Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1.Cl[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[CH3:9]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: COc1ncc([N+](=O)[O-])cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A yellow solution of 2-methoxy-3-methyl-5-nitropyridine (68.8 g, 409 mmol) and tert-butyl 2-chloroacetate (77.0 g, 511 mmol) in THF (1 L) was stirred and cooled to −20° C. in a dry ice/isopropanol bath. Potassium tert-butoxide (115 g, 1.02 mol) was added at a rate so that the reaction temperature was less than −10° C. The reaction mixture turned dark purple. When the addition was complete, the cooling bath was removed and the reaction was stirred for 30 min. The stirred reaction mixture was quenched with HCl (500 mL, 2.4 N). The purple solution turned pale yellow and the mixture separated into two layers. The organic layer was separated, washed three times with brine, and concentrated in vacuo. Hexane was added to the amber residue. The mixture was concentrated in vacuo and then dried under high vacuum for 1 hr to give tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (83.4 g, 72% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 4.09 (s, 2H), 4.02 (s, 2H), 2.21 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.81, 163.63, 147.88, 139.41, 135.19, 120.82, 81.66, 54.69, 44.48, 28.03, 15.27. An analytical sample was recrystallized from hexane to give white needles, mp 71-72.5° C. Anal. calcd. for C13H18N2O5: C, 55.31, H, 6.42, N, 9.92. Found: C, 55.52, H, 6.40, N, 9.84.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[Cl:15]N1C(=O)CCC1=O>C(#N)C>[Cl:15][C:7]1[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]([CH3:14])[C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(-c2cccnc2)nn1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CNc1c(Cl)c(-c2cccnc2)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A mixture of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine (0.35 g, 1.8 mmol) and N-chlorosuccinimide (0.273 g, 2 mmol) was combined in acetonitrile (3 mL), stirred at room temperature for 30 minutes, concentrated under reduced pressure and purified using silica gel chromatography eluting with a gradient of EtOAc in hexanes to yield the title compound as a yellow oil (0.096 g, 23%): IR (thin film) 1581.6 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.5 Hz, 1H), 8.57 (dd, J=4.8, 1.3 Hz, 1H), 8.15 (ddd, J=7.8, 2.0, 2.0 Hz, 1H), 7.33 (dd, J=8.1, 5.1 Hz, 1H), 3.80 (s, 3H), 2.91 (d, J=5.8 Hz, 3H); ESIMS (m/z) 225.6 [M+2].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(F)cc1F
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2F)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 2,4-difluorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 52%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:36]=[CH:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Yield: 83 %

Procedure:
A solution of t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylvinyl)indol-1-ylmethyl]-3-methoxybenzoate (0.54 g) in methanol (20 ml) was treated with 10% palladium on carbon (0.13 g) and shaken under 3.45 bars of hydrogen for 18 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated to give t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (0.45 g, 84%) as a white foam; partial NMR (80 MHz, CDCl3): 1.54(s, 9H, C(CH3)3), 2.69(t, 2H, COCH2), 3.62(s, 2H, COCH2Ar), 3.65(s, 3H, CO2CH3), 3.93(s, 3H, OCH3), 5.25(s, 2H, NCH2Ar).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1)C1CCOCC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-e]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (150 mg, 0.33 mmol) and tetrahydropyran-4-ylcarboxylic acid (45 mg, 0.34 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (51 mg, 34%), MS (ISP) m/z=457.3 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 85 %

Procedure:
10 g (0.05 mol) of 2-(4-nitrophenyl)propanoic acid were dissolved in a mixture of 5 ml of water and 100 ml of methanol and 0.65 g of Pd/C 5% were added. The mixture was submitted to hydrogenation at 60 psi for 2 hours at room temperature. After the separation of the catalyst by filtration on celite the methanol was evaporated under vacuum and the title compound was crystallised from water on cooling (7 g; 85 % yield).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:30])=[CH:9][C:10]([O:28][CH3:29])=[CH:11][C:12]=3[C:13]32[CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC>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.CN(C=O)C>[F:30][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)=[CH:3][CH:4]=3)[C:13]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:12]=2[CH:11]=[C:10]([O:28][CH3:29])[CH:9]=1
Reactant: COc1cc(F)c2c(c1)C1(CSC(NC(=O)OC(C)(C)C)=N1)c1cc(Br)ccc1O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(F)c2c(c1)C1(CSC(NC(=O)OC(C)(C)C)=N1)c1cc(-c3cnccn3)ccc1O2
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A 10 ml resealable tube was charged with tert-butyl 7′-bromo-4′-fluoro-2′-methoxy-5H-spiro[thiazole-4,9′-xanthene]-2-ylcarbamate (300 mg, 0.606 mmol), tetrakis(triphenylphosphine)palladium (70.0 mg, 0.061 mmol) and DMF (3.03 ml) and 2-(tributylstannyl)pyrazine (402 mg, 1.090 mmol). The mixture was stirred for 3 hr at 110° C. The mixture was partitioned between EtOAc and water. The organic layer was washed twice with water, filtered through celite and concentrated under reduced pressure. The solids were triturated with hexane to remove excess tin residue before being filtered. Purification by silica gel chromatography (10-80% CH2Cl2/MeOH/NH4OH in CH2Cl2) to provide tert-butyl 4′-fluoro-2′-methoxy-7′-(pyrazin-2-yl)-5H-spiro[thiazole-4,9′-xanthene]-2-ylcarbamate.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH:2]1[O:4][CH2:3]1.[C:11](OC)(=[O:14])[CH:12]=[CH2:13]>>[CH2:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]1[O:4][CH2:3]1)=[O:14]
Reactant: OCCCCOCC1CO1
Reactant: C=CC(=O)OC
Product: C=CC(=O)OCCCCOCC1CO1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
In each case 20 mMol of 4-hydroxybutyl glycidyl ether (2.92 g) were stirred with 80 mMol of methyl acrylate (6.89 g), 100 mg of Novozym® 435 and 4.0 g of 5 Å molecular sieve were stirred at 20 or 40° C. for 2, 4, 6, 8 or 24 h. Thereafter, the enzyme was filtered off and the excess of methyl acrylate was removed on a rotary evaporator. A colorless acrylate was obtained with 93% (at 20° C.) or 94% (at 40° C.) yield.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH3:12]>C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:9]=[C:8]([Br:1])[CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH3:12]
Reactant: BrBr
Reactant: COc1c(C)cccc1C
Solvent: ClC(Cl)Cl
Product: COc1c(C)cc(Br)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromine is added dropwise to a solution of 2,6-dimethylanisole (12.0 g) in chloroform (100 ml) at about 5°. The solution is stirred at 5° for 2 hr and then allowed to warm to 20°-25°. The reaction mixture is poured into ice-water, and the phases are separated. The chloroform phase is washed with water, aqueous sodium bisulfite solution, then with water, dried over sodium sulfate and concentrated under reduced pressure to give 3,5-dimethyl-4-methoxybromobenzene.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](/[C:19](/[CH2:24][CH3:25])=[C:20](/[F:23])\[CH2:21][OH:22])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1)[CH2:2][CH3:3].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>ClCCl.C(#N)C>[CH2:1]([O:4][C:5]1[C:6](/[C:19](/[CH2:24][CH3:25])=[C:20](/[F:23])\[CH:21]=[O:22])=[CH:7][C:8]2[C:9]([CH3:17])([CH3:18])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-3-(3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enol (2.05 g, 6.13 mmol) in dichloromethane (81 mL) and acetonitrile (16 mL) was treated with tetrapropylammonium peruthenate (0.305 g, 0.92 mmol), 4 Å molecular sieves (0.442 g), and N-methylmorpholine-N-oxide (2.41 g, 15.3 mmol), and the solution was stirred for 0.5 h at ambient temperature. The mixture was filtered through a sintered glass funnel containing a bed of silica gel about 1 inch thick using 20% ethyl acetate in hexane as the eluent. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:9]([N+:20]([O-:22])=[O:21])=[CH:8][N:7]=1.NCC1CCC(C[NH:36][C:37]2C([N+]([O-])=O)=CN=C(NCC3C=CC=CC=3Cl)[N:38]=2)CC1>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:37]([NH2:38])=[NH:36])[CH2:18][CH2:19]2)[C:9]([N+:20]([O-:22])=[O:21])=[CH:8][N:7]=1
Reactant: NCC1CCC(CNc2nc(NCc3ccccc3Cl)ncc2[N+](=O)[O-])CC1
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2Cl)nc1NCC1CCNCC1
Product: N=C(N)N1CCC(CNc2nc(NCc3ccccc3Cl)ncc2[N+](=O)[O-])CC1

Procedure:
This compound was prepared in an analogous fashion to Example 9 using N2-(2-Chloro-benzyl)-5-nitro-N4piperidin-4-ylmethyl-pyrimidine2,4-diamine (Example 11) as a starting material in place of N4-(4-Aminomethyl-cyclohexylmethyl)-5-nitro-N2-(2-chloro-benzyl)-pyrmidine-2,4-diamine, m/z calculated for C18H23ClN8O2: 418.0 found: 419.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:10]2=[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:13][N:9]2[CH2:8][CH2:7][NH:6]1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:10]3[N:5]([C:3](=[O:4])[CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[NH:6][CH2:7][CH2:8][N:9]3[N:13]=2)=[CH:15][CH:16]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(CN1CCOCC1)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A mixture of 2-chloroacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (80 mg, 0.215 mmol), morpholine (37 mg, 0.430 mmol), and triethylamine (22 mg, 0.215 mmol) in 1,2-dichloroethane (2 ml) was stirred for 24 hours at ambient temperature. After dilution of dichloromethane, the mixture was washed with an aqueous saturated sodium bicarbonate solution, and brine. The organic phase was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:ethyl acetate ethyl acetate/methanol; 20/1), and the obtained oil was crystallized from diisopropyl ether to give 7-(4-fluorophenyl)-2-morpholinoacetyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (50 mg).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1>ClCCl.C(N(CC)CC)C>[O:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH2:9][CH2:10]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCC(=O)Cl
Reactant: NCC1CCN(CCOc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCC1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of propionyl chloride (2.37 g) in dichloromethane (10 ml) was added dropwise to a solution of 4-aminomethyl-1-(2-phenoxyethyl)piperidine (6.0 g) in dichloromethane (50 ml) and triethylamine (3.9 ml) at 0° C. The solution was allowed to warm up to ambient temperature with stirring and then stirred at this temperature for a further 2 hours. More propionyl chloride (0.3 ml) was added at ambient temperature and the solution stirred for a further half-hour. Further propionyl chloride (0.3 ml) was added and the mixture stirred for 1 hour. The mixture was extracted with 2M hydrochloric acid. The combined acidic extracts were washed with ethyl acetate, then basified with sodium hydroxide solution and extracted with dichloromethane to give an oil which solidified on standing to give N-[1-(2-phenoxyethyl)piperid-4-ylmethyl]propionamide, m.p. 85°-86° C.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][CH:23]1[O:28][CH:27]([CH3:29])[CH2:26][N:25]([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)[CH2:24]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH2:26][CH:27]([CH3:29])[O:28][CH:23]([CH3:22])[CH2:24]4)=[CH:35][N:34]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: CC1CN(c2ccc(N)nc2)CC(C)O1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)OC(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 25.8 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 6-bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl )-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid (0.358 g, 27.3%). MS (APCl) Calc'd for M+1: 513.2. Found: 513.1. Anal. Calc'd for C24H29BrN6O2: C, 56.14; H, 5.69; N, 16.37. Found; C, 55.90; H, 5.62; N, 16.10.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[C:15]([SiH2:19][O:20][C:21]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[C:29][CH3:30])[CH:23]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:15]([SiH2:19][O:20][C:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:22]1[CH:27]=[CH:26][N:25]2[N:13]=[C:29]([CH3:30])[CH:28]=[C:24]2[CH:23]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC#Cc1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of O-mesitylenesulfonylhydroxylamine (18.6 g, 77.8 mmol, 5.0 equiv) in chloroform (50 ml) is added at 0-10° C. to a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-2-prop-1-ynyl-pyridine in chloroform (50 ml). The resulting mixture is stirred at room temperature overnight. The solvent is removed in vacuo, and N,N-dimethylformamide (50 ml) is added to the residue. Potassium carbonate (4.30 g, 31.1 mmol, 2.0 equiv) is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient from hexane/EtOAc 100:0 to 30:70) affords the title compound (2.6 g, 42%). 1H NMR (400 MHz, d6-DMSO): δ=8.42 (d, J=7.1 Hz, 1H), 7.60-7.58 (m, 4H), 7.43-7.35 (m, 7H), 6.64 (dd, J=7.3/1.9 Hz, 1H), 6.27 (s, 1H), 4.71 (s, 2H), 2.30 (s, 3H), 0.99 (s, 9H). MS (ES+): 401 (M+H)+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11](/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1>CS(C)=O.[H-].[Na+]>[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11]([CH:38]2[CH2:2][CH:39]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Trimethylsulfoxonium iodide (45.1 mg, 0.205 mmol) in anhydrous methyl sulfoxide (4 mL) and 60% sodium hydride in mineral oil (16.4 mg, 0.411 mmol) was stirred for 5 minutes at room temperature and treated with a mixture of ethyl (2E)-3-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]acrylate (108 mg, 0.205 mmol) in methyl sulfoxide (2 mL) was added. After 4 hours the mixture was cooled to room temperature and quenched with saturated ammonium chloride solution (7 mL). The aqueous layer was extracted with dichloromethane (3×10 mL), dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified via HPLC preparative to give the title compound as a white solid (33.6 mg 0.062 mmol): LCMS (Conditions a): MH+=541 Rt =4.20 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1H), 7.99 (1H), 7.69 (2H), 7.58 (2H), 7.35 (2H), 7.18 (1H), 7.15 (1H), 7.06 (1H), 5.49 (1H), 4.18 (2H), 4.04 (3H), 3.91 (3H), 2.45 (1H), 1.86 (1H), 1.56 (1H), 1.47 (1H), 1.26 (3H).
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].[CH2:8]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11].Cl.C(NCCCC)CCC.C1(C=CC(O)=CC=1)O>>[CH2:8]([N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])[CH2:9][CH2:10][CH3:11]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCNCCCC
Agent: Cl
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)N(CCCC)CCCC
Yield: 15 %

Procedure:
200 g of methyl methacrylate, 129 g of dibutylamine, 8.25 g of dibutylamine hydrochloride, 5 g of Fe-(III)-acetylacetonate, and 0.5 g of hydroquinone were heated for 3 hours at 230° C. in an autoclave (pmax =10 atmospheres). In this way, a 15% yield of N,N-dibutylmethacrylic acid amide form. The selectivity, calculated on the methyl methacrylate reacted, was greater than 80%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=1)=[O:29]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:23][CH2:24]4)[CH2:20][CH2:21]3)[N:10]([CH2:27][C:28](=[O:29])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc12
Product: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C3CC3)CC1)n2CC(=O)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 15 starting from 1.40 g (4.09 mmol) 2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 1.02 g (4.09 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:18]>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:17](=[O:18])[N:5]([CH2:4][C:3]2[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=2[Br:1])[CH2:6][CH3:7])=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccc(F)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and 4-fluorobenzyl chloroformate.