Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:31])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[CH:24]=3)[CH2:20][C:19](=[O:31])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-dimethylamino-phenyl}-carbamic acid tert.-butyl ester (Example M15) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (50 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[C:11]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH2:16]([NH2:18])[CH3:17]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([NH:18][CH2:16][CH3:17])=[N:6][N:5]2[C:11]=1[S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: CCN
Reactant: NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Solvent: CC#N
Product: CCNc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (2.00 g, 7.50 mmol) and ethylamine (50%, 10.0 ml) were stirred in acetonitrile (100 ml) at 70° C. for 8 hours. The reaction mixture was concentrated to dryness, dissolved in ice-water (50.0 ml), and adjusted to pH 6 with conc. hydrochloric acid. The precipitated crystals were filtered and washed with water to give the title compound as pale yellow crystals. The yield was 1.10 g (53.3%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][S:42](Cl)(=[O:44])=[O:43])([O-:34])=[O:33].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N+:32]([O-:34])=[O:33])(=[O:43])=[O:44]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1CS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. (2-nitrophenyl)methansulfonyl chloride (12 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-(2-nitrophenyl)methansulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: [OH:1][C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O1CCOCC1.Cl>CO>[NH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:2]2([OH:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(O)CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC1CCN(CC2(O)CCOCC2)CC1
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of tert-butyl ({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate as prepared in 1(3) (50.28 g, 153 mmol) in methanol (100 mL) was added 4N hydrochloric acid dioxane solution (200 mL, 800 mmol) at room temperature. After 4 h, the volatile materials were removed by evaporation. The resulting amorphous was precipitated with diethyl ether/methanol (v/v=5/1). The precipitate was collected and added to the ice cooled 6N aqueous sodium hydroxide solution (200 mL) gradually. The mixture was extracted with dichloromethane/methanol (v/v=10/1, 500 mL×4). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 24.90 g (99%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:30]1[N:35]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:29]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
250 mg (0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 49A) and 83 mg (0.71 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 70 mg (70% of theory)
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17]O.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][CH2:17][C:16]([O:20][CH3:21])=[O:19])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a solution of triflic anhydride (3.7 ml, 20.0 mmol) in methylene chloride (10 ml) at -5° C. under argon, was added dropwise over 30 minutes a solution of methyl glycolate (1.8 g, 20.0 mmol), pyridine (1.55 ml, 20.0 mmol), and anhydrous methylene chloride (5 ml). The reaction was allowed to stir at between 0°-5° C. for 1.5 h. The mixture was then washed with water several times. The organic extract was then washed with water, brine, and dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, methylene chloride) afforded the title compound as a colorless oil (3.0 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O.O>[CH3:20][O:19][C:17](=[O:18])[NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5]
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1ccccc1C(=O)Nc1nnn[nH]1

Procedure:
To a solution of 5.0 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide in 20 ml of dimethylformamide was added 2.3 g of methyl chloroformate. The resulting solution was warmed for 2 hours and then diluted with a small volume of water. The solid which formed on cooling was separated by filtration to give [2-((1H-tetrazol-5-yl)-aminocarbonyl)phenyl]carbamic acid methyl ester melting at about 236°-237° C. after recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=O)[CH3:20])[C:3]=1[S:22][CH3:23].[CH2:24]([SH:27])[CH2:25][SH:26]>[Fe](Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2([CH3:20])[S:27][CH2:24][CH2:25][S:26]2)[C:3]=1[S:22][CH3:23]
Reactant: SCCS
Reactant: CSc1c(C(C)=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: CSc1c(C2(C)SCCS2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Reaction time: 144 h
Yield: 8.4 %

Procedure:
A mixture of 1 g (2.60 mmol) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-acetyl-4-methylthio-1H-pyrazole, 0.26 ml (3.10 mmol) of 1,2-ethanedithiol, 0.084 g (0.5 mmol) of iron(III) chloride and 25 ml of methylene chloride was stirred at 20° C. under an inert atmosphere for 6 days. The mixture was evaporated and chromatographed so as to give 100 mg of yellow oil of the title compound. Mass spectral analysis gave a molecular weight of 460.
Reaction SMILES: [F-].[Cs+].[F:3][C:4]([F:9])([F:8])[CH2:5][NH:6][CH3:7].Br[C:11]1[N:28]([CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]2)[C:14]2[C:15]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)=[N:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=2[N:12]=1>CS(C)=O.O>[Cl:27][C:25]1[CH:26]=[C:21]([C:15]2[C:14]3[N:28]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:11]([N:6]([CH3:7])[CH2:5][C:4]([F:9])([F:8])[F:3])=[N:12][C:13]=3[CH:18]=[C:17]([C:19]#[N:20])[N:16]=2)[CH:22]=[N:23][CH:24]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CNCC(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: CN(CC(F)(F)F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 150 °C

Procedure:
To a sealed reaction vessel was added cesium fluoride (0.085 g, 0.56 mmol). The reaction vessel was heated to 150° C. for 3 hours with stirring, under high vacuum. The vial was cooled to ambient temperature under high vacuum. The reaction vessel was backfilled with argon, and next was added a solution of 2,2,2-trifluoro-N-methylethanamine (purchased from Enamine) (0.019 g, 0.17 mmol) and 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 0.025 g, 0.056 mmol) in DMSO (0.30 mL). The reaction was heated to 100° C. for 12 hours. The reaction was cooled, diluted with H2O (2.0 mL) and extracted with EtOAc (2×5.0 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a crude residue. MS ESI calc'd. for C23H24ClF3N6 [M+H]+ 477. found 477.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH:11]([O:19]C(=O)C)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][O:10][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[C:5]([CH:11]([OH:19])[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c(O)c1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2c(C(O)c3ccc(Cl)cc3)cnc(C)c2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
0.24 g (0.66 mmole) of (+)-2-methyl-3-hydroxy-4- hydroxymethyl-5-[4-chloro-α-acetoxybenzyl]pyridine are poured into a 25 ml round bottomed flask and dissolved in 10 ml of methylene chloride. 190 mg (1 mmole) of p-toluene sulphonyl chloride and 75 mg (1 mmole) of pyridine are then added. The reaction mixture is stirred at room temperature for 18 hours the solvent is then removed under reduced pressure. 5 ml of methanolic ammonia are added and the mixture is stirred at room temperature for 2 hours. The solvent is removed under vacuum, dissolved again in 1 ml of methanol and purified by silica TLC. 170 mg of the title compound were obtained as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][C:30]1([CH2:34][NH2:35])[CH2:33][O:32][CH2:31]1>>[CH3:1][N:2]1[C:10]([CH2:11][NH:35][CH2:34][C:30]2([CH3:29])[CH2:33][O:32][CH2:31]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CC1(CN)COC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC3(C)COC3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and (3-methyloxetan-3-yl)methanamine were reacted to give 259. [M+H]+ 463.6.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[C:7]([C:11](=O)[CH3:12])=[CH:6][N:5]=1>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]2[NH:1][N:2]=[C:11]([CH3:12])[C:7]2=[CH:6][N:5]=1
Reactant: NN
Reactant: CC(=O)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: Cc1n[nH]c2nc(Cl)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of hydrazine (Aldrich, 102.4 mg, 3.2 mmol) in THF (5 mL), 1-(2,4-dichloro-pyrimidin-5-yl)-ethanone (Example 21, 191 mg, 1 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL) and the mixture was extracted with EtOAc/THF(3×5 mL, 1:1 mixture of EtOAc:THF ). The extract was dried with sodium sulfate and concentrated to give a solid. 126 mg, 75%. MS (M+H)+, 169.
Reaction SMILES: [I-].C[NH+:3]1[CH2:8][CH:7]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH2:6][N:5]([C:15](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1.[ClH:34]>C(O)(C(F)(F)F)=O>[ClH:34].[CH3:15][N:5]1[CH2:6][CH:7]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH2:8][N:3]=[CH:4]1
Reactant: Cc1noc(C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[NH+](C)C2)n1
Agent: Cl
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C2CN=CN(C)C2)n1
Temperature: 25 °C

Procedure:
1-Methyl-3-triphenylmethyl-5(3-methyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidinium Iodide (330 mg, 0.6 mmol) was dissolved in TFA (1 mL) with stirring in a stoppered round bottom flask at room temperature. After 18 hours stirring the excess TFA was evaporated in vacuo, and the dark residue triturated with ether. The ether was decanted leaving an oily residue that was taken up in ice cold sat. Na2CO3 and then extracted with chloroform. After drying and evaporation the chloroform fraction gave the free base which was converted to its HCl salt and recrystallized (methanol/ether) to yellow crystals 15 mg (12%) identified by 300 MHz nmr and ms m/z=180.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH3:16].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[C:6]([O:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=2)=[C:7]1[CH3:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Oc1cccc(Br)c1
Reactant: BrCc1ccccc1
Product: Cc1c(Oc2cccc(Br)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(3-bromo-phenoxy)-6-chloro-2-methyl-1H-indole and benzyl bromide.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[F:34][CH:35]([F:48])[O:36][CH2:37][CH:38]([CH3:47])[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]>O1CCCC1>[Br:1][C:38]([CH3:47])([CH2:37][O:36][CH:35]([F:48])[F:34])[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]
Reactant: CC(COC(F)F)C(=O)c1ccccc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)(COC(F)F)C(=O)c1ccccc1
Yield: 172.4 %

Procedure:
3.58 g of phenyltrimethylammonium tribromide was added to a mixture comprising 2.04 g of 3-difluoromethoxyisobutyrophenone and 30 ml of tetrahydrofuran, followed by a reaction for two hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.79 g of oily α-bromo-3-difluoromethoxyisobutyrophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([OH:17])[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[Cl:36])[N:29]([CH3:37])[N:28]=1>>[Cl:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH3:37])[N:28]=[C:27]([CH2:26][O:17][C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=3[CH3:16])[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[O:18])[C:35]=12
Reactant: Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1O
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide (127.4 mg, 0.487 mmol) and potassium carbonate (77.7 mg, 0.551 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.6 mg, 0.346 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step (described in Example 17) or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-N-(4-chloro-phenyl)-4-methyl-benzamide as a white solid. (Yield 25.0 mg).
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[C:31](C1C=CC=CC=1)(=O)C>>[C:6]1([CH:7]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])[CH3:31])[CH:29]=[CH:30][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: CC(=O)c1ccccc1
Product: CC(NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using acetophenone instead of 4-methoxy benzaldehyde. LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.22 (1H, s) 8.02 (2H, d, J=5.37 Hz) 7.76 (1H, d, J=5.37 Hz) 7.45 (1H, d, J=5.47 Hz) 7.21-7.34 (5H, m) 7.08-7.20 (1H, m) 6.79 (1H, d, J=5.37 Hz) 6.43 (1H, d, J=2.73 Hz) 3.67 (1H, q, J=6.51 Hz) 3.18-3.38 (2H, m) 2.34-2.58 (2H, m) 2.14 (1H, br. s.) 1.19 (3H, d, J=6.64 Hz)
Reaction SMILES: C[Li].[Si:3]([O:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[C:17](O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)C.C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1([OH:13])[CH3:17])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)OCC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Methyl lithium (670 μl [1.11 mmol, 1.1 equiv] of a 1.65 M solution in diethyl ether) is added dropwise to a stirred solution of (S)-2-(tertbutyidimethylsilyloxy)-γ-butyrolactone 12 (218 mg, 1.01 mmol) in THF (4.0 ml) cooled to −78° C. is added dropwise. After stirring at −78° C. for 3 h, the reaction is quenched by the addition of glacial acetic acid (72 μl, 1.26 mmol, 1.25 equiv). Diethyl ether (20 ml) and saturated aqueous sodium bicarbonate solution (10 ml) are added. After stirring for 5 min the organic layer is separated and the aqueous layer is extracted with diethyl ether (2×20 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacua. Crude (3S)-3-(tertbutyidimethylsilyloxy)-2-hydroxy-2-methyl-tetrahydrofurane 13 (235 mg, 93%) is obtained as a colourless crystalline solid (mixture of diastereomers) which is used for the synthesis of (S)-3,5-di-(tert-butyldimethylsilyloxy)-pentan-2-one 14 without further purification.
Reaction SMILES: Cl[C:2](=[N:11][OH:12])[C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].C(N(C(C)C)CC)(C)C.O=[C:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=1[C:2]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:29])[O:12][N:11]=1
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of 0.1 g (0.4455 mmol) alpha-Chloro-2,6-dichlorobenzaldoxime in 5 mL methyl 3-oxobutanoate, 0.11 mL (1.5 eq) diisopropylethlamine were added. The mixture was stirred for 24 h then ethylacetate was removed in the vacuo. The residue was dried under high vacuo and the crude product was triturated in water until it became solid. The solid was filtered off and further purified by recrystallization from a water-methanol mixture. The crystals were filtered off, washed with water and dried under reduced pressure to afford 248 mg (87%) of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate. Result of LC/MS [M+H]+: 286.12; 1H NMR (DMSO-d6; CCl4): 2.77 (3H, s, CH3-isooxazole), 3.28 (3H, s, CH3-methoxy), 7.54-7.65 (3H, m, aromatic)
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:11]=1[NH2:12]>>[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:11]=1[NH:12]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH3:8])=[O:6]
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)CC(C)=O
Product: COC(=O)/C=C(/C)Nc1c(F)cccc1F

Procedure:
By the same procedure as a reaction of Example 158, using methyl acetoacetate and using 2,6-difluoroaniline instead of 4-chloro-2,6-dimethylaniline, the title compound having the following physical data was obtained.
Reaction SMILES: [CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[CH3:14][C:15]1(CC)OCC[O:16]1.C(O)CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]1[CH2:15][O:16][C:12]2([CH2:11][CH2:10][CH2:9][C:8]3[C:2]2([CH3:1])[CH2:3][CH2:4][C:5](=[O:6])[CH:7]=3)[O:13]1
Reactant: CC12CCC(=O)C=C1CCCC2=O
Reactant: CCC1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: O
Product: CC12CCC(=O)C=C1CCCC21OCCO1
Temperature: 25 °C
Reaction time: 30 h
Yield: 93.6 %

Procedure:
A mixture of Wieland-Miescher ketone (5.086 g, 28.44 mmol), 2-methyl-2-ethyl-1,3-dioxolane (19.38 mL, 155.0 mmol), ethylene glycol (0.358 mL, 6.43 mmol) and p-toluenesulfonic acid monohydrate (0.4 g, 2.13 mmol) was stirred at room temperature for 30 hours. The reaction was quenched with dropwise addition of triethylamine, diluted with 20 mL of benzene, washed with water, dried over MgSO4, and concentrated under vacuum. The product was triturated from hexanes to yield monoacetal 201 (5.92 g, 94%). 1H NMR (CDCl3) δ 1.36 (s, 3H), 1.6-2.0 (m, 5H), 2.2-2.5 (m, 5H), 3.9-4.1 (m, 4H), 5.80 (d, J=Hz, 1H); 13C NMR (CDCl3) 198.91, 167.55, 125.38, 125.37, 112.12, 65.16, 64.84, 44.81, 33.70, 31.22, 29.81, 26.62, 21.51, 20.27.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:10].BrBr>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Acetylpyridine (3.62 g, 29.9 mmol) was added with acetic acid (30 ml) and 47% hydrobromic acid (5.3 ml) at room temperature, subsequently added dropwise with bromine (1.6 ml in total) four times at an interval of 5 minutes, stirred at room temperature for 2 hours and 30 minutes. The mixture was further added with bromine (1.6 ml), and stirred at room temperature for 20 hours. The reaction solution was filtered, and the resulting crystals were washed with diethyl ether and dried to obtain 12.43 g of the title compound as a salt of hydrogen bromide in the form of orange crystals without purification.