Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:21]3[CH2:23][CH2:22]3)=[C:15](Br)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:21]3[CH2:23][CH2:22]3)=[C:15]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)NC(=O)N1CCn2c(c(C(N)=O)c(Br)c2C2CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(C(N)=O)c3n(c2C2CC2)CCN(C(=O)NC(C)(C)C)C3)cc1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
To a mixture under nitrogen of 0.750 g (1.96 mmol) of N2-tert-butyl-7-bromo-6-cyclopropyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, 0.446 g (2.94 mmol) of 4-methoxyphenylboronic acid (CAS 5720-07-0) and 5.8 ml (12 mmol) of aqueous 2M caesium carbonate solution in a mixture of 15 ml of toluene and 15 ml of ethanol under argon is added 0.64 g (0.78 mmol) of tetrakis(triphenyl-phosphine)palladium (CAS 14221-01-3), and the mixture is heated at 100° C. for 17 hours. After cooling, the mixture is filtered through Celite and the filtrate concentrated under reduced pressure. The residue is then taken up in dichloromethane, the organic phase is washed with water, dried over sodium sulfate and filtered, and the solution is concentrated under reduced pressure. The residue is chromatographed on a column of 15 g of silica gel, eluting with a mixture of 10 to 100% ethyl acetate in dichloromethane, to give 0.19 g of N2-tert-butyl-6-cyclo-propyl-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white solid after crystallizing from a minimum amount of ethyl acetate, rinsing with diethyl ether and drying, and is identical to the compound obtained according to the procedure of Example 12.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH2:14][CH2:12][OH:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CO
Product: O=[N+]([O-])c1cnc(Cl)nc1NCCO
Reaction time: 18 h
Yield: 85 %

Procedure:
19.40 g (0.1 mole) of 2,4-dichloro-5-nitropyrimidine was completely dissolved in 60 ml of methanol and maintained below 15° C. To this solution, a solution of 12.22 g (0.2 mole) of ethanolamine in 20 ml of methanol was added slowly while maintaining the temperature of a reactor below 20° C. The mixture was stirred below 15° C. for 18 hours. After completion of the reaction, the reaction product was maintained below 5° C., and the resulting crystal was filtered, washed and dried, thereby giving 18.58 g (85% yield) of light yellow-colored 2-chloro-4-(2-hydroxyethylamino)-5-nitropyrimidine.
Reaction SMILES: [CH:1]1([Li])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1>C(OCC)C>[CH3:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)=[C:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: [Li]C1C=CC=C1
Solvent: CCOCC
Product: CC(=C1C=CC=C1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, a solution of a cyclopentadienyllithium salt (5.9 g, 81.9 mmol) in dry diethyl ether (100 mL) was cooled in an ice bath, and 4′-methylacetophenone (10.0 g, 74.5 mmol) was dropped thereinto. Then, the product was stirred at room temperature for 20 hours to induce a reaction. After the reaction was terminated, dilute aqueous hydrochloric acid was added thereto, the product was subjected to extraction with hexane, the organic layer was subsequently washed with water and then dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to produce a red liquid. The red liquid was purified by column chromatography (silica gel, solvent: hexane) to produce 9.8 g of 6-methyl-6-(p-tolyl)fulvene. The analytical values were as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]I)=[CH:8][O:9][C:5]=2[CH:4]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: COc1ccc2c(CCI)coc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(CCN3CCN(c4cccc5cccnc45)CC3)coc2c1

Procedure:
A mixture of 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetate:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as yellow oil. Yield: 120 mg (31%); (M+H): 388; 1HNMR (400 MHz, CDCl3): δ□8.82˜8.81 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.05˜8.02 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.44˜6.35 (m, 8H); 3.9 (s, 3H); 3.60˜2.70 (m, 12H).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:20](=[N:22]O)[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH:20]([NH2:22])[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: CC(=NO)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)N)nccc32)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
A mixture of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone oxime (1.29 g, 3.92 mmol), zinc (2.55 g, 39.2 mmol), and NH4Cl (2.10 mg, 39.2 mmol) in MeOH (5 mL) and HOAc (3 mL) was stirred at 80° C. for 4 h. The mixture was cooled to RT and the solid filtered. The filtrate was concentrated under reduced pressure. To the residue was added ammonia solution (50 mL) and the reaction mixture was extracted with DCM (3×50 mL). The combined organic extracts were concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (15:1:0.2) to afford 1.08 g (87.4%) (±)-1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanamine as a yellow solid: MS (ESI) m/z: 316.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:36]1[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[CH2:37]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:36]4[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[CH2:37]4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
To a solution of 3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylbenzaldehyde (D74) (120 mg), acetic acid (0.022 mL) and sodium acetate (31.9 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (90 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (137 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D88) (226 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C26H29ClN2O3S requires 484. found 485.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[CH3:1])[CH2:16][CH2:15]1
Reactant: Cc1c(C=O)cccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Methyl-3-nitrobenzaldehyde (J. Org. Chem. 1981, 46, 1752-1755) (1.0 g, 6.1 mmol) was dissolved in DCE and N-methylpiperazine and HOAc were added followed by sodium triacetoxyborohydride. The reaction was stirred at rt for 1 h and was then quenched with 5% K2CO3 solution. The reaction mixture was extracted (3×) with ethyl acetate, dried over magnesium sulfate, filtered, concentrated onto silica gel and flash chromatographed to give the title compound (1.6 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 3.48 (s, 2H), 2.16-2.42 (m, 1H), 2.10 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:3][C:2]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: CC1(c2ccc(F)c(Br)c2)OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2ccc(F)c(C=O)c2)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
Intermediate 416.1 (1 g, 3.83 mmol) in THF (20 mL) was cooled to −78° C. before adding 1.6 M n-BuLi (2.63 mL, 4.2 mmol) drop-wise. The reaction was stirred for 10 min before quenching with DMF (0.6 mL, 7.7 mmol) and allowing to warm to rt. The crude reaction mixture was quenched with NH4Cl (10 mL), extracted with EtOAc (3×10 mL), washed organic layer with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 550 mg of Intermediate 416.2. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 3H) 3.51-3.92 (m, 2H) 3.90-4.35 (m, 2H) 7.09-7.19 (m, 1H) 7.65-7.79 (m, 1H) 7.99 (dd, J=6.81, 2.42 Hz, 1H) 10.35 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:52])[N:33]([CH2:42][C:43]1[C:44]([O:50][CH3:51])=[N:45][CH:46]=[C:47]([F:49])[CH:48]=1)[C:34]1[N:39]=[CH:38][C:37]([CH:40]=[O:41])=[CH:36][N:35]=1)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[C:27]([O:31][C:32](=[O:52])[N:33]([C:34]1[N:39]=[CH:38][C:37]([CH:40]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:41])=[CH:36][N:35]=1)[CH2:42][C:43]1[C:44]([O:50][CH3:51])=[N:45][CH:46]=[C:47]([F:49])[CH:48]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ncc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cnc2c(c1)c(C(O)c1cnc(N(Cc3cc(F)cnc3OC)C(=O)OC(C)(C)C)nc1)cn2S(=O)(=O)c1ccccc1
Temperature: 5 °C

Procedure:
To a solution of 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (16, 1 equivalent) in 4.0 mL of tetrahydrofuran, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 1 equivalent) is added slowly at −50° C. The reaction is allowed to warm to 5° C. over 70 minutes, then cooled to −45° C. and (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyrimidin-2-yl)-carbamic acid tert-butyl ester (123, 0.78 equivalent) in 2.0 mL of tetrahydrofuran is added. The reaction is allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride and extracted with ethyl ether. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>CS(C)=O>[C:23]([NH:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1F
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1NC(C)(C)C
Yield: 18.2 %

Procedure:
Prepared similarly to that described in Example 260 using 6-(3-fluoro-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (Example 264; 60 mg, 0.203 mmol) and tert-butylamine (0.214 mL, 2.032 mmol) in DMSO (2 mL) at RT for 30 min. The mixture was purified with rpHPLC (Phenomenex Gemini C18 column (100×50 mm, 10 μm), 90 mL/min, 5-40% ACN in water with 0.1% TFA) to give 6-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (13.0 mg, 0.037 mmol, 18% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 349.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (brs, 1H), 11.87 (brs, 1H); 7.99 (1H, d, J=6.8 Hz), 7.87 (1H, s), 7.66 (1H, d, J=7.0 Hz), 7.38 (1H, t, J=7.8 Hz), 7.27 (1H, s), 6.08 (1H, s), 2.57 (3H, s), 1.58 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH:15]([CH2:32]C([O-])=O)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1>CS(C)=O.[Na+].[Cl-]>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:32][CH:15]([O:7][C:6](=[O:5])[CH3:8])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=2)[CH:10]=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCc1ccc(OCC(CBr)CC(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)c1ccc[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(Cn2cccc2C(=O)OC(C)(C)C)OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
0.145 g (0.867 mmol) tert-butylpyrrole-2-carboxylate is dissolved in 10 ml absolute DMSO, mixed with 0.107 g (0.952 mmol) potassium-tert-butylate and stirred at 110° C. for 15 minutes. A solution of 0.333 g (0.864 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 10 ml absolute DMSO is added drop-wise. Following heating at 110° C. for 30 minutes and subsequent cooling, hydrolysis is carried out in saturated NaCl solution. Four extractions with diethyl ether, combination of organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as the crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 80:20) and yields the product as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: NCc1ccncc1
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Product: CCN(CC)C(=O)c1ccc(NCc2ccncc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 87 h
Yield: 49.2 %

Procedure:
Following general procedure 2B, N,N-diethyl-4-fluoro-3-nitrobenzamide (0.272 g, 1.13 mmol) and 4-pyridinylmethanamine (0.11 mL, 1.12 mmol) were stirred at room temperature for 87 h. The crude product was purified by column chromatography (100% EtOAc, then 9:1 CH2Cl2:MeOH) to provide the title compound (0.181 g, 60%). 1H-NMR (CD3OD): δ 8.49 (d, J=6.4 Hz, 2H), 8.27 (d, J=2.8 Hz, 1H), 7.50–7.42 (m, 3H), 6.87 (d, J=8.4 Hz, 1H), 4.77 (s, 2H), 3.44 (br s, 4H), 1.21 (t, J=7.2 Hz; 6H). MS (ESI) (M+H)+=329
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of methyl 4-formylbenzoate (25 g) in methylene chloride (250 mL) is added successively N,N-dimethylethylenediamine (67 g), acetic acid (87 mL), and sodium triacetoxyborohydride (50.6 g). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and to the residue is added a saturated potassium carbonate solution. The mixture is extracted with ethyl acetate, and the organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl 4-[[[2-(dimethylamino)ethyl]amino]methyl]-benzoate (31.9 g, yield; 89%) as a colorless oil. MS (APCI) m/z: 237 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[CH:5][C:6]2[O:10][CH:9]([C:11]#[N:12])[CH2:8][C:7]=2[CH:13]=1.Cl.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[CH:5][C:6]2[O:10][CH:9]([CH2:11][NH2:12])[CH2:8][C:7]=2[CH:13]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)OC(C#N)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)OC(CN)C2
Yield: 22.2 %

Procedure:
5,6-Dimethoxy-2,3-dihydrobenzofuran-2-carbonitrile (Method 16; 2.63 g, 12.94 mmol) was dissolved in ethanol (700 ml) and hydrochloric acid (conc, 2.3 ml) and Pd on charcoal (10%, 1 g) were added. The mixture was hydrogenated under 3.5 atmosphere of hydrogen at 72° C. for 3 days. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in water and washed once with diethyl ether. The pH of the aqueous phase was adjusted to 10–11 with NaOH(aq) and the resulting solution was extracted several times with diethyl ether, then with DCM. The organic layers were dried, filtered and evaporated under reduced pressure. The diethyl ether extraction gave 0.6 g (22%) of pure product and the DCM extraction gave 2.0 g (74%) of pure product. NMR (400 MHz) 2.80–2.87 (m, 3H), 3.21 (dd, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 4.72–4.82 (m, 1H), 6.47 (s, 1H), 6.82 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Product: N#Cc1ccc(N2CCCCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-bromo-3-(trifluoromethyl)-benzonitrile and piperidine (Fluka, Buchs, Switzerland), with a reaction temperature of 95° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4](Cl)[CH:3]=1.[C:14]1([C@H:20]([NH:22][C:23]([NH2:25])=[O:24])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4]([NH:25][C:23]([NH:22][C@@H:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:21])=[O:24])[CH:3]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COCc1nc(Cl)cc(Cl)c1C#N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
A mixture of 4,6-dichloro-2-(methoxymethyl)nicotinonitrile (75.7 mg, 0.349 mmol), (R)-1-(1-phenylethyl)urea (77 mg, 0.469 mmol) and Xantphos G2 (39 mg, 0.044 mmol) in THF (2 ml) was sealed, sparged with argon, charged with triethylamine (0.17 ml, 1.220 mmol) and heated to 50° C. for 17 hr. The mixture was cooled and filtered through celite, eluted with EtOAc before it was concentrated in vacuo and purified via flash chromatography (25-100% Et2O/hexane) to provide (R)-1-(4-chloro-5-cyano-6-(methoxymethyl)pyridin-2-yl)-3-(1-phenylethyl)urea. MS ESI calc'd for C17H18ClN4O2 [M+H]+ 345. found 345.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].O[CH:11]([CH2:23][CH3:24])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH3:20][C:17]([O:16][C:15](=[O:21])[N:14]([CH2:13][CH2:12][CH:11]([O:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:23][CH3:24])[CH3:22])([CH3:18])[CH3:19]
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: Oc1cc(Cl)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.7 %

Procedure:
2,5-Dichlorophenol (325 mg, 2.00 mmol) and (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester (217 mg, 1.00 mmol) were dissolved in tetrahydrofuran (10 ml). To the resulting solution was added triphenylphosphine (393 mg, 1.50 mmol) and then diethyl azodicarboxylate (0.240 ml, 1.52 mmol). The solution was then allowed to stir at room temperature under nitrogen for 24 h. The mixture was then poured into water and extracted three times with diethyl ether. The combined organic fractions were washed with 1N sodium hydroxide solution twice and then brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 180 mg (50%) of the title compound as an oil.