC)[C@H](O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 2-methylpropionaldehyde (0.40 mmol) was added thereto. After reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-1-hydroxy-2-methylpropylphosphonate as a final product in a yield of 95%. The chemical reaction in this Example is shown in chemical formula 41. ##STR35##
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([Cl:16])=[O:13])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2ccccc2c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnc2ccccc2c1
Yield: 90 %

Procedure:
10 g of 3-quinoline carboxylic acid was mixed with 8.5 ml of thionyl chloride and 150 ml of toluene, and allowed to react at 100° C. for 12 hours. The reaction mixture was condensed under a reduced pressure, to obtain a residue that gave 10 g of the title compound (yield 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:22]([CH2:25][OH:26])[CH2:23][NH2:24]>>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:24][CH2:23][CH2:22][CH2:25][OH:26])[CH:3]=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Reactant: NCCCO
Product: OCCCNc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Yield: 73 %

Procedure:
A mixture of 150 mg of 6-chloro-N-(4-phenoxyphenyl)pyridin-2-amine in 304 mg of n-propanolamine in a screw cap vial under argon was treated analogously to the method as set out in Example 16b. 3-(6-(4-Phenoxyphenylamino)pyridin-2-ylamino)propan-1-ol was obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:11]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:24]([O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)=[C:4]([CH3:9])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COC2CCCCO2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
A solution of 2,6-dimethyl-3′-[(tetrahydro-2H-pyran-2-yloxy)methyl]biphenyl-4-ol (1.78 g, 5.70 mmol), benzyl alcohol (0.885 mL, 8.55 mmol) and tributylphosphine (2.13 mL, 8.55 mmol) in toluene (80 mL) was stirred under ice-cooling, and 1,1′-(azodicarbonyl)dipiperidine (2.16 g, 8.55 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 24 hrs. Hexane (40 mL) was added to the reaction mixture and the precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound as a colorless oil (1.71 g, yield 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH2:14][OH:15])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of (3-benzyloxy-1-phenyl-1H-pyrazol-5-yl)methanol (11.20 g), active manganese dioxide (30.00 g) and tetrahydrofuran (300 ml) was stirred overnight at room temperature. Insoluble material was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 3-benzyloxy-1-phenyl-1H-pyrazole-5-carbaldehyde (10.10 g, yield 91%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH3:3].[Br:13][C:14]1[C:15](=[O:24])[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[CH:18][C:19]=1Br.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Br:13][C:14]1[C:15](=[O:24])[N:16]([CH:21]([CH3:22])[CH3:23])[N:17]=[CH:18][C:19]=1[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCOc1ccc(CN)cc1
Reactant: CC(C)n1ncc(Br)c(Br)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(CNc2cnn(C(C)C)c(=O)c2Br)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 0.38 g of 4-ethoxybenzylamine hydrochloride, 0.4 g of 4,5-dibromo-2-iso-propyl-3(2H)pyridazinone, 0.34 g of potassium carbonate, 6 ml of 1,4-dioxane and 18 ml of water, was heated at 90° C. under stirring for 10 hours. The sovent was distilled off under reduced pressure, and water was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off. The product was crystallized from ether to obtain 220 mg of the above identified compound having a melting point of from 151° to 152.5° C. as pale yellow crystals.
Reaction SMILES: N(C([C:6]1[CH2:10][S:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[C:7]=1[N:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:24](=[O:26])[CH3:25])=O)=[N+]=[N-].[C:32]([N:37](C1C(CCCCC(N2CCCCC2)=O)SCC=1N=C=O)C(=O)C)([O:34][CH2:35]C)=[O:33]>CO>[C:27]([N:23]([C:7]1[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[S:9][CH2:10][C:6]=1[NH:37][C:32]([O:34][CH3:35])=[O:33])[C:24](=[O:26])[CH3:25])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)N(C(C)=O)C1=C(N=C=O)CSC1CCCCC(=O)N1CCCCC1
Reactant: CCOC(=O)N(C(C)=O)C1=C(C(=O)N=[N+]=[N-])CSC1CCCCC(=O)N1CCCCC1
Solvent: CO
Product: CCOC(=O)N(C(C)=O)C1=C(NC(=O)OC)CSC1CCCCC(=O)N1CCCCC1
Reaction time: 5 h
Yield: 85 %

Procedure:
2.8 g (.006 moles) of 4-azidocarbonyl-3-(N-carbethoxyacetamido)-2,5-dihydro-2-thiophenevaleric acid piperidide was dissolved in 50 ml. of methanol and brought slowly up to reflux over a 15 minute period. The reaction was allowed to proceed for 5 hrs. at this temperature. Formed as an intermediate in the reaction mixture was 3-(N-carbethoxyacetamido)-4-isocyanato-2,5-dihydro-2-thiophenevaleric acid piperidide. The methanol was then removed, and 2.33 g. (0.0056 mole, 85%) of 3-(N-carbethoxyacetamido)-4-carbomethoxyamino-2,5-dihydro-2-thiophenevaleric acid piperidide was obtained as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)(O[CH2:15][C:16]1([CH3:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=O)=O>CO.[I-].[K+]>[CH3:15][C:16]1([CH2:22][O:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CCCCC2)cc1
Reactant: Cc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(OCC2(C)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a cooled (0° C.), stirred solution of 8.4 g (0.15 mole) of potassium hydroxide in 100 ml of MeOH was added 13.5 g (0.12 mole) of 4-methylphenol over a 15 minute period. The reaction was stirred at room temperature for 0.5 hour and MeOH was evaporated to afford a solid. A solution of this solid, 28.2 g (0.1 mole) of ((1-methyl)cyclohexyl)methyl tosylate and 1.4 g of potassium iodide were heated at 150° C. for 5 hours. The reaction was cooled to room temperature, poured onto ice-water and extracted with EtOAc. The EtOAc layer was washed with 2N aqueous NaOH, brine, dried over MgSO4, filtered and evaporated. The resulting oil was filtered through a plug of silica gel to give 20 g of product as an oil.