Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1)(=[O:29])[NH2:28].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:27](=[O:29])[NH2:28])=[CH:47][CH:46]=1)[CH2:13][C:12](=[O:15])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NC(=O)Cc1ccc(OCCNCc2ccccc2)cc1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)Cc1ccc(OCCN(CC(=O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1

Procedure:
A mixture 3,4-dibenzyloxyphenacyl bromide (32.8 g.), N-[2-(4-carbamoylmethylphenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodium carbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 3 hours, then filtered hot to remove the inorganic sediment and evaporated in vacuo to afford a thick syrup. The latter was recrystallized upon trituration in diethyl ether and a sample of the resultant solid was recrystallized from ethanol to give N-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-carbamoylmethylphenoxy)ethylamine, m.p. 99°- 101°C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)c1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Yield: 93 %

Procedure:
Treatment of give 5-(2-chloroethanoyl)-1,3-dihydrobenzimidazol-2-one with sodium azide, following the procedure described in Example 6. Step 4, gave 6-(2-azidoethanoyl)-1,3-dihydrobenzimidazol-2-one (5.75 g, 93%):
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:37][CH2:38]OC(C)=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:37]=[CH2:38])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (17a) (5.6 g, 11.5 mmol), tetrakis(triphenylphosphine) palladium(0) (2.1 g, 1.8 mmol), and (2-ethenyl)tri-n-butyltin (13.5 mL, 46.2 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (17b) (4.3 g). MS m/z: [M+H+] calcd for C26H28N2O4, 433.2. found 433.4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][C:22]=2[F:24])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1F
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 25.9, 29.6, 42.6, 60.2, 104.7 (t, J 25.8), 112.0 (dd, J 22.9 and 3.5), 127.3, 129.6, 131.5 (d, J 8.8), 131.5 (d, J 9.8), 139.1, 139.4, 159.9 (dd, J 252.0, 11.7) and 163.0 (dd, J 252.0, 11.7).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: COc1cccc(C)c1C(=O)O
Product: COc1cccc(C)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=303.4 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methoxy-6-methylbenzoic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](N(C)C)[CH:32]=[C:33](N=C=O)[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:40].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:6][C:5]([N:9]([CH3:10])[CH3:8])=[O:40])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc2c(N=C=O)cc(N(C)C)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc2ccc(NC(=O)N(C)C)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-dimethylamino-carbonylaminobenzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzaldehyde (12.13 ml, 110 mmol, Aldrich) and pinacolone (12.48 ml, 100 mmol, Aldrich) in absolute ethanol (120 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 3.72 ml, 10 mmol). The clear yellow reaction mixture was stirred at room temperature under argon for 24 hours. The reaction mixture was concentrated to 1/3 volume and partitioned between 50% saturated NH4 Cl and EtOAc. The layers were separated and the organic layer was washed twice with H2O and brine then dried (Na2SO4) and concentrated under reduced pressure. The oily residue was purified by flash chromatography (Merck Silica gel, 10% EtOAc/hexane), yielding the title compound as a colorless oil that slowly solidified. The white solid was recrystallized from hexane, yielding the title compound as white crystals (13.9 g, 67.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9](Cl)[N:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=2[O:26][CH3:25])[N:8]=1)[CH3:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1nc(NCc2ccc(OC)cc2OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a cooled (˜10° C.) solution of (6-chloro-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (8.0 g, 30.8 mmol) in MeCN (80 mL) was added a solution of triethylamine (6.4 mL, 46 mmol) and 2,4-dimethoxybenzylamine (5.5 mL, 37 mmol). The mixture was then stirred for 16 hours at ambient temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and aqueous potassium hydrogenphosphate solution. The EtOAc layer was then washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using SiO2 chromatography (10-50% EtOAc/Petrol) to give [6-(2,4-dimethoxy-benzylamino)-3-nitro-pyridin-2-yloxy]acetic acid ethyl ester (9.53 g) as a yellow solid. MS: [M+H]+ 392
Reaction SMILES: CC(O)=[O:3].O.[F:6][C:7]([F:13])([F:12])[CH2:8][C:9](=[O:11])[CH3:10]>O1CCOCC1>[F:6][C:7]([F:13])([F:12])[CH2:8][C:9](=[O:11])[CH:10]=[O:3]
Reactant: CC(=O)CC(F)(F)F
Reactant: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)CC(F)(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of SeO2 (4.23 g, 38.1 mmol) in dioxane (25 mL) was added AcOH/H2O (1 mL/1 mL). 4,4,4-Trifluorobutan-2-one (3.81 mL, 31.7 mmol) was added dropwise to the above reaction mixture. The resulting solution was stirred overnight at 100° C. The solution was used in the next step without any further work-up or purification.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:6]2[N:7]([C:15]([CH2:18][CH3:19])=[N:16][N:17]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2>CN(C)C=O>[CH2:18]([C:15]1[N:7]2[C:8]3[C:13]([N:14]=[C:5]([NH:3][CH2:1][CH3:2])[C:6]2=[N:17][N:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:19]
Reactant: CCN
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCNc1nc2ccccc2n2c(CC)nnc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Monoethylamine was bubbled through a solution of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, in N,N-dimethylformamide (50 ml.) at 0° C. for about 2 minutes. The clear solution was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was next poured over ice and the precipitate was separated by filtration, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g. (83% yield) of pure 1-ethyl-4-ethylamino-[1,2,4]triazolo[4,3-a]quinoxaline as white solid (m.p. 235°-238° C.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Cl.[F:31][C:32]1([F:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][C:32]([F:38])([F:31])[CH2:33][CH2:34]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)(F)CC2)c1OCCC(C)c1ccc(F)cc1
Yield: 31 %

Procedure:
Example 8a (56 mg, 0.12 mmol) was reacted with 4,4-difluoropiperidine hydrochloride (2.0 eq.) as described under General Procedure J to afford the title compound (19 mg, 31%) as a clear yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.05 (t, J=5.7 Hz, 2H), 3.97 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 3.11-2.89 (m, 1H), 2.66 (t, J=5.7 Hz, 2H), 2.58 (m, 4H), 2.49 (s, 3H), 2.18 (s, 3H), 2.05-1.92 (m, 6H), 1.30 (d, J=6.9 Hz, 3H). MS (ES+) m/z 528 (M+H+).
Reaction SMILES: OCCCCC[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].NC1C=C[C:49]([C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>>[C:33]([C:26]1[CH:27]=[N:28][C:29]2[C:24]([C:25]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[CH:23][C:22]([S:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([NH:10][C:9]1[CH:8]=[CH:7][C:49]([C:52]3[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=3)=[CH:48][CH:47]=1)=[O:12])(=[O:21])=[O:20])=[CH:31][C:30]=2[CH3:32])(=[O:34])[NH2:35]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: COC(=O)CCCc1ccc(-c2ccc(N)cc2)cc1
Product: COC(=O)CCCc1ccc(-c2ccc(NC(=O)c3cccc(S(=O)(=O)c4cc(C)c5ncc(C(N)=O)c(Nc6cccc(OC)c6)c5c4)c3)cc2)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 29 in place of 8-aminooctanol. ES/MS calcd. for C42H39N4O7S+ 743.3. Found m/z=743.4 (M+H)+.
Reaction SMILES: C(=O)(O[CH2:6][C:7](=[CH2:9])[CH3:8])OCC.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:8]([C:18]#[C:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](=[CH2:6])[CH3:9]
Reactant: C=C(C)COC(=O)OCC
Reactant: C#Cc1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)CC#Cc1ccccc1
Yield: 61.5 %

Procedure:
A mixture of ethyl methallyl carbonate (1.58 g, 0.011 mole), phenylacetylene (1.02 g, 0.010 mole) and tetrakis(triphenylphosphine) palladium (O) (0.25 g, 0.21 mmole) in tetrahydrofuran (15 ml) was refluxed for 91 hours under N2. Gas chromatographic analysis showed that the ethyl methallyl carbonate was totally consumed but about 10 percent of phenylacetylene remained. The product, methallylphenylacetylene, was isolated by preparative gas chromatography (0.96 g, 61.5 percent yield) and identified by spectroscopic techniques.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:21])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(C(=O)CC(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Heat a mixture of 3,4′-dimethylbutyrophenone (3 g, 17.02 mmol), NBS (3.787 g, 16.18 mmol), and AIBN (70 mg, 0.425 mmol) in carbon tetrachloride (80 mL) for 14 h at reflux. Cool to ambient temperature and filter the mixture. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1) to provide the title compound as oil (2.802 g, 65%). GC-MS m/z: 255 (Ma).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24]([O:30]C)=[N:25][CH:26]=[CH:27][C:28]=4I)[NH:20]3)=[C:16]([CH3:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:33].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4[Cl:33])[NH:20]3)=[C:16]([CH3:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: COc1nccc(I)c1-c1nc2c(C)nc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[8-(4-iodo-2-methoxy-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 2.54 mmol) in glacial acetic acid (30 mL) was added 11.6 M HCl (30 mL). The reaction mixture was stirred at 75° C. for 6 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (250 mL) followed by the addition of triethylamine (2.78 mL, 20 mmol). The solution was cooled to 0° C. and di t-butyl dicarbonate (573 mg, 2.63 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours, poured on saturated NaHCO3 solution and extracted with CH2Cl2 (3×200 mL). The combined organic layers, were dried over MgSO4 and concentrated to give the title compound as a yellow solid. (0.691 g, 62%). HPLC 93%; LCMS (+ESI, M+H+) m/z 446; IR (KBr, cm−1) 3431, 2974, 1700, 1506, 1229; 1H NMR (400 MHz, DMSO+D2O) δ 7.64 (d, J=7.0 Hz, 0.7H), 7.32 (d, J=7.0 Hz, 0.3H), 6.89 (d, J=7.0 Hz, 0.3H), 6.59 (d, J=7.0 Hz, 0.7H), 3.75 (br s, 4H), 3.45 (br s, 4H), 2.60 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)C=2)C=1.Br[C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[C:43]([C:45]([OH:48])([CH3:47])[CH3:46])[N:42]=[C:41]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH:40]=2)[CH:36]=[N:37][CH:38]=1>>[NH:29]1[CH2:28][CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:33]3[CH:34]=[C:35]([C:39]4[CH:44]=[C:43]([C:45]([OH:48])([CH3:47])[CH3:46])[N:42]=[C:41]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=5)[CH:40]=4)[CH:36]=[N:37][CH:38]=3)[CH:22]=[N:23]2)[CH2:31][CH2:30]1
Reactant: CC(C)(O)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Product: CC(C)(O)c1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step 1) with 2-(5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-propan-2-ol (Example 2.80; step2)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:38])[C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=1.C[Si](Cl)(C)C>C(O)CCC>[C:11]([C:10]1[C:5]2[C:4]([NH:23][CH:24]3[CH2:25][CH2:26]3)=[N:3][C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([N:34]([CH3:38])[C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=3)=[N:7][C:6]=2[NH:8][CH:9]=1)#[N:12]
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NC3CC3)c3c(C#N)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 20 h
Yield: 32.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (165 mg, 0.425 mmol), N-(4-aminophenyl)-N-methylacetamide (107 mg, 0.652 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (50 mg). MS 362.3 (M+H); UV 202.8, 254.0, 280.4 nm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([OH:33])[CH:23]1[CH2:22][CH2:21][N:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: O=C(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccn1)C1CCN(Cc2ccccc2)CC1
Temperature: -65 °C
Reaction time: 8 h

Procedure:
2.1 ml (2.2 10-2 mole) of 2-bromopyridine in solution in 10 ml of tetrahydrofuran (THF) are added dropwise to a solution, cooled to -65° C., of 15.6 ml (2.5 10-2 mole) of n-BuLi and of 20 ml of THF. The mixture is stirred for 1/4 h at -65° C. and then 5.6 g (2 10-2 mole) of 1-benzyl-4-benzoylpiperidine in 20 ml of THF are added dropwise while the temperature is maintained at -65° C. The mixture is allowed to warm up very slowly and is then left overnight. It is heated to the reflux temperature for 2 h and then evaporated to dryness, and the residue is taken up with a mixture of water and ether. The ether phase is washed with water, dried, filtered and evaporated down. Chromatography on silica is carried out (eluent 95/5 CH2Cl2 /MeOH). A product which crystallizes from petroleum ether is collected. M.p.= 142°-143° C.
Reaction SMILES: [C:1]([C@@H:5]([NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18](C(OC(C)(C)C)=O)[NH:19][CH3:20])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[C:1]([C@@H:5]([NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH3:20])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2]
Reactant: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Reaction time: 1 h

Procedure:
To a solution of the product from Step G in methylene chloride was added trifluoroacetic acid (33% by volume). After stirring for 1 h the solution was concentrated in vacuo to yield the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH3:9])[O:6][CH:7]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH2:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[N:4]=1)[CH3:9]
Reactant: CCc1nc(CCl)co1
Reactant: CCOP(OCC)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1coc(CC)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 4-chloromethyl-2-ethyl-1,3-oxazole (3.26 g), triethyl phosphite (8.19 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-ethyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (3.86 g, yield 70%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[F:27][C:28]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:27][C:28]1[CH:36]=[C:35]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)=[N:4][CH:3]=2)[CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31]
Reactant: CN1CCC(COc2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
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: C1COCCO1
Product: CN1CCC(COc2ccc(Nc3ncc(-c4ccc(C(N)=O)c(F)c4)n4ccnc34)cc2)CC1
Yield: 85.2 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-amine (20 mg, 0.048 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (25.5 mg, 0.10 mmol), Pd(PPh3)4 (13.9 mg, 0.001 mmol) and 1M Na2CO3 (0.8 mL) in dioxane (2 mL). Purification by silica gel column chromatography eluting with a mixture 95:5 followed by 90:10 DCM:MeOH affords a solid that was triturated with ethyl acetate to give the title compound (19.4 mg, 85%). LCMS: Rt 1.96 min (94%), m/z (APCI) 475 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 1.48-1.61 (2H, m), 1.98-2.02 (3H, m), 2.51-2.58 (4H, m), 2.70 (3H, br s), 3.91 (2H, d), 6.98 (2H, d), 7.55 (1H, s), 7.65-7.87 (6H, m), 7.98 (2H, d), 8.06 (1H, s), 9.68 (1H, s).