Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=O>C(O)(=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][N:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:14]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: c1cncc(-c2ccnc3ncnn23)c1

Procedure:
A mixture of 2.54 g of 3-amino-1,2,4-triazole, 5.29 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one and 25 ml of glacial acetic acid was heated under reflux for 6 hours. The solvent was removed in vacuo and the solid residue was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated and dried over powdered anhydrous sodium sulfate. This solution was passed through a short column of a hydrous magnesium silicate and the effluent was refluxed on a steam bath with the gradual addition of hexane until crystallization was noted. On cooling the desired compound was separated and collection by filtration gave 1.95 g. of colorless crystals mp. 209°-210° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([N:24]([CH3:35])S(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:35][NH:24][C:20]1[CH:19]=[C:18]([C:17]2[N:12]3[N:11]=[CH:10][C:9]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:8])=[C:13]3[N:14]=[CH:15][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2cccc(-c3ccnc4c(C(=O)c5ccccc5)cnn34)c2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Temperature: 0 °C

Procedure:
Five grams of N-[3-(3-benzoylpyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N,4-dimethylbenzenesulfonamide was added to a mixture of 50 ml of trifluoroacetic acid and 10 ml of concentrated sulfuric acid. This mixture was heated at the boiling point under reflux for 3 hours. It was then poured onto 300 g of ice containing 150 ml of 10N sodium hydroxide solution. The yellow precipitate that formed was collected, washed with water, and air dried. It was dissolved in 100 ml of methylene chloride, the solution dried over magnesium sulfate, and the methylene chloride was then removed in vacuo. A bright yellow residue of 3.4 g of the desired compound was left, mp 134°-136° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].[S:19](Cl)(Cl)=O.C(N(CC)CC)C>C1COCC1>[CH:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:16])[C:15]3[C:2]4=[N:1][S:19][N:18]=[C:3]4[CH:4]=[CH:5][C:6]=3[C:7](=[O:17])[C:8]=2[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)c2c1ccc1nsnc21

Procedure:
The compound 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in THF (30 mL), and thionyl chloride (0.15 g, 20 mmol) is then dripped thereinto; triethylamine (TEA, 3 mL) is lastly added thereinto for catalyzation. After being mixed at room temperature for one hour, the mixture is transferred into a container with 200 mL of icy water for crystallization. After filtration, a precipitate is collected and re-crystallized with hot alcohol, so as to obtain the yellow compound NSC745885 with a melting point of 227-228° C., and the production rate is about 74%.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=1.[OH-].[Na+].Cl>C(O)C>[CH:3]1[C:4]2=[C:13]3[CH:8]([CH2:7][CH2:6][CH2:5]2)[CH2:9][CH2:10][CH2:11][C:12]3=[CH:1][C:2]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Nc2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A suspension of ethyl 4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.154 g) in ethanol (12 ml) was added with 20% aqueous sodium hydroxide (3 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.125 g, yield: 89%) as pale brown needles (melting point: 204-205° C.).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:15][C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(OCCF)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCF)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 102.9 %

Procedure:
Using a procedure similar to that of Example 6-D, methyl 4-(2-fluoroethoxy)-2-hydroxybenzoate (3.6 g, 17.8 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (3.58 g, 17.8 mmol), and triphenylphosphine (5.60 g, 21.4 mmol) in THF (75 mL) is treated with diethyl azodicarboxylate (3.60 g, 17.8 mmol) in THF (15 mL) to afford the crude product (7.28 g) which is used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.S([Cl:21])(C)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:21][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[N:14][CH:13]=1
Reactant: Cc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 37.5 %

Procedure:
Triethylamine (96 ml, 0.69 mol) was added to a solution of (6-methyl-3-pyridyl)methanol (28.4 g, 0.23 mol) in methylene chloride (230 ml) while cooling on ice. Mesyl chloride (26.8 ml, 0.35 mol) was then slowly added dropwise over a period of 20 minutes at the same temperature and the mixture was stirred for 10 hours while gradually raising the temperature to room temperature. After confirming completion of the reaction by thin layer chromatography, the mixture was diluted with ethyl acetate and poured into saturated aqueous NaHCO3. After separating the aqueous layer, extraction was performed with ethyl acetate, and the collected organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield the title compound (12.2 g). This was used without further purification for the following reaction.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[O:17][CH3:18]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[O:17][CH3:18]
Reactant: COc1ccc([N+](=O)[O-])cc1O[C@H]1CCCN1C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1O[C@H]1CCCN1C
Yield: 99.5 %

Procedure:
A solution of (S)-1-methyl-2-(2-methoxy-5-nitrophenoxy)pyrrolidine (D43) (6.79 g; 0.0255 mol) in ethanol (200 ml) was hydrogenated in the presence of 5% Pd/C catalyst (0.5 g added as an aqueous slurry) at atmospheric pressure and RT for 16 hours. The catalyst was removed by filtration through kieselguhr and the filtrate evaporated in vacuo to yield the title compound (D44) (5.64 g; 93%) MH+=237.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])C(=O)C2=CC=CC=C12.O.NN>C(O)C.C(Cl)(Cl)Cl>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cccc(OCCCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(OCCCCN)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 115.3 %

Procedure:
Methyl 3-(4-phthalimidobutoxy)benzoate (6.60 g, 18.68 mmol) was dissolved in 50 mL of ethanol and reacted with hydrazine monohydrate (1.87 g, 37.36 mmol). Following stirring at 80° C. for 1 hour, the resulting mixture was diluted with chloroform, then washed with a saturated sodium bicarbonate solution, water, and brine, and dried with sodium sulfate. The resulting reaction solution was concentrated under reduced pressure to give a white crystal (4.81 g). The white crystal was directly used in subsequent reaction.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]=[N+:10]=[N-:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:12]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:16][N:15]=1)#[CH:13].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.CCOC(C)=O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:28])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)C(=O)OCn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a suspension of azidomethyl pivalate (0.075 g, 0.477 mmol), 4-(2-ethynylpyridin-4-yloxy)-2-fluorobenzenamine from Example A21 (0.109 g, 0.477 mmol) in t-butanol (0.6 mL) and water (0.6 mL) was added sodium ascorbate (0.021 g, 0.095 mmol). Copper(II)sulfate in water (0.048 ml, 0.048 mmol) was added to the above suspension and the dark red mixture was stirred for 3 h at RT. It was diluted with water (30 mL) and EtOAc (20 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to afford (4-(4-(4-amino-3-fluorophenoxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate as a red solid. (0.165 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.46 (brs, 1H), 7.60 (s, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.94 (d, J=3.6 Hz, 1H), 6.83-6.81 (m, 2H), 6.42 (s, 2H), 4.78 (s, 2H), 1.17 (s, 9H); MS (ESI) m/z: 386.1 (M+H+).
Reaction SMILES: CO.Cl[C:4]1[CH:31]=[CH:30][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=3[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:14])=[O:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=1>[Pd].O1CCOCC1>[CH3:11][C:10]1[C:6]2[CH:5]=[CH:4][CH:31]=[CH:30][C:7]=2[S:8][C:9]=1[S:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:13])=[O:14]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccccc3c2C)c(S(C)(=O)=O)c1
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
Into a mixed solvent of 30 mL of methanol and 30 mL of dioxane was dissolved 640 mg of 5% palladium/carbon, followed by 10 minutes of stirring under a hydrogen atmosphere. Under an argon atmosphere, 330 mg of Compound 1 was added, followed by 3 days of stirring under a hydrogen atmosphere at 5 atm. After confirmation of disappearance of the starting material, the reaction mixture was filtered and purified by silica gel column chromatography (ethyl acetate/hexane=2/1) to obtain 70 mg of the title compound as colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:4]([CH3:15])[CH:3]=1.C([Li])CCC.[C:21]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>O1CCCC1.CCCCCC>[OH:27][C:21]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=3)=[C:4]([CH3:15])[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(Br)ccc1C1=NC(C)(C)CO1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C2(O)CCCCC2)ccc1C1=NC(C)(C)CO1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromo-2-methylphenyl)-4,4-dimethyl-2-oxazoline (5 g) in dry tetrahydrofuran (40 ml) is added dropwise a 1.6M solution of n-butyl lithium in n-hexane (14.0 ml) at -70° C. The mixture is stirred at the same temperature for 30 minutes, and thereto is added dropwise cyclohexanone (2.1 ml), and the mixture is stirred for one hour. To the mixture is added water, and the mixture is evaporated to remove the tetrahydrofuran, and then extracted with diethyl ether. The diethyl ether layer is dried over anhydrous magnesium sulfate, evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:1→60:1), recrystallized from acetone/n-hexane to give 2-[4-(1-hydroxy-1-cyclohexyl)-2-methylphenyl]-4,4-dimethyl-2-oxazoline (4.29 g) as white powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CC1
Reactant: CS(N)(=O)=O
Product: Cc1ccccc1C1CCN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CC1
Yield: 28.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-methylphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.19 mmol) obtained in step 2 and methanesulfonamide (0.090 g, 0.950 mmol), the title compound (0.03 g, 30%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-])=O.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C(OCC)C.C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Dissolve 3-nitro-2-carbethoxy-4,6-dichloroindole (38.1 g) in ethanol (1L) and add tin (II) chloride dihydrate (163 g). Warm to between 65° and 75° C. for 4 to 5 hours. Cool to room temperature and pour intoa mixture of ethyl acetate (3L) and water (2L). Add solid potassium carbonate and stir occasionally until the carbon dioxide evolution ceases.Filter through Celite and separate the organic phase of the filtrate. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compoundas an off-yellow solid (33.5 g, 97.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[NH2:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[C:21]([F:27])[C:20]=1[SH:28]>>[F:25][C:24]1[C:19]2[N:18]=[C:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])=[CH:7][CH:8]=3)[S:28][C:20]=2[C:21]([F:27])=[CH:22][C:23]=1[F:26]
Reactant: CCOC(=O)Cc1ccc(CC(=O)O)cc1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Product: CCOC(=O)Cc1ccc(Cc2nc3c(F)c(F)cc(F)c3s2)cc1
Yield: 35.2 %

Procedure:
The procedure of Example 16-i) was repeated using 1,4-phenylene diacetic acid monoethyl ester (510 mg, 2.1 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (2.0 g, 11.7 mmol) to obtain ethyl 4-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]phenylacetate (270 mg, 35%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(N(C)S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
To a suspension of N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (0.50 g, 1.7 mmol) and potassium carbonate (0.28 g, 2.0 mmol) in acetone (10 mL) was added methyl iodide (0.12 mL, 2.0 mmol). The mixture was stirred at room temperature for 18 hours under an atmosphere of nitrogen then diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a yellow solid (0.50 g, 95%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 3.34 (s, 3H), 2.82 (s, 3H), 1.34 (s, 12H). MS=312 (MH)+. 62b) N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (300.0 mg, 1.408 mmol) and N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (500.0 mg, 1.607 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.33 g, 73%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.55 (d, J=5.8 Hz, 1H), 8.12 (d, J=7.5 Hz, 2H), 7.72 (d, J=7.1, 1H), 7.52 (d, J=7.2 Hz, 2H), 6.98 (t, J=6.2 Hz, 1H), 6.11 (s, 2H), 3.29 (s, 3H), 2.98 (s, 3H). MS=318 (MH)+. 62c) N-Methyl-N-(4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.027 g, 23%). MP=205-206° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.57-7.46 (m, 5H), 6.99-6.91 (m, 3H), 6.66 (s, 1H), 3.38 (s, 3H), 3.19-3.14 (m, 4H), 2.90 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[N:4][OH:5].[CH2:6]=[C:7]([CH3:9])[CH3:8].C(=O)([O-])O.[Na+]>C(OCC)C>[C:7]([O:5][N:4]=[CH:3][CH2:2][Cl:1])([CH3:9])([CH3:8])[CH3:6]
Reactant: ON=CCCl
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)ON=CCCl

Procedure:
Then, 0.47 g of chloroacetoaldehyde oxime, 0.1 ml of concentrated sulflic acid, and 10 ml of diethyl ether are placed in a reaction vessel, into which isobutene gas is blown with stirring under ice cooling, and the stirring is further continued at room temperature. After completion of the reaction, the reaction mixture is slowly poured into saturated aqueous sodium hydrogencarbonate solution, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with 10% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate, and concentrated, which affords chloroacetoaldehyde O-tert-butyloxime.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 8 from (Z)-3-[1-(4-ethoxycarbonyl-phenylamino]-1-phenyl-methylidene]-2-indolinone and sodium hydroxide solution in ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:4]2[N:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:27][CH:24]([CH3:26])[CH3:25])[N:5]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:4]2[N:3]=1
Reactant: Clc1nc2nc(-c3ccccn3)nn2c(Cl)c1-c1ccccc1
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)Nc1c(-c2ccccc2)c(Cl)nc2nc(-c3ccccn3)nn12
Temperature: 100 °C
Yield: 80.9 %

Procedure:
1 g (2.9 mmol) 5,7-dichloro-6-phenyl-2-pyridine-2-yl-[1,2,4]triazolo[1,5-a]pyrimidine described in the former example are given in 10 mL DMF (no complete dissolution). After addition of 0.62 mL (7.3 mmol) isopropylamine the reaction mixture is heated in a microwave oven at 100° C. for 20 minutes. From the clear brown solution the DMF is evaporated, the residue is diluted with brine and water and extracted three times with dichloromethane. The combined organic extracts are dried over Na2SO4 and the solvent is evaporated. The reaction is repeated twice with 1 g starting material resp. 200 mg. The crude residues after the work-up are combined and purified jointly by chromatography (silicagel, eluents: dichloromethane, methanol) yielding 856.1 mg (36.5%) of the desired product.