Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=[O:18])[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:2][CH2:3][OH:4])[CH:17]=[O:18])[CH3:12]
Reactant: OCCBr
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCCO
Temperature: 120 °C

Procedure:
2.76 ml of 2-bromoethanol and 5.40 g of potassium carbonate were added to a solution of 5 g of 3-ethoxy-4-hydroxybenzaldehyde in 150 ml of DMF. The reaction mixture was heated to 70° C. overnight and subsequently to 120° C. for a further 4 hrs. Then, the mixture was left to cool to room temperature, filtered and concentrated in a high vacuum. The crude product was isolated by extraction and purified by chromatography on silica gel. There were obtained 6.09 g of 3-ethoxy-4-(2-hydroxy-ethoxy)-benzaldehyde as a white solid.
Reaction SMILES: C1C=CC(/C=C/C[O:10][C@@H:11]2[O:16][C@H](CO)[C@@H:14]([OH:19])[C@H:13](O)[C@H:12]2O)=CC=1.[S:22](=[O:26])(=[O:25])([OH:24])O.C1(=O)OC(=O)C=C1.[OH2:34]>S([O-])([O-])=O.[Na+].[Na+]>[S:22]([CH:12]([C:11]([OH:10])=[O:16])[CH:13]([S:22]([OH:26])(=[O:25])=[O:24])[C:14]([OH:19])=[O:34])([OH:24])(=[O:26])=[O:25]
Reactant: O
Reactant: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=S(=O)(O)O
Agent: O=C1C=CC(=O)O1
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)C(C(C(=O)O)S(=O)(=O)O)S(=O)(=O)O
Reaction time: 1 h

Procedure:
745.4 Parts of rosin addition product (b) are esterified with 196 parts of maleic anhydride, while stirring at 50° to 85° C.; after diluting the mixture with water, 264.6 to 277.2 parts of sodium sulfite (as an aqueous solution) are introduced by stirring within 15 to 120 minutes at 40° to 80° C., and stirring is continued for 1 hour, after the mixture has become clearly water-soluble. The amount of water added may be in the range of from 50 to 85% by weight of the final solution. By way of spray-drying, a light yellow powder is obtained which exhibits a low electrolyte content.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:4][CH2:3]1.O1CCCC1.[ClH:47]>O>[ClH:47].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 720 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(4-methyl-1-piperazinylcarbonyl)-1-methyl-pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 1.2 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 800 mg of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration and the filtrate was washed with diethyl ether. The aqueous solution was concentrated by evaporation under reduced pressure, the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep RP-8, size B) and the column was eluted with 3% by volume aqueous methanol. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 326 mg of the title compound as a colorless powder.
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5]([CH3:7])[CH3:6])(C)C.[C:10]1(C)[CH:15]=CC=C[CH:11]=1.O>CO>[NH:4]1[C:5]2[C:6](=[CH:11][CH:10]=[CH:15][CH:7]=2)[CH:9]=[CH:8]1
Reactant: Cc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: c1ccc2[nH]ccc2c1

Procedure:
In Scheme VIII, Step 4, 4-Benzyloxypropiophenone is brominated in acetic acid with bromine. When the reaction is complete the mixture can be quenched with water and the resulting precipitate is washed with dilute acetic acid, water and heptane. The resulting solid is dried to give IV, 4-benzyloxyaniline hydrochloride. In Step 5, a mixture of IV, N,N-diisopropylethylamine and toluene is heated under reflux with removal of water. When the reaction is complete the mixture may be cooled and diluted with methanol. The solids produced can be collected, washed with methanol and dried to give compound indole V. A mixture of compounds V and III can be mixed in Step 6 with sodium tert-butoxide in N,N-dimethylformamide and stirred until the reaction is complete. Then the mixture may be quenched with brine and extracted with toluene. The extracts are concentrated and the residue diluted with methanol. The resulting solids may be collected, dissolved in ethyl acetate, clarified, and diluted with methanol. The solids may be collected from this dilution and dried to give compound VI.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].C(O)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.[C:31](=[S:33])=[S:32]>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][S:33][C:31]([N:2]2[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:32])=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 65 %

Procedure:
In the same manner as described in Example 16, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.08 g), 2N NaOH (5 ml), 50% ethanol (15 ml), carbon disulfide (0.3 ml) and 4-chlorobenzyl chloride (1.13 g) are reacted and treated. The product is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=97:2:1) to give the title compound (1.36 g, 65%), as pale yellow powder.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>CO>[OH:1][CH:3]([CH2:4][CH3:5])[CH2:2][NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC1CCCCC1
Reactant: CCC1CO1
Solvent: CO
Product: CCC(O)CNC1CCCCC1
Yield: 61.3 %

Procedure:
To methanol (200 ml) are added 1,2-epoxybutane (72.2 g) and cyclohexylamine (99.2 g), and the mixture is refluxed for 6 hours. The mixture is concentrated under reduced pressure to remove the solvent to give N-(2-hydroxybutyl)-N-cyclohexylamine (105 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:22][CH3:23])[C:10]([N:11]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([CH3:34])[C:27]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([CH2:18][N:11]([C:10]2[C:9]([CH2:22][CH3:23])=[N:8][N:7]3[C:2]([C:27]4[C:28]([CH3:34])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=4[O:25][CH3:24])=[CH:3][CH:4]=[CH:5][C:6]=23)[CH2:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH2:21][CH2:20]1
Reactant: CCc1nn2c(Br)cccc2c1N(CC1CC1)CC1CCOC1
Reactant: COc1cc(C)c(OB(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCc1nn2c(-c3c(C)cc(OC)cc3OC)cccc2c1N(CC1CC1)CC1CCOC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
After dissolving N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine (150 mg) in 1,2-dimethoxyethane (20 mL) and water (10 mL), 2,4-dimethoxy-6-methylphenylboric acid (155 mg), tetrakis(triphenylphosphine)palladium (0) complex (92 mg) and barium hydroxide octahydrate (250 mg) were added and the mixture was heated and stirred at 80° C. for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (88 mg) was obtained from the n-hexane:ethyl acetate (6:1) fraction as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:10]([OH:13])(=[O:12])[CH3:11]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:3]1[CH2:4][CH:11]([C:10]([OH:13])=[O:12])[CH2:6][CH2:7][C:2]2=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)C1CCc2c([nH]c3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-fluorophenyhydrazine (0.90 g, 7.14 mmol) was dissolved in glacial acetic acid (25 mL) under a nitrogen atmosphere and added dropwise to a refluxing solution of 3-cyclohexanonecarboxylic acid ethyl ester (1.73 g, 10 mmol) dissolved in glacial acetic acid (15 mL). After the addition was complete, the solution was heated under reflux for 1 hr, cooled to room temperature and allowed to stir overnight. The orange solution was evaporated under reduced pressure to give a yellow-brown solid. The solid was suspended in 10% sulfuric acid and heated under reflux for 5 hrs, cooled to room temperature and allowed to stir overnight. The brown solid was collected by filtration and recrystallized from acetic acid and water to give the compound I (1.21 g), mp: >200° C. MS [M−H]− m/z 232.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1.Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[N:28][OH:29])[CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1
Reactant: O=Cc1ccc2ccn(C3CCN(CCc4ccccc4F)CC3)c2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccc2ccn(C3CCN(CCc4ccccc4F)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A mixture of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindole (1.94 g) obtained in Example 348-4), hydroxylamine hydrochloride (0.5 g) and anhydrous sodium acetate (0.55 g) in methanol (60 ml) was stirred at room temperature for 1 hr. Then the reaction mixtures were concentrated and the residue was partitioned between ethyl acetate (150 ml) and a 1 N aqueous solution (30 ml) of sodium hydroxide. The ethyl acetate layer was washed successively with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindole (1.96 g) as an ivory powder (yield: 96.8%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:26].[CH:28]1[CH2:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([CH:29]3[CH2:28][CH:32]([OH:26])[CH:31]=[CH:30]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: C1=CCC=C1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CS(C)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1C=CC(O)C1
Reaction time: 18 h

Procedure:
A mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (600 mg) and tetrakis(triphenylphosphine) palladium (40 ml) and dry dimethyl sulphoxide (30 ml) was stirred under nitrogen in an ice/water bath and then a solution of cyclopentadiene monoepoxide (200 mg) in tetrahydrofuran (10 ml) was added via syringe under nitrogen at 0° C. The mixture was stirred at ambient temperature (with exclusion of light) for 66 hours and then the tetrahydrofuran was removed under reduced pressure and water was added to the residue. The mixture was allowed to stand for 18 hours and then extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/industrial methylated spirit (9:1) as the mobile phase to give 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopent-2-enol, as an oil. The structure was confirmed by 1Hnmr and mass spectra.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Solvent: c1ccncc1
Product: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Reaction time: 17 h

Procedure:
A mixture of 5-nitroindoline (I, 12.012 g) in pyridine (100 ml) and acetic anhydride (50 ml) is stirred for 17 hr under argon. The mixture is then concentrated under reduced pressure to give the title compound, mp 175°-177°; NMR (CDCl3, 300 MHz) 8.28, 8.10, 8.01, 4.23, 3.31 and 2.28 δ; CMR (CDCl3, 75.47 MHz) 23.95, 27.01, 49.11, 115.73, 119.93, 124.27, 132.4, 143.4 and 169.8 δ; IR (CHCl3) 1680, 1600, 1480, 1470, 1390, 1340 and 1320 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.CN1CCOCC1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:33])=[O:34]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To 5.0 g (33 mmol) of the methyl 3-aminobenzoate (11) prepared in Example 1 in 70 mL of methylene chloride containing 4.0 mL (36 mmol) of N-methylmorpholine was added 7.49 g (33 mmol) of 2-naphthalenesulfonyl chloride. After stirring at room temperature overnight, the reaction mixture was quenched with 1N HCl (100 mL). The suspension was dissolved in ca. 250 mL of THF and enough ether was added to induce phase separation. The organic extract was washed with saturated sodium chloride solution (2×). The organic phase was dried (MgSO4), and concentrated to give 11.0 g (97% yield) of the title compound as a pale yellow solid: 1H-NMR (200 MHz; DMSO-d6) δ 8.46 (s, 1H), 8.13 (t, 2H), 7.99 (d, 1H), 7.55-7.75 (m, 5H), 7.43 (dd, 21H), 7.38 (d, 1H), 3.79 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:14][N:15]=2)=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:35][C:36]1[N:37]=[N:38][C:39](Cl)=[CH:40][CH:41]=1.[C:43]([O-])([O-:45])=[O:44].[K+].[K+]>CN(C=O)C.CO>[F:24][C:2]([F:1])([F:23])[C:43]([OH:45])=[O:44].[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[NH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:39]4[N:38]=[N:37][C:36]([NH2:35])=[CH:41][CH:40]=4)=[CH:18][CH:17]=3)=[N:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Cl)nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(-c3nnc(Nc4ccc(OC(F)(F)F)cc4)[nH]3)cc2)nn1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 58.1 %

Procedure:
4-[5-(4-trifluoromethoxy-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (112.0 mg, 0.33 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (132.8 mg, 0.66 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 3-amino-6-chloropyridazine (47.4 mg, 0.366 mmol) was added, followed by anhydrous K2CO3 (46.0 mg, 0.33 mmol). Then the vial was capped and microwaved at 250° C. for 15 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (52.1 mg of brown crystalline solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[N:14]1[CH2:15][CH2:16][CH:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 14.9 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 3,4,5-trichloropyridine (216 mg, 1.16 mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (35 mg), a white solid, in 15% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.CN([C:22]([O:26][N:27]1N=NC2C=CC=N[C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNOC.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:27]([O:26][CH3:22])[CH3:28])=[O:18])=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Nc2ncc(Br)cn2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1ccc(Nc2ncc(Br)cn2)cc1
Reaction time: 0.17 h

Procedure:
2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)acetic acid 22 (5.0 mmol) and HATU (6.0 mmol) are dissolved in dry DMF (10 mL) and stirred for 10 min. Then N,O-dimethylhydroxylamine (7.5 mmol) and diisopropylethylamine (15.0 mmol) are added to the solution. The reaction mixture is stirred for 1 h at rt. After the reaction is complete, the reaction mixture is added dropwise into water (100 mL). The precipitate is filtered and dried to yield 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-N-methoxy-N-methylacetamide 23. 1H NMR (400 MHz, d6-DMSO) δ 9.82 (s, 1H), 8.58 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 3.67 (s, 3H), 3.34 (s, 2H), 3.10 (s, 3H). MS (m/z) (M+1)+: 351.0, 353.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:26])=[CH:14][C:15]([F:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[C:27](Cl)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:27]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:26])=[CH:14][C:15]([F:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH:17]=1)[N:5]=2)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-2,2,2-trifluoroacetamide (2.03 g, 5 mmol) and N,N-dimethylpyridine-4-amine (0.61 g, 5 mmol) in pyridine (10 mL) was added dropwise acetyl chloride (0.78 g, 10 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed with water (50 mL×2), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether, collected by filtration, and dried under reduced pressure to give the title compound (2.16 g, 96%) as white powder crystals.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].CS(O)(=O)=O.COC1C=CC(O)=CC=1>O.O.[Cu](Cl)Cl>[C:9]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CCCCCCC
Reactant: C=CC(=O)O
Agent: Cl[Cu]Cl
Agent: COc1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: O
Product: C=CC(=O)OCCCCCCCC
Temperature: 105 °C

Procedure:
A mixture of 15.0 g (134 mmoles, 3 eq) of 1-octene, 3.21 g (44.6 mmoles, 1 eq) of acrylic acid, 0.257 g (2.67 mmoles, 0.06 eq) of methanesulfonic acid, 0.0277 g of MEHQ and 0.0034 g of copper(II) chloride dihydrate was heated at 105° C. for 22 hours to give 2.5% conversion to octyl acrylate based on acrylic acid consumed.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cccnc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(OC2CNC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 64.5 %

Procedure:
To 160 mg (0.64 mmol) of 3-(1-t-butoxycarbonyl-3-azetidinyloxy)-pyridine was added 6 mL of solution containing 3 mL of TFA and 3 mL of CH2Cl2 at ice-bath temperature. The reaction solution was slowly warmed to room temperature and allowed to stir 50 min at room temperature. After 50 min, solvents were removed in vacuo and the crude product was purified by flash chromatography (9:1:0.05, CHCl3:MeOH:conc. NH4OH) to obtain 62 mg (67%) of a white solid: 1H NMR (300 MHz, CD3OD) δ8.23 (2H, br s), 7.38 (2H, br d), 5.24 (2H, br s), 4.58 (2H, br d), 4.20 (2H, br d, J=9.8 Hz); Mass spectrum (ESI) m/z 151.7 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=O)=[CH:12][C:4]1=2)[CH3:2].[NH2:17][OH:18].Cl.CC([O-])=O.[Na+].CC(=O)OCC>C1COCC1.O>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=[N:17][OH:18])=[CH:12][C:4]1=2)[CH3:2]
Reactant: CCC1(CC)OB(O)c2ccc(C=O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1(CC)OB(O)c2ccc(C=NO)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a mixture of 3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carb-aldehyde (1.1 g, 5.04 mmol) and NH2OH.HCl (420 mg, 6.05 mmol) in THF (20 ml) and H2O (5 ml) at rt was added NaOAc (578 mg, 7.06 mmol). The mixture was stirred at rt for 16 h, diluted with H2O and extracted with EA (20 ml×2). The combined organic layers were washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 1:1) to give the product (600 mg, yield 51%) as white solid: MS: m/z=234 [M+1]+.