Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH3:21])[CH2:13]2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH3:48])[C:26]2[O:30][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[N:28][C:27]=2[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH3:21])[CH2:13]3)[N:3]=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]4[O:30][C:26]5[C:25]([CH3:48])=[CH:24][C:23]([CH3:22])=[CH:47][C:27]=5[N:28]=4)=[CH:37][CH:36]=3)[C:10]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: COCCN1CCCC(n2nc(I)c3c(N)ncnc32)C1
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: O
Solvent: COCCOC
Product: COCCN1CCCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
The mixture of 3-iodo-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.16 g, 0.0004 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.17 g, 0.00048 mol), tetrakis(triphenylphosphine)palladium (0.023 g, 0.00002 mol) and sodium carbonate (0.11 g, 0.001 mol) in ethylene glycol dimethyl ether (25 mL) and water (5 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 2%-10% methanol/dichloromethane as a mobile phase to give N2-(4-{4-amino-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (0.17 g, 0.00033 mol). 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.22 (s, 1H), 7.95 (d, 2H), 7.65 (d, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 4.79 (br, 1H), 3.50 (m, 2H), 3.25 (s, 3H), 3.10 (br, 1H), 2.90 (br, 1H), 2.55 (br, 2H), 2.54(br, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.05 (br, 3H), 1.80 (br, 1H), 1.70 (br, 1H). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.9 min. MS: MH+ 513
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[CH2:5][C:4](=O)[CH2:3]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[C:19]([SH:21])[CH:20]=1>CS(C)=O>[Br:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:22][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[C:5]=1[S:21]2
Reactant: Nc1ccc(Br)cc1S
Reactant: COC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Br)cc1S2

Procedure:
A mixture of methyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7a (1.43 g, 7.7 mmole) and 5-bromo-2-aminobenzenethiol, 6 (X=Br, 1.44 g, 7.7 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4j, (R=Br), mp 186-189° C. occurs as light orange crystals; 0.14 g (13.9%).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-])=O.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C>[CH2:12]([O:11][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc[n+]([O-])cc1
Temperature: 50 °C
Reaction time: 40 h
Yield: 99 %

Procedure:
4-nitropyridine-N-oxide (12 g) was dissolved in ethanol, sodium ethoxide (8.8 g) was added to the mixture, and the mixture was stirred for 40 hours at 50° C. After allowing the mixture to be cooled to room temperature, the precipitates were filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-ethoxypyridine-N-oxide (11.8 g). To 4-ethoxypyridine-N-oxide (11.8 g) was added dimethyl sulfate (8.56 ml), and the mixture was stirred for 1 hour at 110° C. After diluting with methanol (180 ml), the mixture was heated to reflux for 1 hour, an aqueous solution (18 ml) of ammonium peroxodisulfate (20.6 g) was added dropwise to the solution under heat reflux, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-ethoxy-2-pyridinyl)methanol (2.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([Cl:26])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][C:18]1[N:17]=[C:16]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CCOC(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Oc2nc(Cl)cc3ccccc23)cc1
Reaction time: 3 h
Yield: 66.4 %

Procedure:
A mixture of ethyl 4-hydroxyphenoxyacetate (1.0 g), 1,3-dichloroisoquinoline (1.0 g), anhydrous potassium carbonate (0.7 g) and dry dimethylformamide (10 ml) was heated, with stirring, at a temperature of 120°-130° C. for a period of 3 hours. The solvent was removed by distillation under reduced pressure and the residue was treated with water. The aqueous mixture was extracted with a mixture of acetone and chloroform and the solvents were removed from the organic extract by distillation under reduced pressure. The residue was chromatographed over silica gel with chloroform elution to give ethyl 4-(3-chloro-1-isoquinolyloxy)phenoxyacetate (1.2 g), mp 97° C. The assigned structure was confirmed by proton magnetic resonance spectroscopy, mass spectrometry and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:14])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:15]1([C:21]2[CH:25]=[C:24]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]3)[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:3]([Cl:14])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:34][CH2:33][CH:30]1[CH2:29][CH2:28][N:27]([CH2:26][C:24]2[O:23][N:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=2)[CH2:32][CH2:31]1)=[O:9]
Reactant: CCOc1nc(Cl)c(N)cc1C(=O)O
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Product: CCOc1nc(Cl)c(N)cc1C(=O)NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1

Procedure:
According to the same procedure described in example 225, using the compound prepared in Example 292 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:28]>CC(O)C>[NH2:28][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(I)c3c(Cl)nccn23)CC1
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(I)c12
Temperature: -78 °C

Procedure:
A mixture of benzyl 4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (0.500 g, 0.00101 mol) in IPA (20 mL) was cooled to at −78° C. and treated with a stream of ammonia gas over 3 minutes. The resulting solution was heated at 110° C. in a Parr vessel prior to concentration in vacuo, suspension in DCM and filtration through a bed of Celite. The filtrate was concentrated in vacuo to afford 0.504 g of desired product. 1H NMR (400 MHz, CDCl3): δ 1.88-2.02 (m, 2H), 2.99-3.10 (m, 3H), 4.24-4.41 (m, 2H), 5.15 s, 2H), 6.03 (br, 2H), 7.03 (d, J=4.8 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 7.31-7.40 (m, 5H). MS (ES+): m/z 479.33 [MH+].
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.[C:15]([CH:17]1[CH2:19][NH:18]1)#[N:16].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]([NH:9][CH2:10][C:11]([N:18]2[CH2:19][CH:17]2[C:15]#[N:16])=[O:13])=[O:8])=[CH:5][CH:6]=1
Reactant: N#CC1CN1
Reactant: Cc1ccc(C(=O)NCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCC(=O)N2CC2C#N)cc1

Procedure:
In a manner analogous to Example 10, from 0.96 g. p-toluoylglycine (m.p. 161°-162° C.) and 0.34 g. 2-cyanoaziridine in 10 ml. tetrahydrofuran, after the addition of 1.08 g. dicyclohexylcarbodiimide at 10°-15° C., stirring for 30 minutes at 10°-15° C. and for 2 hours at ambient temperature and after filtering off with suction 1.1 g. dicyclohexylurea (m.p. 228° C.) and evaporation of the filtrate in a vacuum, there is obtained the desired compound in crude form. This is dissolved in ethyl acetate, the solution is shaken up with a saturated aqueous solution of sodium bicarbonate and the organic phase is dried and evaporated. The evaporation residue is repeatedly triturated with diethyl ether to give 0.95 g. 1-(4-methylbenzamidoacetyl)-2-cyanoaziridine; m.p. 92°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:34][C:31]3[CH:32]=[CH:33][C:28]([C:25]4[O:26][CH:27]=[C:23]([CH2:21][CH3:22])[N:24]=4)=[CH:29][C:30]=3[O:35][CH3:36])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5]
Reactant: COC(=O)C(C)n1ccc2cc(OCCCBr)ccc21
Reactant: CCc1coc(-c2ccc(O)c(OC)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1coc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[5-(3-Bromo-propoxy)-indol-1-yl]-propionic acid methyl ester (Example 48, 170.20 mg, 0.50 mmol) and 4-(4-ethyl-oxazol-2-yl)-2-methoxy-phenol (Example 39, 109.68 mg, 0.50 mmol) were dissolved in DMF (2 mL) at rt. Cesium carbonate (244.5 mg, 0.75 mmol) was added to the solution, followed by three drops of water. The mixture was stirred at rt for 17 h. The crude reaction mixture was filtered and purified by HPLC. The desired product was isolated as a white solid (143.8 mg, 60.1%). LC/MS m/z 479.3 (M+H)+; RT 3.59 min. 1H NMR (400 MHz, CD2Cl2) δ 7.58 (d, 1H), 7.56 (s, 1H), 7.41 (m, 1H), 7.24 (d, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 7.00 (d, 1H), 6.88 (dd, 1H), 6.46 (d, 1H), 5.11 (q, 1H), 4.28 (t, 2H), 4.22 (t, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 2.61 (q, 2H), 2.34 (m, 2H), 1.82 (d, 3H), 1.29 (t, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[N:11]1[CH:16]=[C:15]([C:17](O)=O)[CH:14]=[N:13][CH:12]=1.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:17]([C:15]3[CH:16]=[N:11][CH:12]=[N:13][CH:14]=3)[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: O=C(O)c1cncnc1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: c1ncc(-c2nc(-c3ccnnc3)no2)cn1

Procedure:
The titled compound was prepared according to the procedure of Method C using the product of Example 83D and pyrimidine-5-carboxylic acid (Maybridge). 1H NMR (300 MHz, CD3OD) δ 8.41 (dd, J=5.4, 2.4 Hz, 1H), 9.44 (s, 1H), 9.47 (dd, J=5.4, 1.4 Hz, 1H), 9.59 (s, 2H), 9.90 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z=227 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[NH2-].[K+].N.[CH3:14]I>>[C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6]([CH2:9][CH3:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Agent: N
Agent: [K+]
Agent: [NH2-]
Product: CCc1ccc(C#N)c(=O)[nH]1

Procedure:
Boatman et al [J. Org. Chem. 30, 3593-7 (1965)] show the reaction of 3-cyano-6-methyl-2(1H)-pyridinone with potassium amide in liquid ammonia and subsequent reaction of the resulting salt with methyl iodide to produce 3-cyano-6-ethyl-2(1H)-pyridinone (p. 3596, 3a).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([Br:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(Br)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-benzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:15](=O)([O:21]C(OC(C)(C)C)=O)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH:3]1[CH2:6][N:5]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:4]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN(C)C1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of N,N-dimethylazetidin-3-amine (Intermediate 28, 100 g, 1.0 mol) and triethylamine (487 mL, 3.5 mol) in CH2Cl2 (500 mL) was added tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (326 g, 1.5 mol) at 0° C. The mixture was then stirred at r.t. for 5 h. The mixture was then washed with water (4×500 mL) and the organic solution were dried (Na2SO4) and concentrated in vacuo. Purification by FCC gave the title compound (62 g, 31%).
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:19][N:20]1[C:24]([C:25](O)=[O:26])=[C:23]([C:28]([F:31])([F:30])[F:29])[C:22]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:21]1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([CH:54]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50].O>C1COCC1>[Cl:55][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:25]([C:24]2[N:20]([CH3:19])[N:21]=[C:22]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])[C:23]=2[C:28]([F:30])([F:31])[F:29])=[O:26])=[CH:54][C:44]=1[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52]
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1Cl
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 40.9 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (=DMTMM, see Tetrahedron 1999, 55, 13159-13170) (1.25 g, 4.51 mmol, 1.1 eq.) was added to 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (1.28 g, 4.1 mmol; preparation according to WO2010/051926) and tert-butyl (5-amino-2-chlorobenzyl)carbamate (1.05 g, 4.1 mmol, 1.0 eq.) in THF (15 ml), and the mixture was left at room temperature for 18 h. Water (30 ml) was added, the mixture was extracted with ethyl acetate (3×30 ml) and the extracts were dried over MgSO4. After concentration under reduced pressure, the product was purified by column chromatography on silica gel (hexane/ethyl acetate), giving tert-butyl [2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzyl]carbamate (924 mg, 41%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>Cl>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: COC(=O)CCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(O)CCCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A mixture of 6-(4-nitrophenoxy) hexanoic acid methyl ester 39 (125 g, 468.16 mmol) and concentrated HCl (1250 ml) was refluxed for 16 hours. The reaction mixture was cooled to room temperature, filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:6) to get pure 53 (95 g, 80.2%) as a white powder. M.p: 104-107° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.[Pd]>[C:2]1([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
In a 60 ml miniautoclave, 85 mg of palladium in sol-gel matrix (cf. Example 71, metal content 0.1%) are suspended in 20 ml of DMF. After 2 mmol of iodobenzene, 2 mmol of styrene, and 4 mmol of tetrabutylammonium acetate have been added, heating at 60° C. is performed with shaking. After 12 h, 288 mg of stilbene can be isolated from the reaction solution. This corresponds to an 80% yield.
Reaction SMILES: CC([N:5]([CH2:9][C@@H:10]([NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:5][CH2:9][C@@H:10]([NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN(C(=O)[O-])C(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)nc1
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl{(2S)-2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-pyridinyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part c) was dissolved in DCM (2 mL) and treated with TFA (1 mL). After 30 min., the solution was concentrated and neutralized through a plug of silica (2% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15](=O)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH2:40])=[NH:39])=[CH:33][CH:32]=2)[CH:28]=[CH:29][N:30]=1>>[CH3:25][C:26]1[N:27]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:38]3[N:39]=[C:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:3]4[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=4[N:40]=3)=[CH:35][CH:36]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: Cc1ccc(CC(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)cc1
Product: Cc1ccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 44 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenyl amino)-4-(4-methylbenzyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (236 mg, 44%) was synthesised from tert-butyl 4-oxo-3-(2-p-tolylacetyl)piperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for synthesis of pyrimidines. MS (ES+) m/z 511.1 (M+H)+
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:25])[C:20](OCC)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC(C[AlH]CC(C)C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH2:1]([O:17][CH2:18][C:19](=[CH2:25])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: C=C(CO)COCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 139.4 %

Procedure:
To a solution of 21 g of ethyl 2-[(hexadecyloxy)methyl]-2-propenoate in 400 ml of ether cooled to 0° C. under an inert atmosphere is added 2.25 ml of 1.2M DIBAL in hexanes over 30 minutes. The reaction is stirred at ambient temperature for 2 hours then cooled to 0° C. while 20 ml of saturated sodium sulfate is added dropwise. After filtering, the cake is washed with ether. The combined ether washings are dried and the solvent removed. The residue is crystallized from methyl alcohol:water to give 25.8 g of the desired product as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][CH:16]([CH3:18])[CH3:17]>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: Cc1cc(O)no1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(C)C)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a stirred solution of 3-hydroxy-5-methylisoxazole (5.0 g, 50.5 mmol) in acetone (125 mL) at room temperature under argon was added K2CO3 (13.9 g, 101 mmol) and the reaction mixture was heated at 60° C. After 30 min, 1-bromo-2-methylpropane (10.4 g, 75.7 mmol) was added dropwise over 2 min. After 16 h the reaction mixture was cooled, filtered and concentrated. Purification by chromatography (silica, 70 to 100% ethyl acetate in heptane) gave the title compound (700 mg, 9%) as a volatile yellow liquid.
Reaction SMILES: [CH3:1][O-:2].[Mg+2].C[O-].[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C=O>CO.C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:1]=[O:2])=[C:9]([OH:13])[CH:8]=1
Reactant: C[O-]
Reactant: Oc1cccc(F)c1
Agent: C=O
Agent: [Mg+2]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Magnesium methoxide (13 g, 150 mmol, 6% in methanol) in methanol (50 mL) was treated with 3-fluorophenol (22.4 g, 200 mmol). The solution was heated to reflux and approximately half the methanol distilled off. Toluene (300 mL) was added and the reaction mixture was heated with azeotropic removal of solvent until the temperature of the distillate reached 95° C. A slurry of paraformaldehyde powder (22 g, 720 mmol) in toluene (20 mL) was added in small portions over 1 hour to the reaction with concurrent removal of volatile materials by distillation. The mixture was stirred was at 95° C. for 1 hour, cooled to 25° C., quenched by slow addition to 10% sulfuric acid and stirred at 30-40° C. for 2 hours. The layers were separated and the aqueous portion extracted with toluene (2×50 mL). The organic layers were combined, washed with 10% sulfuric acid, washed with water, dried with sodium sulfate, filtered and the solvent was evaporated. The resulting yellow oil was purified by flash chromatography over silica gel eluting with hexane:ethyl acetate (5:1) to provide 9.7 g of the title compound as a white solid.