Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1[OH:31]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:30]4[CH:29]=[CH:28][C:27]([C:32]([F:33])([F:34])[F:35])=[CH:26][C:25]=4[Cl:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C(F)(F)F)cc4Cl)ncnc32)CC1

Procedure:
4-[4-(2-Chloro-4-trifluoromethyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-chloro-4-hydroxybenzotrifluoride (available from Oakwood Products, Inc., West Columbia, S.C., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.99-2.08 (m, 4H), 2.98-3.07 (m, 2H), 4.08-4.11 (m, 2H), 5.00-5.05 (m, 1H), 7.78-7.80 (m, 1H), 7.89-7.91 (m, 1H), 8.15 (s, 1H), 8.49 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=498.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3]1.[Br:10][C:11]1[S:15][C:14]([C:16](O)=[O:17])=[CH:13][CH:12]=1.S(Cl)(Cl)=O.C(N(CC)CC)C>ClCCl>[Br:10][C:11]1[S:15][C:14]([C:16]([NH:1][C:2]2([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3]2)=[O:17])=[CH:13][CH:12]=1
Reactant: NC1(C(=O)O)CCOC1
Reactant: O=C(O)c1ccc(Br)s1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)CCOC1)c1ccc(Br)s1

Procedure:
Prepared analogously to Example 53a from 3-amino-tetrahydrofuran-3-carboxylic acid and 5-bromo-thiophene-2-carboxylic acid with thionyl chloride and N,O-bis-(trimethylsilyl)-trifluoroacetamid in dichloromethane with triethylamine.
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:3](OC)=[O:4].O.[NH2:14][NH2:15].CC(O)=O>CO.C1(C)C=CC=CC=1>[O:4]=[C:3]1[NH:15][N:14]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:2]1
Reactant: NN
Reactant: COC(=O)CCC(=O)C(=O)OC
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C1=NNC(=O)CC1
Temperature: 70 °C

Procedure:
Dimethyl 2-oxoglutarate (1.5 g, 8.98 mmol) was dissolved in MeOH (62 mL). Hydrazine monohydrate (500 mg, 9.88 mmol) and AcOH (540 mg, 8.98 mmol) were added to the solution sequentially. The reaction mixture was warmed at 70° C. for 18 h. The solution was cooled and reduced to a residue which was subsequently redissolved in toluene and evaporated to afford an off-white solid. The solid was tritrated with hexanes and needed no further purification (1.2 g, 100%): 1H NMR (CDCl3, 600 MHz) δ 8.75 (s, 1H), 3.90 (s, 3H), 2.93 (t, 2H, J=8.5 Hz), 2.58 (t, 2H, J=8.5 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13].CC[O-].[Na+]>CCOCC>[CH2:10]([O:11][C:12]([C@H:13]1[C@H:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:7]1)=[O:14])[CH3:9]
Reactant: O=Cc1cccs1
Reactant: CC(=O)OCCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1O[C@H]1c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized using a literature method (Alcaide, B.; Biurrun, C.; Martinez, A.; Plumet, J. Tetrahedron Lett. 1995, 36, 5417). To a solution of thiophene-2-carboxaldehyde (6.33 ml, 69 mmol) and chloroethylacetate (7.35 ml, 69 mmol) in 130 ml of ether was added freshly made NaOEt (4.7 g, 69 mmol) over a period of one hour. The solution was allowed to stir overnight at room temperature. The reaction mixture was then filtered and the filtrate was partitioned between water and ether. The ether layer was extracted and washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% EtOAc in hexanes containing 1% NEt3, Rf=0.55). The title compound was isolated as a red oil in 64% yield. 1H NMR (CDCl3, 200 MHz) δ:7.30 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.4 Hz, 1H), 6.99 (dd, J=5.0 Hz, 3.4 Hz, 1H), 4.33 (s, 1H), 4.28 (qd, J=7.0 Hz, 2.0 Hz, 2H), 3.68 (d, J=2.0 Hz, 1H), 1.33 (t, J=7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 168.0, 138.6, 127.5, 127.4, 126.3, 69.1, 57.5, 54.9, 14.3 ppm.
Reaction SMILES: [CH:1]1([N:13]([OH:17])[C:14]([NH2:16])=[O:15])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[Cl:18]N1C(=O)CCC1=O>C1COCC1>[Cl:18][C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[N:4]2[CH2:3][CH2:2][CH:1]([N:13]([OH:17])[C:14]([NH2:16])=[O:15])[C:5]=12
Reactant: NC(=O)N(O)C1CCn2c1cc1ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: NC(=O)N(O)C1CCn2c1c(Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-N-hydroxy urea (from Example 1, 231 mg, 1 mmol) in THF (9 mL) there was added N-chlorosuccinimide (147 mg, 1.1 mmol) and the mixture was stirred at r.t. for 30 minutes as a clear solution resulted. After evaporation to dryness, the residue was partitioned between H2O and EtOAc. The product obtained from evaporation of the organic fraction was chromatographed on a short column of silica gel, eluting with 5% EtOH in CH2Cl2 to afford a solid which on trituration in Et2O and filtration afforded the title compound as a white solid, m.p.: 192° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCCC.C(O)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1

Procedure:
The e.e. of N-benzyloxycarbonyl-3-hydroxypyrrolidine was measured by analytical HPLC with a chiral column [Chiralpak AS (Daicel), 250 mm×4.6 mm; eluent: hexane/isopropanol (100:4); flow rate: 1 ml/min; detection wavelength: 210 nm; retention times: 32.9 min for the (S)-form and 36.7 min for the (R)-form]. (R)-N-benzyloxycarbonyl-3-hydroxypyrrolidine was obtained in as 85% e.e.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:23]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: Oc1ccccc1
Reactant: C=CCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Phenol (376 g, 4 mol), hexadecene (α-olefin) (449 g, 2 mol) and ion exchange resin (trade-mark: Dia-ion RCP-145HD) (34 g) were charged in a reactor and stirred at 110° C. for 2 hours. The ion exchange resin was filtered off and the excessive phenol and hexadecene were distilled off under reduced pressure. After distillation under reduced pressure, mono-hexadecylphenol was obtained. The yield was 510 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:10]([CH3:25])([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1.[O:33]1[CH2:35][CH:34]1[CH2:36][O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46].C(#N)C>N1C=CC=CC=1.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:35][C@H:34]([OH:33])[CH2:36][O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:46])([F:47])[F:48])=[CH:30][CH:31]=3)[C:10]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:20]=3)([CH3:25])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Reactant: FC(F)(F)C(F)(F)CCCSCCOCC1CO1
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OC[C@H](O)COCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Yield: 86.3 %

Procedure:
A mixture of (3RS,4RS)-7-methoxymethoxy-3-methyl-3-(4-methoxymethoxyphenyl)-4-(4-hydroxyphenyl)chroman (31 1 mg, 0.71 mmole), 1-((2-oxiranyl)methoxy)-2-(4,4,5,5,5-pentafluoropentylthio)ethane (568 mg, 1.93 mmole), acetonitrile (9 ml), water (3 ml) and pyridine (5 drops) was refluxed for 10 hours. After cooling, the reaction mixture was diluted with water and the aqueous phase was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (448 mg, yield 86%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CCC(C)CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1

Procedure:
690 g of p-hydroxybenzoic acid, 650 g of (-)2-methylbutanol, 3 l of benzene, and 30 ml of conc. sulfuric acid were stirred under heating in a container provided with a Dean-Stark reflux condenser to remove generated water. After the reflux for about 11 hours, the solution was cooled and stripped of sulfuric acid by the addition of ice water. The reaction mother liquor was distilled of benzene after being washed by an aqueous solution of sodium carbonate and water to obtain oily p-hydroxybenzoic acid 2-methylbutyl ester.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:2]=2[CH:27]2[CH2:29][CH2:28]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)N(C)C)c2c1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(C3CC3)n(CC(=O)N(C)C)c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate (prepared as in published International patent application WO2004/087714) in toluene (0.24 M) was added cyclopropylboronic acid (1.3 eq.) followed by potassium phosphate (3.5 eq.). The mixture was degassed, then Pd(OAc)2 (0.1 eq.) and tricyclohexylphosphine (0.2 eq.) were added. The reaction was stirred under nitrogen at 100° C. for 1.5 h and then cooled to RT. EtOAc was added and the organic phase was washed with water and brine, dried over NaSO4 and evaporated in vacuo to leave a residue which was purified by flash chromatography (PE/EtOAc 1/1) to give the title compound (70%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:3]=1[O:4][CH2:5][C:6]([NH2:8])=O.B.CSC.[ClH:18]>O1CCCC1>[ClH:18].[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:3]=1[O:4][CH2:5][CH2:6][NH2:8]
Reactant: NC(=O)COc1c(Br)cccc1Br
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: NCCOc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A solution of 2-(2,6-dibromo-phenoxy)acetamide (9.3 g, 0.03 mol) in tetrahydrofuran (100 mL) was heated to reflux and borane-dimethylsulfide (4.5 mL, 0.045 mL) was added in drops over a period of 15 min. After 3 h, 20 mL of ethanolic hydrogen chloride (2M, 0.4 mol) was added. The solution was refluxed for 30 min. Upon cooling to ambient temperature a white solid precipitated which was filtered and washed with diethyl ether (20 mL) to give 2-(2,6-dibromo-phenoxy)ethylamine, hydrochloride salt (7.25 g, 73.3%). MS: MH+=294. M.p. 249.7-252.3° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=4)=[O:21])[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and 3-trifluoromethylaniline were converted to the title compound (560 mg).
Reaction SMILES: Cl[C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3].[CH3:22][NH2:23]>>[CH2:22]([NH:23][C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=C(Cl)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Product: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12

Procedure:
Reaction of 3-chlorocarbonyl-1-(phenylsulfonyl)indole [XXIII] with an excess of methylamine as above gave N-methyl-1-(phenylsulfonyl)indole-3-carboxamide [XXIV: R8 =Me]; mp (MeOH) 192.5°-195° C.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CCCCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (0.50 g, 1.476 mmol, Example #5, Step C) in DCM (10 mL) was added cyclohexanecarbonyl chloride (0.221 mL, 1.623 mmol) followed by DIEA (0.644 mL, 3.69 mmol). The reaction mixture was stirred for about 4 h at ambient temperature and then saturated aqueous NaHCO3 (20 mL) and DCM (20 mL) were added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with 20-80% EtOAc in DCM to provide N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.49 g, 80%) as a colorless solid: LC/MS (Table 1, Method a) Rt=2.40 min; MS m/z: 413 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=3)[CH2:12][CH2:11]2)=[CH:4][N:3]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:22][CH:21]([C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)=[N:3][CH:4]=3)[CH2:11][CH2:12]2)[O:20][N:19]=1)[CH3:23]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)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
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Yield: 21.5 %

Procedure:
5-[({1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (51 mg, 21%) was prepared from 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (220 mg, 0.52 mmol), [4-(methylsulfonyl)phenyl]boronic acid (105 mg, 0.52 mmol), 2M Na2CO3 (5 mL), Pd(PPh3)4 (50 mg, 0.04 mmol) and DME (5 mL) in a manner similar to Example 21, Step 3.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([Cl:65])[CH:61]=[CH:62][CH:63]=2)[N:58]=[C:57]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=2)[C:56]=1[CH3:72].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:65][C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:59]=1[N:58]=[C:57]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=1)[C:56]([CH3:72])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(Cl)cccc2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2c(Cl)cccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.055 mmol), 2,5-dimorpholinopyridin-3-amine (0.110 g, 0.415 mmol), 4,8-dichloro-3-methyl-2-(pyridin-2-yl)quinoline (0.10 g, 0.35 mmol) and Pd2dba3 (0.013 g, 0.014 mmol) in toluene (3.46 mL) was added sodium t-butoxide (0.083 g, 0.865 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. After which the reaction was cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (3×10 mL) and DCM (1×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc/hexane) to give the desired product 8-chloro-N-(2,5-di-4-morpholinyl-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.71 (1H, d, J=4.3 Hz), 8.15 (1H, d, J=7.8 Hz), 7.93 (1H, m), 7.82 (1H, d, J=7.4 Hz), 7.76 (1H, br. s.), 7.60 (1H, d, J=2.5 Hz), 7.34-7.47 (2H, m), 6.79 (1H, br. s.), 6.21 (1H, br. s.), 3.93 (4H, br. s.), 3.67-3.79 (4H, m), 3.25 (4H, br. s.), 2.93 (4H, br. s.), 2.49 (3H, s). Mass Spectrum (ESI) m/e=517.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:21]([O-])=O)=[C:10]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:21][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([OH:1])[CH:3]=2)=[CH:11][C:10]=1[N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1N
Yield: 83.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(3-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (7.8 g), palladium on carbon (10%, 0.9 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (6 g).
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7]([CH3:19])=[CH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]#[N:12]>C1(C)C=CC=CC=1>[CH3:6][C:7]1([CH3:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]([C:11]#[N:12])[CH2:9][CH2:8]1
Reactant: CC(C)=CCC(C#N)c1ccccc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C#N)c2ccccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
46.3 g of 85% phosphoric acid, 46.3 g of polyphosphoric acid, 250 ml of toluene and 92.6 g of 5-methyl-2-phenyl-4-hexene nitrile are mixed together and heated at 100° C. while stirring for 3 hours. The mixture is then poured on to ice. The mixture is now extracted with ether, washed with water, with 10% sodium carbonate solution and again with water until neutral, dried, evaporated and distilled in vacuo. There are obtained 85.3 g of 1,1-dimethyl-4-cyano-tetralin of boiling point 114° C./2 mm; nD20 =1.5351; yield 92%. Odour: pleasantly fruity, tobacco-like, after straw with a resemblance of patchouli and amber.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:17]1([CH2:16][NH:23][CH2:2][C:3]([NH:5][C:6]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[NH:8][N:7]=2)=[O:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: NCc1ccccc1
Solvent: CC#N
Product: O=C(CNCc1ccccc1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.67 cm3 of benzylamine. The reaction medium is refluxed for 1 hour and the precipitate formed is filtered off, washed with 5 cm3 of acetonitrile and 5 cm3 of methylene chloride, then purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (97/2.5/0.25 by volume). The fractions containing the expected product are combined and the residue is taken up in 20 cm3 of diisopropyl ether, filtered off and dried under reduced pressure (90 Pa; 45° C.) to give 305 mg of 2-[(phenylmethyl)amino]-N-(6-chloro-1H-indazol-3-yl)acetamide in the form of a white powder melting at 156° C.