Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][C:37]([NH:40][CH2:41][CH2:42][CH2:43][NH2:44])([CH3:39])[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][CH2:41][NH:40][C:37]([CH3:39])([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CC(C)(C)NCCCN
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCNC(C)(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 79.6 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N-(1,1-dimethylethyl)-1,3-propanediamine (0.042 mL, 0.26 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (27 mg, 80%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 12H), 1.12 (m, 2H), 1.56 (m, 2H), 1.70 (m, 2H), 2.31 (s, 3H), 2.48 (m, 2H), 3.12 (m, 2H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Fc1ccc(C(OCCN2CCCCC2)c2ccc(F)cc2)cc1
Yield: 26.4 %

Procedure:
1-[Bis(4-fluorophenyl)methoxy]-2-chloroethane (3) (1.03 g, 3.6 mmol) was added to a flask containing acetonitrile (70 ml) and potassium carbonate (1.54 g, 11.1 mmol). This was followed by addition of piperidine (0.69 g, 8.1 mmol). The resulting mixture was heated to reflux for 48 hours under an atmosphere of nitrogen. At the end of this time, the solution was added to ether (75 ml), washed with water (100 ml) followed by brine (100 ml). The solution was then dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The resulting clear yellow oil was then chromatographed on silica gel and eluted with 3:1 ethyl acetate/methanol to afford the desired product (5) (315 mg, 26.1%) as a clear and colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21].C[O-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:4](=[N:11][C:20]([NH2:21])=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])[N:9]=2)[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: N#CCc1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2nc(-c3ccccc3Cl)c(N)nc2n1

Procedure:
A stirred solution of 1.5 grams (0.010 mole) of 2,4,6-triamino-5-nitrosopyrimidine in 80 mL of N,N-dimethylformamide was heated to reflux, and 2.0 grams (0.01 3 mole) of 2-chlorophenylacetonitrile was added in one portion. Upon completion of addition, the reaction mixture was cooled, and 0.7 gram (0.013 mole) of sodium methoxide was added in one portion. The reaction mixture was again heated at reflux for 15 minutes. The reaction mixture was cooled in an ice-bath and then was filtered to collect a solid. The solid was slurried in diethyl ether and then was again collected by filtration, yielding, when dried, 2.5 grams of 2,4,7-triamino-6-(2-chlorophenyl)pteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-:9]#[N:10].[Na+]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:9]#[N:10])=[CH:4][CH:5]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:2]([C:5]1[CH:4]=[C:3]([CH2:2][C:9]#[N:10])[CH:8]=[CH:7][CH:6]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1ccc(Cc2ccccc2)cc1
Product: N#CCc1cccc(Cc2ccccc2)c1
Yield: 9.2 %
Yield: 33 %

Procedure:
The crude bromomethylbenzene intermediate (19.6 g, 75 mmole) was treated with NaCN as in Example 2 and, after chromatography over silica gel (10 to 100% EtOAc in hexane), 5.2 g (33%) of 4-benzyl-l-cyanomethylbenzene and 1.43 g (9.2%) of 3-benzyl-1-cyanomethylbenzene were obtained, both as oils.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH2:6][C:7]([I:11])=[C:8]([I:10])[I:9].[I-].[Na+]>CC(C)=O>[I:11][C:7](=[C:8]([I:10])[I:9])[CH2:6][S:1][C:2]#[N:3]
Reactant: N#C[S-]
Reactant: ClCC(I)=C(I)I
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#CSCC(I)=C(I)I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
9.14 g (0.113 mole) of sodium thiocyanate are dissolved in 200 ml of acetone; 51.4 g (0.113 mole) of 3-chloro-1,1,2-triiodo-1-propene are then added. In addition, 0.2 g of sodium iodide are also introduced as the catalyst. The reaction mixture is stirred at room temperature for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:15][NH:16]C(OC(C)(C)C)=O.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([N:31]=[C:32]=[O:33])=O)=[C:27]([F:36])[CH:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]1[C:32](=[O:33])[NH:31][C:29]([C:28]2[CH:34]=[CH:35][C:25]([Cl:24])=[CH:26][C:27]=2[F:36])=[N:16]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C2CC2)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(Cl)cc3F)[nH]c2=O)c1)C1CC1
Yield: 55.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate (step-7 of Intermediate-48, 0.060 g, 0.17 mmol), 4-chloro-2-fluorobenzoyl isocyanate (Intermediate-58, 0.035 g, 0.71 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.040 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 0.67-0.69 (m, 4H), 1.59-1.60 (m, 1H), 4.31 (d, J=5.9 Hz, 2H), 7.36 (dd, J=6.24 Hz, 1H), 7.45 (dd, J=8.5 Hz, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.64 (t, J=6 Hz, 1H), 12.51 (br s, 1H); MS (m/z): 421.08 (M+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>CN(C)C=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[F:13][C:10]([F:11])([F:12])[C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccncc1)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Dissolve anhydrous cobalt(II) acetate (700 mg, 4 mmol) in dimethylformamide. Add 2,2'-dipyridyl (620 mg, 4 mmol) and stir for 30 minutes. Add 3-(trifluoromethyl)acetophenone (9.4 g, 50 mmol) and 4-pyridinecarboxaldehyde (5.3 g, 50 mmol). Heat at 80° C. for 18 hours. Evaporate the solvent and purify the residue by silica gel chromatography (1:1 toluene/ethyl acetate) to yield 9.4 g. Recrystallize (ethyl ether/hexane) to yield the title compound; mp 89°-90° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[N:10]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)=[N:12][CH:11]=1.N1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:25][CH:22]2[CH2:21][CH2:20][N:19]([C:13]3[N:12]=[CH:11][NH:10][C:15]4=[N:16][CH:17]=[CH:18][C:14]=34)[CH2:24][CH2:23]2)=[O:8])[CH:3]=1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-methyl-3-isoxazolecarbonyl chloride (0.029 g, 0.200 mmol) in DCM (1 mL) and DMF (0.5 mL) was added to a solution of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (0.043 g) in DMF (1.5 mL) in the presence of polymer-supported morpholine (0.279 g, 0.600 mmol, loading 2.15 mmol/g). The reaction mixture was shaken overnight at room temperature. The morpholine resin was filtered off and washed with a DCM:DMF (1:1) mixture. The unreacted acid chloride was removed by filtration on a Si—NH2 cartridge [Biotage] eluting with a DCM:DMF 1:1 mixture, and then the solvents were removed in vacuo. The crude mixture was purified by MDAP using a formic acid method to afford E16 (23.4 mg); 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.64 (1H, d), 8.14 (1H, s), 7.18 (1H, d), 6.59 (1H, d), 6.52 (1H, s), 4.71 (2H, dt), 4.12 (1H, m), 3.15 (2H, dt), 2.44 (3H, s), 1.85 (2H, m), 1.60 (2H, m), MS(ES+) 326 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)([Cl:17])=O>>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Product: O=C(Cl)c1ccc(-n2cncn2)cc1
Yield: 100 %

Procedure:
4-(1H-1,2,4-triazol-1-yl)benzoic acid (100 mg, 0.529 mmol) in sulfurous dichloride (2 ml) was refluxed at 110° C. for 2 h. After the excess SOCl2 was removed, the residue was dried in vacuo to give 4-(1H-1,2,4-triazol-1-yl)benzoyl chloride (110 mg, 0.529 mmol, 100% yield) as a white solid which was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCC(NC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-fluorobenzoylamino)piperidine (0.15 g) in dichloromethane (5 ml) were added in turn pyridine (0.14 ml) and methanesulfonyl chloride (96 μl) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. To the mixture was added N,N-dimethylaminopyridine (0.13 g) and allowed to stir for another 1 hour. The reaction mixture was taken up into a mixture of water and dichloromethane. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 4-(4-fluorobenzoylamino)-1-methylsulfonylpiperidine (0.30 g).
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[F:13])=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCCc1ccccc1F
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCc1ccccc1F)c1ccnc(NC(=O)c2ccccc2)c1

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(2-fluorophenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(2-fluorophenyl)ethyl]-isonicotinamide was obtained as a colorless 2H), 3.00 (t, J=7.0 Hz, 2H); MS (ES+) m/z 364.6 (M+1).
Reaction SMILES: [Br-:1].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].[S:23]([O:28]C)([O:26][CH3:27])(=[O:25])=[O:24]>>[CH3:27][O:26][S:23]([O-:28])(=[O:25])=[O:24].[Br-:1].[CH3:27][N+:22]1[C:14]([C:11]2[CH:12]=[CH:13][N+:8]([CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:9][CH:10]=2)=[N:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C[n+]1ccc(-c2nc3ccccn3n2)cc1
Agent: [Br-]
Product: CCOC(=O)C[n+]1ccc(-c2nn3ccccc3[n+]2C)cc1
Product: COS(=O)(=O)[O-]
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
2-(1-Ethoxycarbonylmethylpyridinium-4-yl)-s-triazolo[1,5-a]pyridine bromide (5.0 g), prepared as in Example 4 and dimethyl sulphate (5 ml) were mixed together, heated slowly to 150° C. and kept at that temperature for 30 minutes. The mixture was then cooled and triturated with isopropanol to give an off-white solid. Filtration, washing with ether and drying yielded 5.20 g of 1-methyl-2-(1-ethoxycarbonylmethylpyridinium-4- yl)-s-triazolo[1,5-a]pyridinium bromide methyl sulphate, m.p. 156°-158° C.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]O.O>ClCCl>[N+:1]([O-:4])([O:3][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])=[O:2]
Reactant: OCCCCBr
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])OCCCCBr
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
In reactor cooled to −5 to 5° C., nitric acid fuming (8.5 g-135 mmol) was slowly added to a solution of 98% sulfuric acid (13.0 g-130 mmol) in dichloromethane (18.0 g-212 mmol). 4-bromobutanol (10.2 g-66.6 mmol) was then added to this mixture and the reaction medium was stirred at −5 to 5° C. over a period of 2-5 hours. The mixture was poured into cold water (110 g) keeping the temperature between −5° C. and 3° C. After decantation, the upper aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, adjusted to pH=6-7 by addition of 27.65% sodium hydroxide, washed with brine and dried over magnesium sulfate. Dichloromethane was distilled off under vacuum and crude 4-bromobutyl nitrate (12.7 g-64.1 mmol) was recovered in a yield of about 96%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a mixture of 4-benzyloxy-phenyl-acetohydroximoyl chloride (1.2 g, 4.4 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (34 mL) were added 3-Ethynyl-pyridin-2-ylamine (260 mg, 2.2 mmol) described in Manufacturing Example 1-2-3 and triethylamine (3.0 mL, 22 mmol) at 0° C., which was stirred for 1 hour at room temperature. To the reaction mixture was added water at room temperature, which was then extracted with ethyl acetate-tetrahydrofuran (2:1). The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (240 mg, 15%).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]([O:9]C(=O)C)(=O)[CH3:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([N:25]([CH2:36]OCC)[C:26](=[O:35])[C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=2)[CH2:22][CH:23]=[CH2:24])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+].C(#[N:47])C>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][C@@H:21]2[CH2:22][C@@H:23]([NH:47][C:6](=[O:9])[CH3:7])[CH2:24][CH2:36][N:25]2[C:26](=[O:35])[C:27]2[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=2)=[CH:18][CH:19]=1
Reactant: CC#N
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC(Cc1ccc(Cl)cc1)N(COCC)C(=O)c1cc(C)cc(C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N[C@H]1CCN(C(=O)c2cc(C)cc(C)c2)[C@H](Cc2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
0.61 ml of tin tetrachloride and 0.24 ml of acetic anhydride are added successively to a solution of 1.0 g of N-{5-(4-chlorophenyl)pent-1-en-4-yl}-N-ethoxymethyl-3,5-dimethylbenzamide in acetonitrile cooled to -20°. The reaction mixture is then stirred at -20° for 2 hours and at 25° for 1 hour, poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is separated off, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude title compound (orange oil) is purified by chromatography on silica gel with dichloromethane/methanol/25% strength ammonia solution (95:5:0.1) as mobile phase. TLC (dichloromethane/methanol/25% strength ammonia solution; 90:10:0.1):Rf =0.45; FD-MS:M+=398
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCCCCl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(OCCCCl)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
To a cooled (0° C.), stirred solution of 1-chloro-3-(4-aminophenoxy)propane (680 mg, 3.66 mmol) and pyridine (319 mg, 4.03 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (461 mg, 4.03 mmol). After 18 hours, the mixture was washed with 1N HCl and brine, dried (MgSO4), and concentrated to give 865 mg (90%) of product as an off-white solid m.p. 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][Br:32])([O-:28])=[O:27]>>[Br-:32].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N+:26]([O-:28])=[O:27])[CH:7]=1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: O=[N+]([O-])c1ccccc1Cn1cc[n+](CC(OCc2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c1
Product: [Br-]

Procedure:
mp. 138.5° -141° C., by the reaction of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-imidazole and o-nitrobenzyl bromide.
Reaction SMILES: C(OC(=O)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1)(C)(C)C.I[C:26]1[C:34]2[CH:33]=[N:32][CH:31]=[N:30][C:29]=2[N:28]([Si](C(C)C)(C(C)C)C(C)C)[CH:27]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[CH:10][N:9]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)cn2)cc1

Procedure:
(4-Chloro-benzyl)-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine P-0001 was prepared in two steps from (4-chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 13 and 5-Iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 38 as shown in Scheme 8.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCNCC2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)CC1
Yield: 98.4 %

Procedure:
A solution of 4,6-dichloropyrimidine (8.60 g), 1-[1-(tert-butoxycarbonyl)-piperazin-4-ylcarbonyl]piperazine 15.64 g) and triethylamine (21.95 ml) in ethanol (300 ml) was stirred at room temperature for 30 minutes. Solvent was evaporated and the residue dissolved in dichloromethane and washed with water, saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated to give, as a pale yellow solid 1-[1-(tert-butoxycarbonyl)-piperazin-4-ylcarbonyl]-4-(6-chloro-pyrimidin-4-yl) piperazine (21.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:23]=3[CH3:33])=[CH:16][CH:15]=2)=[CH:9][C:3]=1[O:4][CH2:5][C:6](O)=[O:7].Cl.C([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])C>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:23]=3[CH3:33])=[CH:16][CH:15]=2)=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:50][CH2:49][CH2:48][C:47]([OH:51])=[O:46])=[O:7]
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2ccc(Cl)c(OCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2ccc(Cl)c(OCC(=O)NCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 91I and β-alanine ethyl ester hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.94 (t, 1 H), 7.40 (d, 1 H), 6.87-7.35 (m, 10 H), 6.76 (d, 1 H), 6.50 (dd, 1 H), 4.56 (s, 2 H), 4.08 (s, 2 H), 4.06 (s, 2 H), 3.32 (q, 2 H), 2.90 (s, 3 H), 2.39 (t, 3 H), 2.33 (s, 3 H); MS (ESI) m/z 688 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([C:10]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[O:11])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCN1CCOCC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)N1CCN(c2ccccc2)CC1

Procedure:
Following the procedure of Example 5, N-(2-aminoethyl)morpholine and 1,1'-carbonyldiimidazole are reacted together in tetrahydrofuran and the product thereof is reacted further with 1-phenylpiperazine to give the title compound.