Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=[O:2].[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]>O1CCOCC1.O>[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18](=[O:2])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Agent: CCOC(=O)Cc1csc(=NC(=O)OC(C)(C)CC)[nH]1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1

Procedure:
To a solution of selenium dioxide (0.11 g.) in a mixture of dioxane (2.5 ml.) and water (0.1 ml.) was added a mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.3 g.) and dioxane (2.5 ml.) at 110° C. with stirring. The mixture was stirred for 30 minutes at the same temperature, and selenium dioxide (0.055 g.) was further added thereto and then the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction liquid is separated by decantation, and the residue was washed with a small amount of dioxane. The reaction liquid and washing are combined together, and then the solvents were distilled off. The residue was dissolved in ethyl acetate. The solution was washed with water and dried and then the solvent was distilled off to give brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, (0.22 g.).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)o1
Yield: 67.6 %

Procedure:
In the same manner as in Example 259 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (84 mg, 0.59 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.71 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (140 mg, 67%) was obtained as a white solid. melting point 202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([N:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:31]([N:24]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:4]1[C:5]([CH3:23])=[C:6]([CH:22]=[C:2]([C:41]2[CH:46]=[N:45][C:44]([N:47]3[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]3)=[CH:43][CH:42]=2)[CH:3]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:32]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.5 g, 0.99 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.43 g, 1.48 mmol), and tetrakis (0.114 g, 0.09 mmol) in dioxane (7 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.377 g, 3.5 mmol, 2 mL) was added and again degassed for 10 min. Reaction mixture was heated at 100° C. for 16 h. On completion, it was concentrated to obtain crude material which was column purified to afford the title compound (0.35 g, 60.13%).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH:22]1([N:28]=[C:29]=[N:30]C2CCCCC2)[CH2:27][CH2:26][CH2:25]C[CH2:23]1.NC1C=CC=C(C)N=1>ClCCl>[CH3:23][C:22]1[N:28]=[C:29]([NH:30][C:14](=[O:16])[CH:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:21][CH:20]=3)=[CH:19][CH:18]=2)[CH3:17])[CH:25]=[CH:26][CH:27]=1
Reactant: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1cccc(N)n1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C(C)Oc2ccc(Oc3ccc(C#N)cc3)cc2)n1
Temperature: 0 °C
Yield: 58.3 %

Procedure:
To 100 ml of dichloromethane solution containing 1.99 g of 2-[4-(4-cyanophenoxy)-phenoxy]-propionic acid, which was cooled with ice water, was added slowly 1,46 g of dicyclohexylcarbodiimide with stirring. After this mixture was stirred for 15 minutes, 0.76 g of 2-amino-6-methylpyridine was added thereinto with stirring. A temperature of reacting mixture was returned to room temperature with stirring. A precipitated solid was removed through filtration, and then the obtained solution was poured into 200 ml of chilled water. An organic layer was separated therefrom, and it was washed with dilute hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride in this order, from which the solvent was distilled away after drying. The residue was purified through a column-chromatography [silica gel, developed with benzene/ethyl acetate=10/1(V/V)] to give 1.53 g of the title compound having melting point of 109°-111° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>O1CCCC1>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)=[O:20])=[CH:14][CH:13]=1
Reactant: Cc1nc(C(O)CN)cs1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C(O)CNC(=O)Cc2ccc(O)cc2)cs1
Reaction time: 8 h

Procedure:
3.16 g (20 mmol) of 2-Hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine are dissolved in 80 ml of absolute tetrahydrofuran and, successively, 3.84 g (20 mmol) of 4-hydroxy-phenylacetic acid, 6.3 g (24 mmol) of triphenylphosphine, 5.6 ml (40 mmol) of triethylamine and 2 ml (20 mmol) of carbon tetrachloride are added. After stirring overnight, the mixture is concentrated, the residue is taken up in 2N hydrochloric acid and the solution is extracted three times with methylene chloride. The aqueous phase is then adjusted to pH 7 with 2N sodium hydroxide solution and evaporated to dryness. The residue from evaporation is extracted by boiling several times with a mixture of chloroform/methanol (1:1). The extracts are concentrated, and the residue is purified on a silica gel column using ethyl acetate/methanol =50:1 as eluant.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](C2C=CC(N)=CC=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 89.7 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 35, step (b) using 4-nitrophenylboronic acid (167 mg, 1.00 mmol) and 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in Example 13, step (a), 295 mg, 1.00 mmol). Silica gel chromatography (10% EtOAc in hexanes) afforded the title compound (273 mg, 90%) as an oil. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 6.23 (m, 1H), 4.12 (m, 2H), 3.66 (m, 2H), 2.54 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)=[CH:8][CH:7]=1.[OH-].[K+].C(O)(=O)C>CO>[O:21]1[CH2:2][CH:3]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)=[CH:8][CH:7]=1
Reactant: OC(CCl)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[p-(3-chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole (1.92 g.) in methanol (100 ml.) is added crushed potassium hydroxide (1.5 g.). The mixture is stirred 3 hours at room temperature, neutralized with acetic acid and concentrated under reduced pressure (20 mm. Hg.) over steam. The residue is triturated with water (25 ml.), filtered and recrystallized by dissolving in benzene and adding hexane until turbid. A yield of 1.2 g. of 2-[4-(2,3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 152°-153.5° C.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1.ClCCl>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:34])([F:35])[F:33])=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)=[O:36]
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)NCCCCc1cccnc1
Yield: 68.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis[2-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester (1.45 g) and 3-pyridinebutanamine (0.44 g) in tetrahydrofuran (10 mL) was stirred for 1 hour at 25° C. and was worked up in the usual fashion. The crude product was passed through a column of silica gel (12 g) made up in dichloromethane and the amide was eluted with ethyl acetate. The material was crystallized from ethyl acetate-hexane to give 1.01 g of (E)-5,5-bis[2-(trifluoromethyl)phenyl]-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 110°-112° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[CH:17]=[N:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:28][CH3:29]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:28]([N:14]1[C:13](=[O:22])[N:12]2[C:20]3[N:19]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=4)=[CH:10][CH2:11]2)[N:18]=[CH:17][C:16]=3[C:15]1=[O:21])[CH3:29]
Reactant: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCn1c(=O)c2cnn3c2n(c1=O)CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5.0 g of 8-(3-(trifluoromethyl)phenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylene-3,5(4H)-dione (prepared as described in Example 14) in 50 ml of dry N,N-dimethylformamide, under nitrogen, is added 800 mg of 60 percent sodium hydride (dispersion in mineral oil). The mixture is stirred at room temperature for 2 hours, then 10 ml of iodoethane is added and stirring is continued for 48 hours. The reaction mixture is evaporated to dryness, then treated with water, and the gummy solid which is isolated is dissolved in chloroform and the extract dried over anhydrous sodium sulfate. Evaporation gives an oil which is triturated with diethyl ether-hexane to provide a yellow solid which is collected by filtration to give 2.0 g of the desired product as a white solid. The product is recrystallized from isopropyl alcohol, mp 161-163° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC.O.C(Cl)(Cl)Cl.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>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a solution of 4,6-dichloro-5-methylpyrimidine (1 g, 6.13 mmol) in dimethoxyethane (28 mL) and water (14 mL) was added sodium carbonate (1.69 g, 16.0 mmol), 4-trifluoromethylphenylboronic acid (1.165 g, 6.13 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.14 g). The resulting mixture was heated at reflux under nitrogen for 18 h, the reaction mixture was allowed to cool to room temperature and diluted with water (100 mL) before extraction into CHCl3 (2×100 mL). The organic solution separated by hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting with 19:1 cyclohexane:EtOAc afforded the title compound as a white solid (1.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.[CH3:28]C(C)=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:26]([S:27][CH3:28])=[N:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)=O
Product: COc1ccc(N=C(SC)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-Benzyloxycarbonylpiperazine (6.35 g) was dissolved in acetone (40 mL) and 4-methoxyphenyl isothiocyanate (5.19 g) were added under ice-cooling. The mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (80 mL). Methyl iodide (2.7 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 17 hr. The reaction solution was added to a saturated a aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The extract solution washed with saturated brine, dried and concentrated under reduced pressure to give 1-benzyloxycarbonyl-4-[(methylthio)(4-methoxyphenyl)iminomethyl]piperazine (12.8 g) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]#[N:19])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].CCO.[CH2:24](N)[CH2:25][NH2:26]>C(O)(=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[N:9]=[C:10]([C:18]3[NH:26][CH2:25][CH2:24][N:19]=3)[C:11]=12
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2c(N)ncnc21
Reactant: NCCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1nc(C2=NCCN2)c2c(N)ncnc21
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of (4-amino-3-cyano-pyrazolo[3,4-d]pyrimidin-1-yl)-acetic acid tert-butyl ester (80 g, 0.291 mol) and EtOH (800 mL) in an ice water bath was added acetic acid (67 mL) and then ethylenediamine (195 mL). The resulting mixture was refluxed for 90 min, cooled to room temperature and filtered. The solid was suspended in water (1 L), filtered and dried in vacuo to give of tert-butyl 2-(4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (84.6 g, 90% yield). MS (ES) m/z 318.1 (M+H+).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)=[O:5].[CH3:17][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4](=[O:5])[CH3:17])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)c1ccc2ncccc2c1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of quinoline-6-carboxylic acid methoxy-methyl-amide (11.97 g, 55.35 mmol) in anhydrous THF (200 mL) was added MeMgBr (1.5 M in THF, 55 mL, 83 mmol) at 0° C. under nitrogen. The reaction was allowed to warm to ambient temperature over 16 hours. Sat. NH4Cl (20 mL) was added to quench the reaction. The reaction solution was then extracted with EtOAc (3×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give 1-quinolin-6-yl-ethanone (9.2 g, 97% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([Mg]Br)[CH:12]([CH3:14])[CH3:13].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(F)c1
Reactant: CC(C)C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
97 mg of 3-fluorobenzeneacetaldehyde and 0.386 mL of isobutyl magnesium bromide (2 M/diethyl ether solution) were dissolved in of 0.2 mL of THF, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (ethyl acetate:hexane=1:2) to obtain 102 mg (yield 74%) of a title compound as a pale yellow oily substance.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:30])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1>C(Cl)Cl>[C:10]1([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:30])[C:9]=1[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(NC2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.3 %

Procedure:
After adding trifluoroacetic acid (10 mL) to a solution of tert-butyl 4-(mesitylamino)piperidine-1-carboxylate (5.71 g, 17.9 mmol) in methylene chloride (30 mL), the mixture was stirred at room temperature for 22 hours and then concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), toluene (20 mL) was added, and concentration under reduced pressure was repeated. The residue was purified by silica gel column chromatography (75 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1-1:1-chloroform:methanol=10:1) to obtain the title compound as a brown solid (3.57 g) (65% yield, 2 steps).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[C:23](Br)[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:35]C(C)([O-])C.[K+].CB(O)O.C(O)(=O)C>CN(C)C=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>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[C:23]([CH3:35])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Reactant: CC(C)(C)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(C)c1
Temperature: 160 °C
Yield: 48.3 %

Procedure:
A mixture of {4-[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetra-hydro-indazol-1-yl}-acetic acid ethyl ester (70 mg, 0.123 mmol, prepared as described above in example 2-1), tetrakis(triphenylphosphine)palladium(0) (1 mg, 0.012 mmol), potassium tert-butoxide (2.5 mg, 0.29 mmol), methylboronic acid (12 mg, 0.184 mmol) in N,N-dimethylformamide (1.5 ml) was heated in a microwave oven at 160° C. for 30 minutes, then acidified to pH 6 by addition of acetic acid. The resulting precipitate was filtered through a glass funnel to afford {4-[6-(4-chloro-phenoxy)-5-methyl-pyridine-3-sulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 48%) as a white solid. MS cald. for C23H25ClN4O5S 504, obsd. (ESI+) [(M+H)+] 505.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 53 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyloxy)benzoyl]piperidine (0.050 g, 0.099 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.135 g, 0.247 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.025 g, 0.0525 mmol, 53%).