Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-2:1].[La+3:2].[O-2:3].[O-2:4].[La+3].[O-2].[Cr+3:7].[O-2].[O-2].[Cr+3]>O>[Cr:7]([O-:4])([O-:3])=[O:1].[La+3:2].[Cr:7]([O-:4])([O-:3])=[O:1].[Cr:7]([O-:4])([O-:3])=[O:1].[La+3:2]
Reactant: [Cr+3]
Reactant: [O-2]
Agent: *CC*
Agent: [La+3]
Solvent: O
Product: O=[Cr]([O-])[O-]

Procedure:
A hundred parts of lanthanum oxide having an average particle diameter of 1 μm, 125 parts of chromium oxide having an average diameter of 1 μm, and 100 parts of ion-exchanged water were put into a polyethylene pot together with zirconia balls, subjected to pulverization and mixing for 20 hours, and then dehydrated by filter pressing. A resultant cake was dried in a drying chamber at 120° C. for 24 hours. The dried cake was ground coarsely, and placed in an aluminacrucible, and heated in air at 1,200° C. for 2 hours to form lanthanum chromite. A hundred parts of the lanthanum chromite powder thus obtained and 100 parts of ion-exchanged water were put into a polyethylene pot together with 200 parts of zirconia balls, and pulverized for 48 hours to provide an average particle diameter of 0.5 μm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][Cl:20])[CH:23]=3)[CH:3]=2)=[O:19])=[CH:12][CH:13]=1)#[N:18]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1cccc(CCl)c1

Procedure:
Using an analogous procedure to that described in Example 10, N-(3-amino-4-methylphenyl)-4-cyanobenzamide was reacted with 3-(chloromethyl)benzoyl chloride to give the title compound as a solid (0.267 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.84 (s, 2H), 7.25 (d, 1H), 7.55 (m, 2H), 7.64 (m, 1H), 7.83 (s, M1), 7.99 (m, 4H), 8.1 (d, 2H), 9.97 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M−H− 402.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:23][NH2:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:9](=[O:10])[NH:24][N:23]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: COc1ccc(C(=O)c2ccc(C)c(C)c2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc(C)c(C)c3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(3,4-dimethylbenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19](OCC)=[O:20])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:25]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH2:25])=[O:20])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: N
Reactant: CCOC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 60 °C

Procedure:
A mixture of ethyl (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 0.22 g, 0.65 mmol) in 2M ammonia in methanol (5–6 mL) is heated in a closed vial at 60° C. for approximately 1 h. The resulting mixture is cooled to ambient temperature and concentrated under reduced pressure, and the crude product is recrystallized from methanol to give the title compound, MS (ESI+) for C14H16N3O4F m/z 310 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:9]=1.[Br:30]C(Br)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Br:30][C:13]1[N:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:15]2[C:11]([N:12]=1)=[C:10]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][C@H:24]1[CH3:29])[N:9]=[C:8]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C@H:2]1[CH3:1])[N:16]=2
Reactant: ClC(Cl)(Cl)C(Cl)(Br)Br
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2ncn(C3CCCCO3)c2n1
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Diisopropylamine (290 μl, 2.04 mmol) was dissolved in 4 mL of THF at −60° C., when butyllithium in hexane was added (1.27 mL, 2.04 mmol) to form LDA. 2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9-(tetrahydro-pyran-2-yl)-9H-purine (585 mg, 1.45 mmol) was dissolved in 8 mL of THF and added to the reaction mixture at −78° C. within 10 minutes. The reaction was stirred for 1 hour at −78° C. Dibromotetrachloroethane (947 mg, 2.91 mmol) in 4 mL of THF was added within 10 minutes. The reaction was stirred for 2 hours at −78° C. The reaction was quenched by addition of saturated aqueous NH4Cl and warmed to room temperature. The mixture was diluted with 80 mL of EtOAc and 50 mL of brine. The organic layers were separated, dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography (30 g SiO2, heptane/TBME in a ratio 7/3) to give the product as a foam (546 mg, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].C([O-])([O-])=O.[K+].[K+].C(C(N)CBr)(O[C:23](C)([CH3:25])[CH3:24])=O>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:23]([CH3:25])[CH3:24])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)C(N)CBr
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of compound 3 (5.000 g, 17 mmol) in DMF (15 mL) was added K2CO3 (3.51 g, 26 mmol) and Boc-2-amino ethyl bromide (4.56 g, 20.35 mmol). The resulting mixture was stirred at 60° C. for three hours. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (4.08 g, 55%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-:15].C([N+](C)(C)C)C1C=CC=CC=1.O=O.C>N1C=CC=CC=1>[F:1][C:2]1[C:3](=[O:15])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:5]=2
Reactant: Fc1ccc2c(c1)Cc1ccccc1-2
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: c1ccncc1
Product: O=C1C(F)=CC=C2C1=Cc1ccccc12

Procedure:
2-Fluorofluorene (824.7 g, 4.48 mol) was dissolved in pyridine (4 L) and stirred. A 40% solution of Triton B (100 mL of benzyltrimethylammonium hydroxide 40% in pyridine according to a general procedure of U. Sprinzak, J. Amer. Chem. Soc. 80 (1958) 5449) was added and oxygen was bubbled into the vigorously stirred solution. This exothermic reaction was run for 20 hours whereupon an additional portion of the Triton B solution (50 mL) was added with continued stirring and oxygen addition for an additional 24 hours. The resulting dark green reaction mixture was treated with Norite (100 g, neutralized charcoal), stirred for 30 minutes and filtered through a Celite pad (diatomaceous earth filter aid). The filter pad was then washed with pyridine (1 L). The combined filtrates were concentrated to a small volume in vacuo with heat. A 5% solution of hydrochloric acid in water (1 L) was added and the pyridine was azeotrophed in vacuo with heat. This process was repeated until a total of 6-8 L of water were evaporated. The granular product was filtered and washed with water (4 L) and air dried. The yellow-orange product was melted and distilled through a large bore short path distillation apparatus (bp 167°-170° C.; 1.5 mm Hg) to yield into a chilled receiving flask the bright yellow 2-fluorofluorenone (600 g) with a m.p. 113°-115° C. and m/e+. 198 for C13H7FO.
Reaction SMILES: C(C(C(C(O)=O)O)O)(O)=O.[CH2:11]([O:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCNC1
Temperature: 25 °C

Procedure:
The organic phase was dried (MgSO4) and the solvent evaporated in vacuo affording a residue which was dissolved in acetone (85 ml). To this solution (R)-3-piperidinecarboxylic acid ethyl ester tartrate (9.0 g, 0.03 mol) and potassium carbonate (7.0 g, 0.051 mol) were added and the mixture was heated at reflux temperature for 16 h. After cooling to room temperature and filtration on filter aid (celite) the solvent was removed by evaporation. The residue was dissolved in diethyl ether (100 ml) and extracted with a 5% tartaric acid solution (3×125 ml). The combined aqueous extracts were washed with diethyl ether and pH was adjusted to 7-8 with a potassium carbonate solution. The neutralised aqueous mixture was extracted with ethyl acetate (4×200 ml). The combined ethyl acetate extracts were washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo affording 2.6 g (32%) of 1-(4-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-butyl!-3-piperidinecarboxylic acid ethyl ester, obtained as an oil. The residue was purified further by column chromatography on silica gel (65 g) using a mixture of dichloromethane and methanol (99.2:0.8) as eluent. Rf : 0.20 (SiO2 ; n-heptane/ethyl acetate=1:1 ).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
N-Phenyl-o-phenylenediamine (50 g, 0.27 mol) is dissolved in anhydrous DMF (400 ml) under N2, and 4-bromobenzaldehyde (45.5 g, 0.25 mol) is added dropwise. The reaction mixture is warmed to 40° C., and Oxone (potassium hydrogen monopersulfate, 98.1 g, 0.16 mol) is added in portions. After the mixture has been stirred at room temperature for 120 min., 1 l of water is added. The precipitated product is filtered off, washed with water and dried in vacuo. Recrystallisation from acetonitrile gives a cream-coloured solid (31 g, 35%).
Reaction SMILES: CC(C)([O-])C.[K+].[Li]CCCC.[CH3:12][O:13][O:14][C@H:15]1[C@H:20]([O:21][O:22][CH3:23])[C@@H:19]([CH2:24][O:25][O:26][CH3:27])[O:18][CH:17]=[CH:16]1.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:37]([Sn:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:33][CH2:34][CH2:35][CH3:36])[C:17]1[O:18][C@H:19]([CH2:24][O:25][O:26][CH3:27])[C@@H:20]([O:21][O:22][CH3:23])[C@H:15]([O:14][O:13][CH3:12])[CH:16]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COOC[C@H]1OC=C[C@@H](OOC)[C@@H]1OOC
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@H](OOC)[C@H](OOC)[C@@H](COOC)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of potassium tert-butoxide (0.42 g, 3.75 mmol) in anhydrous THF (10 mL) was added nBuLi (4.13 mmol) at -78° C. After 15 minutes, tri-O-methoxy-D-glucal (Example 7, 0.194 g, 1.03 mmol) was added in THF (5 mL). After stirring for one hour, tributylstannyl chloride was added and the mixture was allowed to warm to room temperature at which time it was cooled to 0° C. and quenched with ammonium chloride (sat.) and extracted with ethyl acetate three times. The organic layer was washed with water and brine, dried (NaSO4), filtered and concentrated to yield the title compound (0.24 g, 49%) as a clear liquid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21]>C(O)C>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(O)c(N)c1
Solvent: CCO
Product: Cc1ccc(O)c(Nc2ccnc3nc(C)ccc23)c1
Temperature: 25 °C

Procedure:
The product from Example 1d (893 mg, 5 mmol) and 2-Amino-4-methyl-phenol (616 mg, 5 mmol) in ethanol (20 mL) were refluxed for 4 hours. The mixture was cooled to room temperature and evaporated. The residue was triturated with hexane/ethyl acetate (3:1) to give the title compound in quantitative yield as the hydrochloride salt.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[I:11]([O-])(=O)=O.[K+].II.C(OCC)C>C(O)(=O)C.O>[I:11][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[OH:10]
Reactant: CC(C)c1cccc(O)c1
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CC(C)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 286.2 %

Procedure:
To a solution of 3-isopropylphenol (25.0 g, 0.184 mol) in acetic acid (200 mL), a suspension of potassium iodate (7.88 g, 0.0368 mol) in water (75 mL) and iodine (18.7 g, 0.0736 mol) were added. This reaction mixture was stirred at room temperature for 20 hours. After addition of diethyl ether (400 mL) and water (300 mL), the organic layer was separated. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to give 2-iodo-5-isopropylphenol (27.6 g, 57%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][CH:5]1[C:11](OC)=[N:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].[Cl-:16].[NH4+:17]>CO>[ClH:16].[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1=[NH:17])[CH3:2]
Reactant: [Cl-]
Reactant: CCC(CC)CC1CCCCN=C1OC
Reactant: [NH4+]
Solvent: CO
Product: CCC(CC)CC1CCCCNC1=N
Product: Cl

Procedure:
The product of EXAMPLE 195 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[C:12]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30])C.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[CH3:26][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:2]2[N:7]=[C:6]([N:8]3[C:16]4[C:11](=[C:12]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
1-(2-Chloro-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (300 g), 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (155 g), and K2CO3(170 g) in NMP (2.35 L) were stirred at 80° C. for 5 h and then stirred overnight at room temperature. The reaction mixture was then stirred on an ice bath, and 2.5 L water was slowly added while stirring, and cooling continued until completion of the exothermic reaction. Upon cooling, the mixture was filtered, and resulting solid was rinsed with H2O and dried in vacuo overnight to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methyl ester (97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[N:22]1([C:28](=[O:30])[CH3:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:25]4[CH2:26][CH2:27][N:22]([C:28](=[O:30])[CH3:29])[CH2:23][CH2:24]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCNCC1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CC(=O)N1CCN(CCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 1-piperazin-1-yl-ethanone were converted to yield 1-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-piperazin-1-yl)-ethanone as colorless oil, MS: 474 (MH+,1Br).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C:21]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23][CH2:22]2)=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[C:25]([C:21]1([NH:20][C:6]2[N:7]=[C:8]([NH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=2)[CH2:24][CH2:23][CH2:22]1)(=[O:26])[NH2:27]
Reactant: N#Cc1ncc(NC2(C(N)=O)CCC2)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(NC2(C(N)=O)CCC2)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 1-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)cyclobutanecarboxamide (10 mg, 0.028 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (7 mg). MS378.2 (M+H); UV 204.8, 267.7, 297.8, 358.5 nm; t 0.423 min.
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][C:9]=1[Cl:10].[NH3:15]>CN1CCCC1=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][C:9]=1[NH2:15].[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[NH2:15]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: N
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1cc(C(F)(F)F)ccc1Cl
Product: Nc1ccc(C(F)(F)F)cc1Cl
Temperature: 247.5 °C
Yield: 77 %
Yield: 13 %

Procedure:
N-methylpyrrolidone (1050 ml) was charged in an autoclave along with 102 g anhydrous activated potassium fluoride, 377 g 3,4-dichlorobenzotrifluoride was added. Ammonia (158 g) gas was passed in the reactor from the pressure pot at ambient temperature. The content of the reactor was heated to 245° C.-250° C. over a period of 2 hours to get reactor pressure of 30-32 kg/cm2. Excess NH3 was fed from the pressure pot to maintain the reactor pressure at 38-40 kg/cm2 at 245-250° C. liquid temperature. Reaction mixture was maintained at 245-250° C. and at 38-40 kg/cm2 pressure for further 8 hours. Reaction mixture was cooled to ambient temperature and NH3 was vented and recovered. Reaction mixture was filtered and on fractionation gave 77% yield of 2-chloro-4-trifluoromethylaniline and 13% yield of 2-chloro-5-trifluoromethyl aniline based on consumed 3,4-dichlorobenzotrifluoride.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].I[C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=3)[C:24]=12
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Product: CC(C)n1nc(-c2ccc(NS(C)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 2.6 %

Procedure:
A solution of 4-Methanesulfonylaminophenylboronic acid (24 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA40 (0.9 mg, 3% yield). ESI-MS (M+H)+ m/z calcd 347.1, found 347.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Se](=O)=O>O1CCOCC1.C(O)C>[OH:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(CO)n1
Agent: O=[Se]=O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(O)c(C=O)n1
Yield: 57.3 %

Procedure:
3-Hydroxy-6-methyl-2-pyridine methanol (20.0 g, 0.14 mol) and selenium dioxide(8.0 g, 72 mmol) were dissolved in 140 mL of 1,4-dioxane and 280 mL of absolute ethanol. The resulting mixture was heated at 80°-85° C. for 12 h. The selenium precipitate was removed by filtration and the filtrate was concentrated to dryness in vacuo. The dark red residue was sublimed at 90° C. and 14 mmHg for 6 h to obtain 11.0 g (56%) of pure product, m.p. 101°-102° C.; 1H NMR (CDCl3) d: 10.50 (br s, 1H), 10.03 (s, 1H), 7.27 (s, 2H); 2.53 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2O)nc1-c1ccc(C)cc1
Yield: 70.9 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 2-hydroxyphenylboronic acid (124 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to yield 83 mg (49%) of the title compound.