Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][Si:2]([CH3:5])([CH3:4])[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cncnc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[Si](C)(C)c1cncnc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
In a 500 ml 4 neck round bottom flask stirring under N2 was charged 1.2 g of Mg (0.050 moles, 1.0 eq) and 5.43 g of chlorotrimethylsilane (0.050 moles, 1.0 eq.) in 50 ml of HMPA (hexamethylphosphoramide) which was heated at 80° C. for 4 hours. To the reaction was added dropwise, 6.4 g of 5-bromopyrimidine (0.040 moles, 0.8 eq.) in 50 ml of HMPA while maintaining the temperature at 80° C. The reaction mixture was stirred for 18 hours at 75° C. after which GLC indicated complete consumption of the 5-bromopyrimidine. The reaction was quenched by adding 100 ml of water, acidified with 10% HCl and extracted with 2×250 ml of ethyl acetate (EtOAc). The acidic aqueous solution was neutralized with 6M NaOH to pH 10 and extracted with 250 ml of EtOAc. The extractions were combined and washed with 4×250 ml aliquots of distilled water. Drying and concentrating afforded 1.2 g of crude product which was purified by flash chromatography with 1:4 ethyl acetate/hexane and afforded 0.6 g of a clear oil (9.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:15][C:8]=2[O:7]1)=[O:5])[CH3:2].[OH:23][C:24]1[C:29]([CH2:30][CH2:31][CH3:32])=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=1[C:34](=[O:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOCC.CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:33][C:28]3[CH:27]=[CH:26][C:25]([C:34](=[O:36])[CH3:35])=[C:24]([OH:23])[C:29]=3[CH2:30][CH2:31][CH3:32])=[CH:15][C:8]=2[O:7]1)=[O:5])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)C1CCc2ccc(OCCCCCBr)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCc1c(OCCCCCOc2ccc3c(c2)OC(C(=O)OCC)CC3)ccc(C(C)=O)c1O
Reaction time: 6 h
Yield: 83.1 %

Procedure:
A mixture of 1.2 g (3.23 mmoles) of racemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester, 1.0 g (5.15 mmoles) of 2',4'-dihydroxy-3'-propylacetophenone, 1.8 g (13.0 mmoles) of anhydrous potassium carbonate, 30 ml of acetone, and 15 ml of N,N-dimethylformamide was stirred and refuxed for 6 hr. After being cooled, the mixture was diluted with ether. The ether phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (2.1 g) was chromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethyl acetate afforded 1.3 g (83%) of racemic-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:17]=3)[C:13]#N)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:28]([Mg]Cl)[CH3:29].S(=O)(=O)(O)[OH:33]>C1COCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:13](=[O:33])[CH2:28][CH3:29])[CH:15]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(COc2cc(C#N)cc(-c3ccc4c(c3)OCO4)c2)cc1
Reactant: O=S(=O)(O)O
Reactant: CC[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1cc(OCc2ccc(OC)cc2)cc(-c2ccc3c(c2)OCO3)c1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 3-benzo[1,3]dioxol-5-yl-5-(4-methoxy-benzyloxy)-benzonitrile (250 mg) in anhydrous THF (3 mL) were added a solution of ethylmagnesium chloride (517 μL of 2 M solution in diethyl ether) and catalytic amount of cuprous bromide (2 mg). The resulting reaction mixture was refluxed for 1 h and then additional amount of ethylmagnesium chloride (517 μL of 2 M solution in diethyl ether) was added and heating was continued for 30 min. After it was cooled down, 10% sulfuric acid (1.5 mL) was added and stirring was continued for 30 min at room temperature. Then the reaction mixture was diluted with diethyl ether, washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 136 mg of the title compound (50% yield). HRMS calcd for C24H22O5 [M+H]+ 391.1540, observed 391.1541.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:19]#[N:20]>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][N:27]([C:4](=[O:6])[C:3]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=2[I:1])[CH2:26][CH2:25]1)[C:19]#[N:20]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C#N)cc3F)CC2)c1

Procedure:
Example CL was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 3-Fluoro-4-piperazin-1-yl-benzonitrile (WO9625414). MS (m/e): 514.0 (M+H+, 100%).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:6]=[C:5]1[CH2:17][C:18]([O:20]CC)=[O:19]>O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:6]=[C:5]1[CH2:17][C:18]([O-:20])=[O:19].[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.88 ml of 2M sodium hydroxide are added to a solution of 1.62 g of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 67, in 20 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hours at ambient temperature. The precipitate formed is filtered through sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried in a rotary evaporator. 730 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.F[C:30]1C=CC(N2C(C(OCC)=O)=C(C)N=C2S)=CC=1.FC1C(F)=CC=C(F)C=1CBr.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:30])[N:10]=[C:9]2[S:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: Fc1ccc(F)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)nc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
Ethyl 1-(4-fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (58) was prepared in a similar manner as that described for the synthesis of compound 10 using 1-(4-fluorophenyl)-2-mercapto-4-methyl-1H-imidazole-5-carboxylate (57) (500 mg, 1.78 mmol), 2,3,6-trifluorobenzyl bromide (560 mg, 2.49 mmol) and potassium carbonate (736 mg, 6 mmol) in acetone (18 mL).
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CCNC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C([C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21)N1CCCC1
Yield: 62 %

Procedure:
A pale yellow amorphous solid of 1-[1-(2-indenyl-acetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-proline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 62%).
Reaction SMILES: [C:1]1(C)[C:2](C)=CC=C[CH:6]=1.C(Br)CBr.[C:13]1(/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O.CCOCC>[CH3:2][C:1]([CH:23]([OH:24])[CH2:22][CH2:21]/[CH:20]=[CH:19]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:6]
Reactant: Cc1ccccc1C
Reactant: OCCC/C=C/c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(O)CC/C=C/c1ccccc1
Temperature: 25 °C

Procedure:
Magnesium (a) (12.5 g) was flame dried in a 250 ml 3-necked flask equipped with mechanical stirrer, reflux condenser, and addition funnel. The magnesium was covered with 52 ml of dry tetrahydrofuran (b) and reaction was initiated by the addition of ca. 0.5 ml of ethylene dibromide under a nitrogen atomosphere. To the stirred mixture was added 30.9 g of 2-bromopropene (c) dropwise at a rate which maintained reflux without external heating. After the addition, the Grignard solution was stirred until it had cooled to room temperature (0.5-1 hour) and then cooled to -15°. Then 27.35 g of trans-5-phenyl-4-pentenal (d) was added dropwise over 15 minutes. After the resultant green mixture was stirred at room temperature for 2 hours, 130 ml of a saturated solution of ammonium chloride was added followed by 200 ml of water. The layers were separated and the aqueous portion extracted with ether (3×200 ml). The organic layer were worked up in the usual manner to give after evaporation, the alcohol as an orange liquid (33 g). TLC; silica gel HF254 ; ethyl acetate/benzene 2:8 Rf 0.45.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][N:65]([C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:20][CH:19]=2)[CH2:64][CH2:63]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.083 g, 0.00031 mol) in DMF (5 mL) was added DIPEA (0.099 g, 0.00077 mol), HOBt (0.041 g, 0.000307 mol) and EDCI.HCl (0.073 g, 0.00038 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.063 g, 0.00026 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.04 g (33%) of N-{2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LCMS: 463.17 (M+1)+, 95.82%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.5 (q, 3H), 7.2 (t, 3H), 7.1 (d, 2H), 6.9 (q, 2H), 6.6 (t, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 2.0 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[F-:11].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:11])[C:5]#[N:6]
Reactant: [F-]
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(F)c(Cl)c1
Temperature: 170 °C
Yield: 92 %

Procedure:
172 g of 3,4-dichlorobenzonitrile, 200 g of dimethylsulfoxide, 69.6 g of potassium fluoride, and 3.95 g of (N,N-dimethylimidazolidino)tris-(diethylamino)phosphazenium chloride were placed in a 1 liter four-neck flask equipped with anchor stirrer, thermometer, and reflux condenser with bubble counter. The mixture was then heated with stirring to 170° C. and this temperature was maintained for 6 hours. The mixture was then cooled to room temperature, water was added to the reaction mixture in a volumetric ratio of 1:1, and the 3-chloro4-fluorobenzonitrile that precipitated was isolated by filtration, washing, and drying. 3-Chloro4-fluorobenzo-nitrile was obtained in a yield of 92% of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:43])=[C:19]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:30]=[C:31]4[CH2:42][CH2:41][NH:40][CH2:39][C:32]4=[N:33][C:34]=3[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]2)=[O:22])[CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([F:43])=[C:19]([CH:20]=1)[C:21]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[C:31]3[CH2:42][CH2:41][N:40]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:39][C:32]3=[N:33][C:34]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]1)=[O:22].[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCN(C(=O)N(C)C)C2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (3.2 mg, 0.029 mmol) was added to a solution of (5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone TFA salt (8.0 mg, 0.015 mmol) and triethylamine (6 μL, 0.044 mmol) in DCM (150 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (3.9 mg, 43.1%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (d, J=6.6 Hz, 6H), 1.85-2.05 (m, 4H), 2.77-2.84 (m, 2H), 2.91 (s, 6H), 2.93-3.01 (m, 2H), 3.36-3.41 (m, 1H), 3.51-3.59 (m, 4H), 4.07-4.15 (m, 1H), 4.31 (s, 2H), 7.28 (dd, J=10.4, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.76 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([Mg]Br)=[CH2:16].C1COCC1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH:15]=[CH2:16])([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.5 mmol) was dissolved in 25 ml of diethylether and cooled to 0° C. A 1M solution of vinylmagnesiumbromide in THF (16.3 ml, 16.31 mmol) was added dropwise at 0° C. After 90 min stirring at 0° C., the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was further purified by flash chromatography (silicagel, cyclohexane/ethylacetate 4:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[NH:15][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CC(O)C>[NH:13]1[C:12]2[CH:17]=[CH:18][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:10][C:11]=2[NH:15][C:14]1=[O:16]
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: O=c1[nH]c2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3ncc(F)c(Nc4ccc5[nH]c(=O)[nH]c5c4)n3)cn2)CC1
Temperature: 85 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a vial with 5-(2-chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one (28.0 mg, 0.1 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 0.2 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the solution was stirred at 85° C. for 2 days. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(Benzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine was obtained as a purple solid: 26.2 mg (60% yield); 1H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.27 (br d, J=2.3, 1H), 8.00 (br d, J=3.8, 1H), 7.84 (dd, J=2.3, 9.1, 1H), 7.30 (dd, J=1.7, 8.2, 1H), 7.17 (d, J=1.7, 1H), 6.86 (d, J=8.2, 1H), 6.73 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H); LCMS (M+) m/z 436.50.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27].Cl.[NH2:29][OH:30].CC([O-])=O.[Na+]>CO.O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([CH:22]=[N:29][OH:30])([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27]
Reactant: NO
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=NO)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (1.6 g, 4.3 mmol) in MeOH (30 ml) was added hydroxylamine hydrochloride (1.2 eq, 5.16 mmol, 356 mg) and a solution of NaOAc (trihydrate, 1.5 eq, 6.45 mmol, 890 mg) in water (10 ml). The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo and the solid residue was suspended in water (15 ml), collected, washed with water and dried to afford a white powder (1.4 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([OH:10])[CH3:9])=[CH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)[C:17]2=[N:24][CH:25]=[C:26]([C:27]#[N:28])[N:16]2[N:15]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[CH3:29][S:30]([O:10][CH:8]([C:7]1[CH:6]=[C:5]([C:11]#[N:12])[CH:4]=[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH:21]3[CH2:22][CH2:23]3)[C:17]3=[N:24][CH:25]=[C:26]([C:27]#[N:28])[N:16]3[N:15]=2)[C:2]=1[Cl:1])[CH3:9])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Yield: 101.2 %

Procedure:
A solution of 2-((2-chloro-5-cyano-3-(1-hydroxyethyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 677) (56 mg, 0.14 mmol) in THF (4 mL) was cooled in an ice bath and methanesulfonyl chloride (28 μL, 0.36 mmol) was added. The bath was removed and quenched after 5 min with a little water. This was extracted with EtOAc and the organic extracts were washed with brine and dried with sodium sulfate. The solvent was removed to leave 1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)ethyl methanesulfonate (67 mg) as a white solid that was used as such.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1.CO>ClCCl>[NH:12]1[C:16]2=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(Antonini, Ippolito; Claudi, Francesco; Cristalli, Gloria; Franchetti, Palmarisa; Grifantini, Mario; Martelli, Sante; J. Med. Chem. 1982, 25(10), 1258-1261) 540 g (2.35 mol) of 3-chloroperbenzoic acid are dissolved in 6.11 l of dichloromethane, and the water that separates off is removed. The organic phase is dried over sodium sulfate and cooled to 0° C. A solution of 163 g (1.38 mol) of 1H-pyrrolo[2,3-b]pyridine (Hands, D.; Bishop, B.; Cameron, M.; Edwards, T. S.; Cottrell, I. F.; Wright, S. H. B.; Synthesis 1996 (7), 877-882) in 1.00 l of dichloromethane is then added, and the temperature is allowed to rise to room temperature. After 2 hours, such an amount of methanol is added that the precipitate formed redissolves. The mixture is filtered through silica gel (mobile phase: dichloromethane/methanol 95:5). After concentration, the product fractions are dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:43](O)=[O:44])[CH2:42][CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:43]([C:39]4([C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[O:38])[CH2:42][CH2:41][CH2:40]4)=[O:44])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CCC1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CCC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 10.7 %

Procedure:
4-(Dimethylaminomethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (114 mg) was dissolved in N,N-dimethylformamide (4.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclobutanecarboxylic acid (279 mg), triethylamine (0.164 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (520 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with 0.5N hydrochloric acid (4 times), water, a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of a mixture of diethyl ether and heptane (1:3) to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (19.1 mg, 11%).