Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25][C:26](O)=[O:27])=[CH:23][CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:20]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:26](=[O:27])[CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[3-({2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[CH:11][CH:12]=[N:13][C:14](I)=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[CH:40]=[O:41])[CH2:30][O:31][CH3:32])(=[O:28])=[O:27])=[CH:22][C:21]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[CH:40]([OH:41])[C:10]2[CH:11]=[CH:12][N:13]=[C:14]3[N:6]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:7]=[CH:8][C:9]=23)[CH2:30][O:31][CH3:32])(=[O:27])=[O:28])=[CH:22][C:21]=1[C:42]([F:44])([F:45])[F:43]
Reactant: COCN(c1cc(Cl)ccc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(I)nccc21
Agent: [Cl-]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)ccc1C(O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a solution of 1-(tert-butyl-dimethyl-silanyl)-4-iodo-1H-pyrrolo[2,3-d]pyridine (97.4 mg, 0.27 mmol) in THF (2 mL) under nitrogen atmosphere at 0° C. was added drop wise isopropylmagnisum chloride (2 M solution in THF, 0.27 mL, 0.54 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 4-chloro-N-(5-chloro-2-formyl-phenyl)-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (120 mg, 0.27 mmol) in THF (2 mL) at 0° C. The mixture was stirred at room temperature for overnight, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 30% EtOAc-hexanes) to obtain 4-chloro-N-{5-chloro-2-[hydroxy-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-phenyl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (88 mg) in 48% yield. ESMS m/z (relative intensity): 674 (M+H)+ (100).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]([Cl:20])([Cl:19])[CH:8]([NH2:18])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>CC(C)=O>[Cl:6][C:7]([Cl:19])([Cl:20])[CH:8]([NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:18][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(CCl)NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (79g) in acetone (100 ml) was added dropwise to a solution of 1,1,1-trichloro-2-amino-2-(benzamido)ethane (170g) in acetone (500 ml) containing triethylamine (64.2g). The mixture was stirred for 2 hours. The reaction mixture was poured into water (750 ml). The solid was collected, washed with water and dried (195g). Recrystallisation from nitromethane (or dioxane) gave pure 1,1,1-trichloro-2-benzamido-2-(chloroacetamido)ethane (156g, m.p. 210°-213°)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=2[CH2:15]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=2[CH2:15][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[OH:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccccc1
Reactant: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(CO)n(C)c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(Cc2ccccc2O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a solution of 100 mg of 4-(3,5-dichlorophenylthio)-5-(hydroxymethyl)-3-isopropyl-1-methyl-1,3-dihydro-2-imidazolone, 30 mg of phenol and 100 mg of triphenylphosphine in 5 mL of tetrahydrofuran at 0° C. was added 70 μL of diisopropylazodicarboxylate in 5 mL of tetrahydrofuran over 20 min. The reaction was stirred overnight warming to room temperature. The mixture was then diluted with ethyl acetate and washed with 0.5N hydrochloric acid solution then 0.5N sodium hydroxide solution, dried, concentrated and purified by flash chromatography eluting with 3:1 hexane: ethyl acetate to give 16 mg of a colourless oil. Mass spectrum (ES) m/z 423 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=O.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:20](/[CH:19]=[CH:1]/[C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cccc(-n2cccc2C=O)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)c1cccc(-n2cccc2/C=C/C(=O)O)c1
Reaction time: 3 h

Procedure:
The mixture of methyl 3-(2-formylpyrrol-1-yl)benzoate (3.0 g), malonic acid (2.7 g), pyridine (30 ml) and piperidine (0.3 ml) was stirred for 3 hours at 90°-100° C. The reaction mixture was poured into water, and the mixture was adjusted to pH 1 with 6N-hydrochloric acid. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give methyl 3-[2-((E)-2-carboxyethenyl)pyrrol-1-yl)benzoate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].Cl[CH2:13][C:14](=[N:18][OH:19])[C:15](=[O:17])[CH3:16]>>[CH2:7]([O:9][CH:10]1[O:19][N:18]=[C:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:11]1)[CH3:8]
Reactant: C=COCC
Reactant: CC(=O)C(CCl)=NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC1CCC(C(C)=O)=NO1
Reaction time: 21 h
Yield: 97.9 %

Procedure:
A 1000 ml three-neck flask equipped with a mechanical stirrer, a reflux condenser, and a nitrogen inlet adapter was heat dried and charged with nitrogen. When the flask was at room temperature, it was loaded in order: 39.5 g (0.37 mole) of anhydrous sodium carbonate; (with stirring) 132 g (1.83 mole) of ethyl vinyl ether; and (portionwise over a period of 7 minutes) 10.0 g (0.074 mole) of 1-chlorobutan-2,3-dione-2-oxime [Oglobin et al., J. Gen. Chem. U.S.S.R. 34, 2710 (1964)]. Stirring was continued for 21 hours. The reaction mixture was filtered, the solid cake rinsed with diethyl ether, and the combined filtrate and rinses were evaporated under reduced pressure (bath temperature maintained at <40° C.). There was obtained 12.4 g (98%) of the title compound as an oil; nmr spectroscopy indicated it to be essentially 100% pure. This procedure is essentially that described by T. L. Gilchrist, G. M. Iskander and A. K. Yagoub (J. Chem. Soc., Chem. Commun. 1981, 696-698).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.OB(O)[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:16][CH2:15]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([S:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:16][CH2:15]3)=[N:3][CH:4]=1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(B(O)O)ccc32)cc1
Reactant: COc1ccc(I)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3c(c2)CCN3S(=O)(=O)c2ccc(C#N)cc2)nc1
Temperature: 90 °C
Yield: 51.5 %

Procedure:
394 mg 2-Iodo-5-methoxypyridine, 500 mg 4-(5-Dihydroxyboranyl-2,3-dihydro-indole-1-sulfonyl)-benzonitrile and 1.49 g cesium carbonate were dissolved in a mixture of 5 ml water and 17 ml dimethylformamide. The reaction mixture was degassed with argon and then 88 mg tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 90° C. for two hours. The cooled reaction mixture was diluted with 100 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 307 mg 4-[5-(5-Methoxy-pyridin-2-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.CO.[ClH:31].C[CH2:33][O:34]CC>C(Cl)(Cl)Cl>[ClH:31].[C:4]1(=[O:23])[N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[CH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:34][CH3:33])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: CCOCC
Reactant: N#Cc1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=N)c1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.7 g of 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzonitrile in 100 ml of chloroform was added at room temperature slowly dropwise 30 ml of anhydrous methanol saturated with anhydrous hydrogen chloride. The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of methyl 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzimidate hydrochloride; m.p. 230°-234° C. (decomp.).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])C.[OH-].[Na+]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][C:39]3[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][C:32]([OH:33])=[O:31])=[CH:37][CH:38]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(Nc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and [4(2-ethoxycarbonylethyl)phenyl]boronic acid using the procedure of example 110 followed by hydrolysis with NaOH; MS (ESI) m/z 527([M+H]+).
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])C1C=CC=CC=1.CC(OC(NCC(O)=O)=O)(C)C>C(Cl)Cl>[NH2:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](CCCCN)C(=O)O
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, three fold molar excess of resin capacity of benzyl-Boc-L-lysine [Lys (Z), Peninsula, supra.] dissolved in methylene chloride is added to the residue of step (B) above. The resulting mixture is shaken and after about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide dissolved in 10-15 ml. of methylene chloride is added with stirring. The resulting mixture is shaken at room temperature for 4.5 to 5 hours. At the end of this period, the reaction mixture is filtered and the residue washed with methylene chloride, ethanol and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:29](=[O:31])[CH3:30])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:33][C:34]1[C:39]([CH2:40][CH2:41][CH3:42])=[C:38]([OH:43])[CH:37]=[CH:36][C:35]=1[C:44](=[O:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:29](=[O:31])[CH3:30])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:43][C:38]3[CH:37]=[CH:36][C:35]([C:44](=[O:46])[CH3:45])=[C:34]([OH:33])[C:39]=3[CH2:40][CH2:41][CH3:42])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(OCCOCCOCCOCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 81.9 %

Procedure:
A mixture of 3 g of [[8-acetyl-7-[2-[2-[2-[2-bromoethoxy]ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.36 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.2 g of anhydrous potassium carbonate in 60 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography (35% ethyl acetate-toluene) to yield 3 g (82%) of [[8-acetyl-7-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(O)(=O)C>O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g) and acetic acid (50 g) was heated at 90° to 95° C. for 7 hours. The reaction mixture was cooled to room temperature, and water (75 g) was added thereto. The precipitated crystals were collected by filtration to give the compound (I) (15.7 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:15]2[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[CH:19][CH:20]=2)[CH:8]=1)(=O)=O.[NH:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:38]2[CH:39]=[N:35][NH:36][CH:37]=2)=[CH:8][C:9]=1[C:15]1[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]2[CH2:23][C:24]([CH3:30])([CH3:31])[NH:25][C:26]([CH3:29])([CH3:28])[CH2:27]2)=[CH:19][CH:20]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cn[nH]c2)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C
Yield: 80.8 %

Procedure:
To a microwave vial was added 4-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (100 mg, 0.20 mmol), 1H-pyrazol-4-ylboronic acid (33.4 mg, 0.30 mmol), potassium phosphate (127 mg, 0.60 mmol), Pd2(dba)3 (18.22 mg, 0.02 mmol), and SPhos (16.4 mg, 0.04 mmol), followed by addition of 1,4-dioxane (1.6 mL)/H2O (0.4 mL). The vial was purged with N2 for 5 minutes and the reaction mixture was heated at 100° C. in the microwave for 1 hour. The reaction mixture was concentrated in vacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueous solution and loaded on an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 6-(2-methoxy-5-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (68 mg) MS [M+H+]=421.3.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9]O.[Sn]=O>[O-2].[Fe+2].[O-2].[Cr+3].[O-2].[O-2].[Cr+3].[O-2].[Mn+2].O>[C:6]1([OH:7])[C:5]([CH3:9])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: CO
Agent: [Cr+3]
Agent: [Fe+2]
Agent: [Mn+2]
Solvent: O
Product: Cc1cccc(C)c1O

Procedure:
o-cresol, methanol and water in a molar ratio of 1:2,5:2,5 were reacted as described in Example 1. The catalyst contained iron oxide, tin oxide, chromium oxide and manganese oxide in a molar ratio of 100:2:1:1. After working up, 2,6-xylenol was obtained with a selectivity of 98,7%.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[OH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.O>C(Cl)Cl>[S:1]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCc1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)OCCc1ccccn1
Yield: 12 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride solution prepared in (a) was reacted as in Example 12 with 16.7 g (0.136 mole) of 2-(β-hydroxyethyl)pyridine using 54.9 g (0.544 mole) of triethylamine in 100 ml of methylene chloride. Water, 150 ml, was added to the reaction mixture with agitation and the layers were separated. The organic layer was discarded, pH of the aqueous layer was adjusted to 8 with sodium carbonate. The mixture was extracted with three 200 ml portions of methylene chloride. The organic extracts were washed twice with 200 ml portions of water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 7.1 g of a brown, viscous oil which solidified on standing. The solid was recrystallized from methylene chloride-petroleum ether (bp range 30°-60° C.) to give 3.2 g (12%) of title compound as white needles, mp 89°-91° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:14][C:8]=2[C:7]=1[OH:19])=[O:5])C.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C[O-].[Na+].CO>[C:15]([C:13]1[S:14][C:8]2[C:7]([OH:19])=[C:6]([C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5])[N:11]=[CH:10][C:9]=2[N:12]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1ncc2nc(C(C)(C)C)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1nc2cnc(C(=O)NCC(=O)O)c(O)c2s1
Temperature: 120 °C
Yield: 8.7 %

Procedure:
A suspension of 2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (103 mg, 0.37 mmol) and glycine (247 mg, 3.3 mmol) in 5.9 mL of 0.5 N NaOMe in methanol was heated to 120° C. for 15 min with microwave irradiation using a CEM Discovery microwave reactor. The resultant mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate and extracted three times with saturated aqueous sodium bicarbonate solution. The combined aqueous fractions were acidified with conc. HCl and extracted twice with ethyl acetate. The organic fractions were dried over anhydrous sodium sulfate and concentrated to a residue. The crude product was purified by reverse phase chromatography on a C-18 column, eluting the desired product with a gradient of 5-80% acetonitrile in water+0.1% formic acid. The lyophilized material fractions provided 10 mg of white solid. MS (ESI−): m/z 308.1 (M−1).
Reaction SMILES: [H-].[Na+].O1C[CH2:6][CH2:5][CH2:4]1.[C:8]1([CH2:16][OH:17])[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.C(Br)C#C>O.CN(C)C=O>[CH2:6]([O:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:16][OH:17])=[CH:9][CH:10]=1)[C:5]#[CH:4]
Reactant: C1CCOC1
Reactant: OCc1ccc(CO)cc1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a mixture of sodium hydride (400 mg, 8.4 mmol, 50% in oil) and tetrahydrofuran (30 mL) was added 1,4-benzenedimethanol (2.3 g, 17 mmol) at 0° C., and then N,N-dimethylformamide (30 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes, after which propargyl bromide (1.0 g, 8.4 mmol) was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 1 hour, after which water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed and saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:2) to obtain the title compound (860 mg, 58%).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:35][O:36][CH2:37][CH2:38]Br>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:38][CH2:37][O:36][CH3:35])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and 2-bromoethyl methyl ether in N,N-dimethylformamide, to give the desired product as a white foam (69%).