Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[C:18]([Cl:20])[C:15]([C:16]#[N:17])=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[N:13]=2)=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:20][C:18]1[C:15]([C:16]#[N:17])=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[N:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=2)[CH:19]=1
Reactant: CC(=O)Cl
Reactant: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(-c2cc(Cl)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
Acetyl chloride (0.013 mL, 0.181 mmol) was added to a suspension of 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile (48 mg, 0.121 mmol, from Step 3 of Example 199) and Hunig's base (0.084 mL, 0.483 mmol) in dichloromethane (1 mL) at room temperature. After 90 min at room temperature, additional acetyl chloride (0.05 mL) was added. After additional 23 h, the reaction was stopped and the mixture purified by silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, to give N-(4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)phenyl)acetamide as yellow solid (24.9 mg, 47% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (2H, δ, J=8.78 Hz), 8.00-8.03 (2H, m), 7.79 (1H, s), 7.68 (2H, δ, J=8.53 Hz), 7.35-7.44 (3H, m), 7.19 (1H, t, J=7.40 Hz), 7.08-7.15 (4H, m), 2.23 (3H, s); MS (ES+) m/z: 440 (M+H); LC retention time: 4.668 min (analytical HPLC Method A). Unreacted starting material was also recovered (13.7 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([O:24]CC3C=CC=CC=3)[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12].C1(SC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[NH2:8][C:9]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:10]=1[C:11]([NH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=2[CH:19]=1)=[O:12]
Reactant: Nc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CSc1ccccc1
Product: Nc1ccc(C(=O)NCc2cc3ccc(O)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a trifluoroacetic acid (5 mL) solution of 2,6-diamino-N-(6-benzyloxy-benzofuran-2-ylmethyl)-nicotinamide (238 mg, 612 μmol) described in Example 1 was added thioanisole (287 μL, 2.45 mmol) at 0° C., which was stirred at room temperature for 2 hours. To the reaction solution were added sodium bicarbonate and water at 0° C., followed by extraction with ethyl acetate. After washing the organic layer with sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (101 mg, 55%) as a pale brown solid.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][O:23][C:22]1=[O:26].C[Al](C)C.O>C1COCC1>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([NH:2][C:22](=[O:26])[C:21]([CH3:27])([CH3:20])[CH2:25][CH2:24][OH:23])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Reactant: CC1(C)CCOC1=O
Agent: Br
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCO)C(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 50 °C
Yield: 46 %

Procedure:
A mixture of 7-amino-4-bromo-9H-carbazole-1-carboxamide hydrobromide (Example 54-2, 500 mg, 1.299 mmol) and 3,3-dimethyldihydrofuran-2(3 H)-one (222 mg, 1.948 mmol) in THF (10 mL) was treated with trimethylaluminum (2 M in toluene, 562 mg, 7.79 mmol) dropwise at rt. The mixture was heated at 50° C. for 1.5 h, cooled to rt and treated with water. The mixture was filtered through Celite and the solids were washed thoroughly with DCM and methanol. The filtrate was washed with water, dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from DCM to 10% ammonia-methanol-DCM) to provide 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide as a yellow solid (250 mg, 46%). Mass spectrum m/z 418, 420 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:22])=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>C(OCC)(=O)C>[ClH:22].[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:1][CH2:2][CH2:3][NH:4][CH3:5])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)c1ccc(OC(F)(F)F)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 25 h
Yield: 82.3 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.30 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 4-trifluoromethoxybenzoyl chloride (1.83 g) and pyridine (0.72 mL). The mixture was stirred at 60° C. for 25 hrs. Ethyl acetate (60 mL) was added to the reaction mixture, and the mixture was washed with water (30 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 14.5 hrs., the mixture was concentrated under reduced pressure. The residue was washed twice with ethyl acetate (15 mL), and dried under reduced pressure at 60° C. to give the title compound (1.83 g) as a white solid.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.O1CCCC1>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[CH:13]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)nc2)cc1O
Yield: 26 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions to afford 4-hydroxy-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one as a cream solid (26% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C1CCN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2C1=O

Procedure:
8-Chloro-1-(2,6-difluorophenyl)-3,4-dihydro-benzo[c]azepin-5-one (4aa) (4.2 g, 15 mmol) was dissolved in toluene (100 mL) and N,N-dimethylformamide dimethyl acetal (19 mL) and heated at 80° C. for 2 h. The solution was evaporated in vacuo and the resulting residue was purified by column chromatography (silica gel, 0 to 75% EtOAc/hexanes) to afford 5aa (2.6 g, 78%) as a pale brown solid MS m/z=361 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>C(OCC)(=O)C.CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cn2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)Oc1ccc(Oc2ccc(Cl)cn2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to column chromatography (ethyl acetate/heptane (1:5) (85%, white solid). HPLC-MS: m/z=355.1 (M+1); Rt: 4.56 min.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH2:6])[CH3:2].[F:7][C:8]([F:15])([F:14])[C:9]([O:11]CC)=O.O>C(#N)C>[F:15][C:8]([F:7])([F:14])[C:9]([NH:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])=[O:11]
Reactant: CCNCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CCNCCNC(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of N-ethylethylenediamine (10.0 g, 113.4 mmol) and ethyl trifluoroacetate (32.0 mL, 261 mmol) in the mixture of acetonitrile (110 mL) and water (2.5 mL, 139 mmol) was refluxed with stirring overnight (˜18 h). Solvents were evaporated in vacuo. Residue was re-evaporated with i-PrOH (3×100 mL). Residue was dissolved in dichloromethane (500 mL) and left overnight at room temperature. The formed crystals were filtered, washed with dichloromethane (100 mL) and dried in vacuo to provide compound JJ (24.6 g, 82.4 mmol) as white solid powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]\[C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].CO[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C.FC(F)(F)C(O)=O>CCOC(C)=O.FC(F)(F)C(O)=O>[CH2:32]([N:26]1[CH2:27][C@H:5]([C:6]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:7]=2[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C=C\c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Temperature: 65 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a solution of (Z)-isopropyl 2-(3-methoxy-3-oxoprop-1-enyl)-6-(trifluoromethyl)benzoate (2.5 g, 7.9 mmol) in 30 mL of EtOAc was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (2.34 g, 9.9 mmol) and trifluoroacetic acid (0.12 mL, 1.6 mmol). The solution was allowed to stir at 65° C. for 4 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.0 g, 4.2 mmol) and trifluoroacetic acid (0.05 mL, 0.65 mmol) were added and the reaction was stirred at 65° C. for an additional 3 h. The reaction was allowed to cool and was diluted with EtOAc, washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (5:1 hexane/EtOAc) to afford 3.3 g (93%) of the title compound as an oil. LRMS (ES)+: 450.35 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1/[C:25](=[CH:17]/[C:14]1[NH:13][C:9]3[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=3[C:15]=1[CH3:16])/[C:26](=[O:32])[NH:27]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cccc(Br)c43)c(C)c2C1=O
Yield: 45.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 4-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 13 (30 mg, yield 45.5%) as an orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1.[Na+].[I-:18]>CC(=O)CC.CCCCCCC>[I:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)C1(CCCCCCl)CC1
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)C1(CCCCCI)CC1
Yield: 97.7 %

Procedure:
To a solution of tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g, 128 mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166 mmol). The reaction mixture was stirred under reflux for 24 h, diluted with heptane (220 mL) and filtered through a layer of silica (˜2 cm) in a glassfilter. The residue was eluted with a mixture of heptane and EtOAc (3:1, 5×100 mL). The combined filtrate and elutes were evaporated in vacuo to give tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (42.3 g, 99%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=3.18 (t, J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=174.0, 79.9, 34.1, 33.6, 30.8, 28.2 (3×), 26.8, 24.3, 15.4 (2×), 7.4. HRMS calcd for C13H23IO2 (M+): 338.0743, found: 338.0743.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.CO.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16](/[CH:18]=[N:8]/[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(O)cc1
Solvent: CO
Product: CN(C)/C=N/C(=O)c1ccc(O)cc1

Procedure:
A solution of 4-hydroxybenzamide (5.58 g, 40 mmol) in 15 mL of dimethylformamide dimethyl acetal was stirred at 120° C. for 1.5 h with distillation of the product methanol. After cooling, the solid was collected and tritrarated with diethyl ether, DCM to give desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:22](Br)[CH3:23].Cl>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:14][CH2:23][CH2:22][O:13][C:12]=12)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Reactant: CC(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(OC)c2c(c1)OCCO2
Reaction time: 24 h

Procedure:
Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.5 g, 2.5 mmol) and potassium carbonate (1.74 g, 12.65 mmol) in acetone (25 mL). Add dibromoethane (2.37 g, 12.65 mmol). Heat to reflux. After 24 hours, cool in an ice bath, acidify with a 1 M aqueous hydrochloric acid solution (35 mL), add water (25 mL), and extract three times with ethyl acetate. Combine the organic layers and extract with brine. Dry over MgSO4, filter, and concentrate in vacuo to give methyl 3-methoxy-4,5-ethylenedioxybenzoate.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:16][CH:17]=2)=[N:1]1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(OCc3ccccc3)cc2)=N1
Reaction time: 48 h
Yield: 90 %

Procedure:
To a stirred and cooled (0° C.) mixture of 4.5 parts of 2-amino-2-methyl-1-propanol and 130 parts of dichloromethane were added portionwise 4.93 parts of 4-(phenylmethoxy)benzoyl chloride. Upon complete addition, stirring was continued for 48 hours at room temperature. The precipitate was filtered off and the filtrate was evaporated. The residue was stirred in 2,2'-oxybispropane. The precipitated product was filtered off and stirred in 9.6 parts of thionyl chloride during 1 hour. After evaporation, the residue was taken up in a sodium hydroxide solution 10%, crushed ice and methylbenzene. The separated organic layer was washed with water, dried, filtered and evaporated, yielding 5 parts (90%) of 4,5-dihydro-4,4-dimethyl-2-[4-(phenylmethoxy)phenyl]oxazole as a residue (int. 1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([O:15][CH3:16])=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[C:10]=2[O:15][CH3:16])=[N:19][CH:20]=1
Reactant: CCN1CCc2ccc(N)c(OC)c2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1

Procedure:
3-Ethyl-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (50.0 mg, (0.23 mmol) was dissolved in isopropanol (3 mL) and the mixture was treated with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (58 mg, 0.17 mmol) and 4N HCl/Dioxane (0.056 mL, 0.20 mmol). The reaction was then irradiated at 140° C. for 20 minutes. The solution was reduced en vacuo and the product was isolated and purified by flash column chromatography (0% MeOH/DCM-15% MeOH/DCM) to afford 3.83 mg of N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a white foam, LC/MS (ESI)=523.39 (M+H). 1H NMR (400 MHz, DMSO, d6) δ 7.93 (s, 1H), 7.82 (m, 2H), 7.07 (d, 1H, J=8.59), 6.86 (m, 1H), 6.77 (m, 1H), 3.71 (m, 2H), 3.62 (s, 3H), 2.89 (s, 3H), 2.67 (m, 4H), 2.59 (m, 1H), 2.53 (m, 2H), 2.42 (m, 2H), 2.34 (m, 1H), 2.04 (m, 2H), 1.70 (m, 2H), 1.35 (m, 2H), 1.23 (m, 2H), 1.03 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:13](Cl)=[O:14])[S:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([NH2:25])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCCl.O>[CH2:16]([NH:25][C:13]([C:8]1[S:12][CH:11]=[CH:10][CH:9]=1)=[O:14])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC/C=C/c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: O=C(NC/C=C/c1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
(E)-N-Cinnamyl-2-thiophenecarboxamide may be obtained in the following manner: triethylamine (8 g) and then thenoyl chloride (6.5 g) are added to a solution, maintained under a nitrogen atmosphere and at a temperature in the region of 25° C., of (E)-cinnamylamine (5.3 g) in 1,2-dichloroethane (80 cc). The suspension obtained is stirred for 1 hour at a temperature in the region of 25° C. and then poured into water (80 cc). The aqueous phase is acidified to a pH in the region of 5 with 4 N aqueous hydrochloric acid solution and then extracted with 1,2-dichloroethane (2×50 cc). The combined organic phases are washed with water (2×40 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (4 kPa) at 40° C. The residue is stirred in isopropyl ether (40 cc). The solid is separated by filtration, washed with isopropyl ether (4×10 cc) and dried in the air. (E)-N-Cinnamyl-2-thiophenecarboxamide (5 g), m.p. 110° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC1CCCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cycloheptyloxy)benzonitrile (Example 32b) and ethyl 3-oxobutanoate as a bright yellow solid (72%). 1H NR (400 MHz, DMSO-d6) δ 1.32 (t, J=8.0 Hz, 3H), 1.49-1.65 (m, 8H), 1.78-1.87 (m, 2H), 2.04-2.10 (m, 2H), 2.53 (s, 3H). 4.31 (q, J=8.0 Hz, 2H), 4.79 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 8.14 (brs, 2H). MS 343 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][Mg]Cl)[CH2:3]1.[C:11](#N)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH2:19].[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:19])[CH2:3]1
Reactant: O
Reactant: CN1CCCC(C[Mg]Cl)C1
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCCC(CC(=O)c2ccccc2)C1

Procedure:
1-Methyl-3-piperidylmethylmagnesium chloride was prepared essentially as described in Example 1 from 30.5 g of 1-methyl-3-chloromethylpiperidine. Sufficient tetrahydrofuran was employed to provide a final solution volume of 305 ml. To 114 ml of this final solution of 1-methyl-3-piperidylmethylmagnesium chloride was added 8.9 g of benzonitrile dissolved in about 30 ml of tetrahydrofuran and the resulting solution was heated at reflux for 30 minutes. The reaction solution was cooled and added to 100 ml of water to which 4.5 g of ammonium chloride had been added. A tetrahydrofuran layer separated from the aqueous phase which was extracted with two 75-ml portions of diethyl ether. The resulting extracts and the tetrahydrofuran layer were combined and the resulting organic solution was washed with two 25-ml portions of water and extracted with three 75-ml portions of 3 N hydrochloric acid. The acid extracts were combined and washed with diethyl ether, heated to distill residual diethyl ether and tetrahydrofuran, then heated at reflux for 45 minutes. The resulting hydrochloric acid solution was cooled and made strongly alkaline with 3 N sodium hydroxide. The alkaline solution was extracted with three 100-ml portions of diethyl ether. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and filtered. The diethyl ether solution was concentrated under reduced pressure and the residue was vacuum distilled to give 10.7 g of 1-methyl-3-phenacylpiperidine, bp 104°-114°/0.9 mm (collected as three fractions). The infrared and nuclear magnetic resonance spectra of the product were consistent with the assigned structure. The elemental analysis of the second fraction was as follows:
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>O1CCCC1.C(N(C)C)=O.CCCCCC>[CH2:1]([O:9][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Br:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrCc1ccccc1Br
Reactant: CCCCCCCCO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCOCc1ccccc1Br

Procedure:
prepared from octanol and n-butyllithium, in a mixture of tetrahydrofuran/hexane dimethyl formamide was condensed with 2-bromobenzyl bromide to yield 2(octyloxy)methylbromobenzene. This material was treated with n-butyllithium in ether/hexane mixture and subsequently treated with paraformaldehyde to yield 2-(octyloxy)methylbenzyl alcohol. This material was then treated with triphenyl phosphonine bromide to yield [2-[(octyloxy)-methyl]phenyl]methyl]triphenyl phosphonium bromide. Condensation of this material with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester, as in Example 3, followed by hydrolysis, as in Example 5, gave the (All-E)-3,7-Dimethyl-9-[2-[(octyloxy)-methyl]phenyl]-2,4,6,8-nonatetraenoic acid, mp 120-121 (from dichloro methane/hexane mixture).