Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1>N.CO.O.[Ni]>[NH2:25][CH2:24][CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]3[CH2:9][C:8](=[O:26])[NH:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]=3[N:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N#CCc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: NCCc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
To a solution of [3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-acetonitrile (I-78) (0.131 g, 0.349 mmol) in saturated NH3 in MeOH solution (50 mL) was added a catalytic amount of Raney 2800 Ni in H2O and the mixture was placed under H2 (50 psi) and stirred for 12 h at 22° C. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to give crude product as a yellow oil. Purification by C-18 RP LC-MS chromatography afforded I-86 (0.019 g, 14%): MS (AA) Rt=1.25 min, m/z=380 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:25])[CH2:8]1)=O)[CH3:2].P(Cl)(Cl)(Cl)=O.C(OC([S-])=[S:37])C.[K+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:25])[CH2:8]1)=[S:37])[CH3:2]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(SC)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=S)N[C@H]1C[C@@H]2c3c(SC)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At -20° C., 5.79 g of 1,1-diethyl-3-(6-methyl-12-methylthio-8α-ergolinyl)urea (15 mmol) is dissolved in a mixture of 4.13 g of freshly distilled phosphorus oxychloride (45 mmol) and 50 ml of anhydrous methylene chloride and the temperature is allowed to rise within 4 hours to +10° C. The mixture is stirred overnight at room temperature and then another 2 hours at 40° C.,and the solvent is subsequently distilled off under vacuum. The residue is dissolved in 50 ml of anhydrous acetonitrile, cooled to -10° C., combined with 7.2 g of potassium ethylxanthate (45 mmol), and stirred at room temperature for 20 hours. The solvent is exhaustively removed by distillation; then the mixture is distributed between ethyl acetate and saturated sodium carbonate solution; the organic phase is dried with sodium sulfate and evaporated. The residue is crystallized from ethyl acetate, yielding 82%.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:27])=O>CN(C=O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([Cl:27])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)C(=O)Cl

Procedure:
To 17.11 g. (0.05 mole) of 2-[[4-[4-(trifluoromethoxy)phenoxy]phenoxy]]propanoic acid is added 1 ml. of DMF, followed by 50 ml. of thionyl chloride. After evolution of HCl ceases, the thionyl chloride excess is removed in vacuum. The residue is extracted with methylene chloride and the methylene chloride solution washed with ice water, dried, and the solvent removed, leaving 2-[[4-[4-(trifluoromethoxy)phenoxy]phenoxy]]propanoyl chloride.
Reaction SMILES: Br[C:2]1[C:9]2[S:8][CH:7]=[N:6][C:5]=2[N:4]([CH:10]([CH3:14])[CH2:11][O:12][CH3:13])[C:3]=1[CH3:15].[C:16]([Cu])#[N:17]>CN(C)C=O>[CH3:13][O:12][CH2:11][CH:10]([N:4]1[C:5]2[N:6]=[CH:7][S:8][C:9]=2[C:2]([C:16]#[N:17])=[C:3]1[CH3:15])[CH3:14]
Reactant: COCC(C)n1c(C)c(Br)c2scnc21
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COCC(C)n1c(C)c(C#N)c2scnc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 6-bromo-4-(1-methoxypropan-2-yl)-5-methyl-4H-pyrrolo[2,3-d]thiazole (2.0 g, 6.92 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added cyano copper (1.24 g, 13.84 mmol). The resulting reaction mixture was heated to 150° C. and allowed to stir for 2 hours at 150° C. The reaction mixture was washed with water and brine, and extracted with acetic ester (30 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 30:1-20:1-10:1) to give the title compound (1.0 g, 62%) as yellow oil. LCMS (M+H+) m/z: calc'd. 235.08. found 236.0.
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([N:16]([CH2:29][CH2:30]C)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[C:27](=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:15])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[O:32]1[C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=[N:33]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O>[CH2:29]([N:16]([CH:14]([CH3:15])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:27](=[O:28])[CH2:26][CH2:25][N:24]([C:37]([C:36]2[O:32][N:33]=[CH:34][CH:35]=2)=[O:38])[CH2:23][CH2:22]1)[CH3:30]
Reactant: O=C(Cl)c1ccno1
Reactant: CCCN(CCCCN1CCNCCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CCCCN1CCN(C(=O)c2ccno2)CCC1=O)C(C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-(4-{[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamino)butyl)-[1,4]diazepan-5-one dihydrochloride (0.15 g, 0.3 mmole) in toluene (5 mL) and saturated sodium carbonate (2 mL) was added isoxazole-5-carbonyl chloride (0.04 g, 0.31 mmole). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried (magnesium sulfate), and concentrated to give 4-(4-{ethyl-[2-(4-methanesulfonyl-phenyl)-1-methylethyl]amino}butyl)-1-(isoxazole-5-carbonyl)-[1,4]diazepan-5-one as a hygroscopic hydrochloride salt (0.14 g) in ethyl acetate/diethyl ether, 316, M+H=505.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH2:7][OH:8].[Cl:19][C:20]1[CH:27]=[C:26](O)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.OO>O1CCCC1.C(OCC)C>[Cl:19][C:20]1[CH:27]=[C:26]([O:8][CH2:7][C:6]2[S:5][C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=3)=[N:3][C:2]=2[CH3:1])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: OO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an ice cooled solution of 2.76 g [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol, 2.06 g 2-chloro-4-hydroxybenzonitrile and 3.03 g triphenylphosphine in 30 ml tetrahydrofuran were added 1.74 ml diethylazodicarboxyate. The reaction mixture was stirred at room temperature overnight. 0.56 ml 30% H2O2 were added and the reaction mixture diluted by addition of 200 ml diethylether. The organic layer was washed with 50 ml 1N NaOH and 50 ml water, dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 2.02 g 2-Chloro-4-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-ylmethoxy]-benzonitrile as a lyophilisate.
Reaction SMILES: B#B.O=[C:4]1[CH2:21][S:20][CH2:19][CH2:18][S:17][CH2:16][C:15](=O)[NH:14][CH2:13][CH2:12][S:11][CH2:10][CH2:9][S:8][CH2:7][CH2:6][NH:5]1>O1CCCC1>[S:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][S:20][CH2:21][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: O=C1CSCCSCC(=O)NCCSCCSCCN1
Agent: B#B
Solvent: C1CCOC1
Product: C1CSCCSCCNCCSCCSCCN1
Temperature: 25 °C

Procedure:
A solution of diborane (20 ml.; 1.5 N) in anhydrous tetrahydrofuran is added dropwise to a suspension of 2 g. of the diamide obtained in Example 32 in 50 ml. anhydrous tetrahydrofurane under nitrogen at room temperature. The solid dissolves giving a clear solution. After the addition is completed the mixture is refluxed during four hours and a solid precipitate is formed. After cooling to room temperature, the excess reagent is destroyed by adding carefully 10 ml. of water. The solvents are evaporated to dryness and 6 N hydrochloric acid (50 ml.) is added to the solid residue. The mixture is refluxed for three hours: the solid does not dissolve, the mixture remaining heterogeneous. The mixture is evaporated to dryness and a solution of 10% sodium hydroxide in water (50 ml.) is added to the residue.
Reaction SMILES: [NH2:1][CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][C:4]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH2:33]([O:35]CC)C>CC#N>[C:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:7][N:6]3[C:4](=[O:5])[CH2:3][CH:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:1][C:33]3=[O:35])[CH2:9][CH2:10]2)=[O:15])[CH2:17][CH2:18]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CNC(=O)CC(N)c3ccccc3)CC2)CC1
Reactant: CCOCC
Solvent: CC#N
Product: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN3C(=O)CC(c4ccccc4)NC3=O)CC2)CC1

Procedure:
A solution of 3-amino-N-[trans-4-(4-isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-3-phenyl-propionamide (0.13 g, 0.29 mmol) and 1,1-carbonyldiimidazole (0.10 g, 0.58 mmol) in CH3CN was irradiated with microwave at 100° C. (250 watt) for 10 minutes. The solvent was removed under reduced pressure and the residue was washed with H2O and then with diethylether, affording 31 mg of the titled compound (22% yield).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1(C)C=CC=CC=1.[Cl-].[NH4+]>>[OH:12][C:10]1([CH3:18])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[C:7](=[O:17])[NH:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: Cc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(O)c2ccccc2NC(=O)c2ccccc21
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a suspension of 5H-dibenzo[b,e]azepine-6,11-dione (2) (50 g, 0.22 mol) in toluene (800 mL) methyl magnesium iodide (3 M in Et2O, 200 mL, 0.6 mol) was added. The reaction mixture was heated under reflux for 6 h, then poured into aqueous ammonium chloride and stirred for 10 minutes. The product was filtered off and dried to give 11-hydroxy-11-methyl-5,11-dihydro-dibenzo[b,e]azepin-6-one (3) as a white solid (51.6 g, 96%). Data: (m/z)=240 (M+H)+.
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>CCN(CC)CC>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23]([NH:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:24]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a CHCl3 (350 mL) solution of tert-butyl 4-aminopiperidine-1-carboxylate (35.0 g), Et3N (122 mL) and 3-chloro-4-fluorobenzoyl chloride (37.1 g) were added under ice cooling and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to obtain tert-butyl 4-[(3-chloro-4-fluorobenzoyl)amino]piperidine-1-carboxylate (62.0 g). To an EtOAc (300 mL) suspension of the compound obtained, a 4 M HCl/EtOAc solution (300 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and 1 M aqueous NaOH solution (300 mL) was added to the residue and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was suspended in EtOAc/hexane (200 mL, 1/1; v/v) and the mixture was stirred for one hour. The precipitate was filtrated to obtain 3-chloro-4-fluoro-N-piperidin-4-ylbenzamide (37.7 g, a colorless solid).
Reaction SMILES: [CH:1]1([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].O1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])S1(=O)=O.Cl>CN(C)C=O>[CH2:13]([O:12][C:10](=[O:11])[C:4]([CH2:21][CH2:20][NH:19][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH:1]1[CH2:3][CH2:2]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: CCOC(=O)C(C(=O)OCC)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCNC(=O)OC(C)(C)C)(C(=O)OCC)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of diethyl cyclopropylmalonate (7.7 g) obtained in Step A of Example 388 in N,N-dimethylformamide (90 mL) was added sodium hydride (60% in mineral oil, 1.8 g), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.4 g) at the same temperature, and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.7 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][C:6]1[C:14]2[O:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]=[S:17]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:16](=[S:17])[NH:15][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][O:13][C:14]=2[C:6]=1[CH3:5]
Reactant: Cc1c(N=C=S)ccc2c1OCC2
Reactant: NCCN
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.205 g of ethylenediamine in 1 mL of methylene chloride is added dropwise a solution of 0.13 g of 7-methyl-6-isothiocyanato-2,3-dihydrobenzofuran in 2 mL of methylene chloride. The mixture is stirred at room temperature for 1 hour and evaporated to provide 6-[N'-(2-aminoethyl)thioureido]-7-methyl-2,3-dihydrobenzofuran as the crude product.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:12]([Mg]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.O1CCCC1>[NH2:11][C:10]1[CH:9]=[C:8]2[C:3](=[C:1]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1)[N:4]=[CH:5][CH:6]=[CH:7]2
Reactant: N#CCc1cccnc1C#N
Reactant: Br[Mg]Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cc2cccnc2c(Cc2ccccc2)n1

Procedure:
To a solution of 2-cyano-3-pyridylacetonitrile (2 g, 0.014 mol) in toluene (20 ml) is added benzylmagnesium bromide 8.4 ml, 2N in tetrahydrofuran, 0.17 mol) at ambient temperature. After 1 h the reaction is quenched with a saturated solution of ammonium chloride. The product is extracted with ethyl acetate and the organic layer washed with 2N NaOH and water. The product is purified by flash column chromatography on silica gel (10:3 toluene/acetone) affording the title compound. Mass M+H 236; mp 113-116° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH:27]=[CH:26][C:25](B(O)O)=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.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>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:27]2[NH:23][N:24]=[CH:25][CH:26]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
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: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2ccn[nH]2)n1
Yield: 26.1 %

Procedure:
(4-Chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester (350 mg, 1.03 mmol), 1H-pyrazole-3-boronic acid (128 mg, 1.13 mmol) and sodium carbonate (218 mg, 2.06 mmol) in water (1 mL) and ethanol (4 mL) were degassed with argon for 30 minutes before tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.051 mmol) was added. The reaction mixture was heated to reflux over night. Water was added and the mixture was concentrated in vacuo. The remaining aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with brine, dried over sodium sulphate, filtrated and evaporated. The crude product was purified by column chromatography (ethyl acetate/heptane as eluent) to give (4-chloro-phenyl)-[6-(2H-pyrazol-3-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester (100 mg, 26%) as a colourless solid.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](Cl)=[O:19])=[CH:12][CH:11]=1>O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:19])=[CH:14][CH:15]=1
Reactant: NCC(=O)O
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 26 mmol sodium hydroxide in 7 ml water 8.7 mmol of glycine were added. The mixture was cooled in an ice-bath and a solution of 8.7 mmol 3-(4-chloro-phenyl)-propionyl chloride (CA [52085-96-8]) in 10 ml dioxane was slowly added over a period of 20 minutes. After stirring overnight at room temperature, the mixture was extracted with diethyl ether. The aqueous phase was acidified by addition of diluted hydrochloric acid and filtered. Trituration of the solid in diethyl ether yielded the title compound as a colorless solid. Yield=42%.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1.C[CH2:17][N:18](CC)CC.CS(Cl)(=O)=O.CN.CCO>C(Cl)Cl>[CH3:17][NH:18][CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1
Reactant: CCN(CC)CC
Reactant: OCCN1CCn2c1nc1ccccc12
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCO
Product: CNCCN1CCn2c1nc1ccccc12
Temperature: 0 °C
Yield: 78.6 %

Procedure:
To a cooled (0° C.), stirred suspension of 1-N-(2-hydroxyethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (882 mg, 4.34 mmol) in CH2Cl2 (18 mL) was added Et3N (0.67 mL, 4.77 mmol) and MsCl (0.37 mL, 4.77 mmol). The resulting solution was stirred at room temperature for 1 hour, washed with brine, dried (MgSO4) and concentrated to give an off-white solid. 33% CH3NH2 /EtOH (45 mL) was added and the solution was stirred at room temperature over the weekend. The mixture was concentrated, taken up in 10% aqueous HOAc (20 mL) and extracted with EtOAc. The extracts were dried (MgSO4) and concentrated to give 738 mg (79%) of an off-white solid m.p. 60°-63° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][NH:15][C:16]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][N:2]=1)=[S:17]
Reactant: NCCNCc1ccsn1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCNCc1ccsn1

Procedure:
By the procedure of Example 40(a)(ii), N-(3-isothiazolylmethyl)ethylenediamine is reacted with 2-dimethylaminoethyl isothiocyanate to give N-(2-dimethylaminoethyl)-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea. Reacting with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[N:48]=[CH:47][C:46]([C:49](OC)=[O:50])=[CH:45][N:44]=2)[CH2:39][CH2:38]1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[CH:13]=[C:12]([NH:11][C:49]([C:46]3[CH:47]=[N:48][C:43]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[N:44][CH:45]=3)=[O:50])[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)nc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.6 %

Procedure:
A solution of NaHMDS (2.100 ml, 2.10 mmol) in THF (1.0M) was added to a stirred solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (0.486 g, 1.4 mmol) and methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.397 g, 1.68 mmol) in THF (7.00 ml, cooled to −20° C.), over a period of 5 mins under nitrogen. The resulting solution was stirred at room temperature for 18 h. The mixture was heated to reflux for 90 min, then cooled to room temperature. More NaHMDS (2.100 ml, 2.10 mmol) was added and the mixture stirred for 70 mins. The mixture was allowed to stand for 96 h and then partitioned between ethyl acetate and 2.0M aqueous hydrochloric acid. The aqueous layer was separated and basified with 50% aqueous sodium hydroxide solution and then extracted with ethyl acetate (75 mL). The organic layer was washed with saturated brine (50 mL) and then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (4.00 mg, 0.633%) as a white solid;
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9]C#N.Cl.C([O:19][CH2:20][CH3:21])(=O)C>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([CH2:9][C:20](=[O:19])[CH3:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: N#CCc1cccc(Br)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylaluminium in toluene (30 mL, 2M) was added to a -78° C. solution of m-bromobenzyl cyanide (3.92 g, 20 mmol) in toluene (20 mL) and the mixture was slowly warmed up and refluxed for 12 h. After being cooled to 0° C., the solution was carefully added to crushed ice and made acidic with 6N HCl. Ethyl acetate was added and the mixture was vigorously stirred for 1 h. The organic layer was washed with NaHCO3, brine and dried with MgSO4. Removal of the solvent left an oil (4.53 g) which was used as such in the next step.