Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[CH2:21][C@H:22]([O:24][C:25]3[CH:30]=[N:29][C:28]([CH:31]4[CH2:33][CH2:32]4)=[CH:27][N:26]=3)[CH2:23][C@H:17]2[CH2:16]1)(=[O:14])=[O:13].[Cu][C:35]#[N:36]>CN(C)C=O>[CH:31]1([C:28]2[N:29]=[CH:30][C:25]([O:24][C@H:22]3[CH2:21][N:18]4[CH2:19][CH2:20][N:15]([S:12]([C:3]5[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=5[C:35]#[N:36])(=[O:14])=[O:13])[CH2:16][C@@H:17]4[CH2:23]3)=[N:26][CH:27]=2)[CH2:33][CH2:32]1
Reactant: O=S(=O)(c1cc(C(F)(F)F)ccc1Br)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of Example 201A (105 mg, 0.192 mmol) in N,N-dimethylformamide (1 mL) was added copper(I) cyanide (52 mg, 0.58 mmol), and the resulting mixture was heated at 120° C. and stirred for 24 hours. The cooled mixture was partitioned between water and ethyl acetate, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified on silica gel using a solvent gradient of 0-60% ethyl acetate in hexanes. The title compound was obtained as a colorless solid (70 mg, 74%). 1H NMR (300 MHz, CDCl3) δ ppm 0.88-0.99 (m, 4H), 1.77-1.91 (m, 1H), 1.93-2.06 (m, 2H), 2.35 (dd, J=10.00, 5.26 Hz, 1H), 2.39-2.61 (m, 3H), 2.81-2.96 (m, 1H), 3.03 (dd, J=8.82, 2.37 Hz, 1H), 3.68 (dd, J=10.17, 6.78 Hz, 1H), 3.89 (dd, J=10.51, 1.70 Hz, 1H), 3.96-4.08 (m, 1H), 5.23-5.39 (m, 1H), 7.90-7.98 (m, 2H), 7.99-8.06 (m, 2H), 8.30 (s, 1H); MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1>ClCCl>[Br:10][C:11]1[CH:7]=[CH:6][C:5]([OH:8])=[C:13]([C:14](=[O:17])[CH2:15][CH3:16])[CH:12]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of aluminium trichloride (2.5 kg) in dichloromethane (5000 ml) at room temperature was added propanoyl chloride (864 g) over a 5 minute period. The mixture was stirred for 45 minutes at room temperature and then a solution of 4-bromoanisole (875 g) in dichloromethane (1000 ml) was added over 15 minutes. The reaction was heated under reflux for 6 hours then cooled and stirred at room temperature overnight.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][C:13]1[C:14](B(O)O)=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=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>[CH3:12][C:13]1[C:14]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1
Reactant: COc1ccc(C=O)cc1Br
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 3-bromo-4-methoxybenzaldehyde (19.0 g, 88.4 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (23.8 g, 97.2 mmol) and potassium carbonate (48.8 g, 353.6 mmol) in 1,2-dimethoxyethane (500 mL) and water (40 mL) was degassed with argon for 60 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol) was added and the mixture heated at reflux under argon for 16 hours. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane, 1:9) to give 26.8 g of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde (90%). 1H NMR (500 MHz; CDCl3): δ 1.26 (s, 6 H); 1.32 (s, 6 H); 1.70 (s, 4 H); 2.08 (s, 3 H); 3.89 (s, 3 H); 7.06 (d, J=8.5 Hz, 1 H); 7.09 (s, 1 H); 7.16 (s, 1H); 7.71 (d, J=2.0 Hz, 1H); 7.88 (dd, J132 2.0 Hz, J2=8.5 Hz 1 H), 9.91 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[C:23]([CH:30]=O)=[CH:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[CH3:34][NH2:35]>CO>[CH3:34][NH:35][CH2:30][C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[CH:29][C:21]=2[C:18]2[N:17]=[C:16]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])=[C:3]([C:2]([F:33])([F:32])[F:1])[CH:4]=3)[O:20][N:19]=2)[NH:25][CH:24]=1
Reactant: CN
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]cc(C=O)c34)no2)cc1C(F)(F)F)C(F)(F)F
Solvent: CO
Product: CNCc1c[nH]c2cccc(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-3-carboaldehyde (150.0 mg) in CH3OH (1.5 ml) was added a 40% CH3OH solution of CH3NH2 (74.5 mg) at 0° C. After warming to room temperature, the solution was stirred at room temperature for 3 hours. After confirming the production of an iminium salt, the organic solvent was evaporated under reduced pressure. The residue was dissolved in EtOH (1.5 ml). To this was added NaBH4 (12.09 mg) at 0° C. After warming to room temperature, the solution was stirred at room temperature for 15 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 90:10) to obtain N-methyl-1-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)methanamine (87.4 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.N1C=CC=NC=1>CC(C)=O>[CH:1]1([N:6]([C:22]2[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=2)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)CCNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: c1cncnc1
Product: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
Methyl 3-(cyclopentylamino)propanoate (0.838 g, 0.005 mol, 1 eq) and K2CO3 (0.676 g, 0.005 mol, 1 eq) were added to acetone (5 mL) and the resulting mixture cooled to 0° C. before the dropwise addition of 2,4-dichloro-5-nitropyrimidine (1.04 g, 0.0055 mol, 1.1 eq). The reaction mixture (RM) was warmed to rt and stirring continued for an additional 16h before the addition of a further 0.12 eq of the pyrimidine. Stirring continued for a further 3h. The RM was evaporated under reduced pressure and the product extracted using EtOAc/H2O. The organic extracts were washed with sat NaCl, dried (MgSO4) and evaporated under reduced pressure to give the product as a brown oily residue (1.04 g, 65%); MS+ve: 329.2; Rt=3.78 min (Analytical—1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Cl.[F:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:31]4[CH2:32][CH2:33][CH:29]([F:28])[CH2:30]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Reactant: FC1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCC(F)C3)cc2)C1
Yield: 21.6 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 400 mg, 1.2 mmol) in anhydrous toluene (5 mL) were added Pd2(dba)3 (5.6 mg, 0.006 mmol), BINAP (11.2 mg, 0.018 mmol), sodium tert-butoxide (230 mg, 2.4 mmol) and 3-fluoro-pyrrolidine hydrochloride (170 mg, 1.32 mmol) at r.t. and reaction mixture was refluxed for 3 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford the title compound as viscous liquid (90 mg, 22%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:19][N:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH3:21].[Li+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][N:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])(=[O:30])=[O:31])=[CH:25][CH:24]=1)[CH3:19]
Reactant: CN(C)Cc1ccc(S(=O)[O-])cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN(C)C)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.65 g, 10.00 mmol, 1.00 equiv), lithium 4-((dimethylamino)methyl)benzenesulfinate (3.075 g, 15.00 mmol, 1.50 equiv) and potassium carbonate (1.38 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was stirred overnight at 70° C. Water (150 mL) was added and the resulting solution was extracted with 3×200 mL of ethyl acetate. The combined organic layers was washed with 3×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 0.9 g (16%) of methyl 4-(4-((4-((dimethylamino)methyl)phenylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoate as a light yellow solid. LC-MS: (ES, m/z): 429 [M+H]+, 175, 120.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])[N:16]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[N:16]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)Cc1csc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(Oc2nc(CC(=O)O)cs2)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 80.8 %

Procedure:
2,6-Di-tert-butyl-4-[(4-ethoxycarbonylmethyl-2-thiazolyl)oxy]phenol (produced in Example 41) (0.40 g) was dissolved in 15 ml of ethanol, 8 ml of 2 N aqueous sodium hydroxide was added to the solution at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and, after acidification to Congo red with 36% hydrochloric acid, extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product obtained was washed with diethyl ether-hexane (1:10) to give 0.30 g of the desired compound as a colorless solid.
Reaction SMILES: [CH:1]([CH:3]([OH:26])[C@H:4]1[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][C@@H:5]1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH2:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[C:28]([O:26][CH:3]([CH:1]=[CH2:2])[C@H:4]1[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][C@@H:5]1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cl
Reactant: C=CC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC(OC(=O)OCC)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 5'-vinyl-3'-O-t-butyldimethylsilyl thymidine (2.0 g) in 30 ml of methylene chloride was added ethyl chloroformate (6 eq.) and pyridine (12 eq.) and the resulting mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, then with water (2×25 ml), and then with brine. Then the organic layer was dried. The title compound was purified by flash chromatography using 20% ethyl acetate/hexane.
Reaction SMILES: [Na].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]#[N:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=3)[N:12]=[C:29]([NH2:30])[CH2:28]2)=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CC=Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc(N2N=C(N)CC2c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium (3.19 g) was added portionwise to ethanol (160 ml) After all sodium was dissolved, 4-methoxyphenylhydrazine hydrochloride (14.5 g) was added in one portion to the solution. The mixture was stirred at room temperature for 10 min. To this mixture was added 3-(4-benzyloxyphenyl)acrylonitrile (16.3 g) in one portion, and the mixture was refluxed for 3 days.
Reaction SMILES: [Cl:1]C1N=C(Cl)N=C(Cl)N=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH:18](O)[CH3:19]>CN(C)C=O.ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH:18]([Cl:1])[CH3:19]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(O)c1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cl)c1c(Cl)cccc1Cl
Yield: 100.3 %

Procedure:
a solution of 5 g of 2,4,6-trichloro-1,3,5-triazine in 5.5 cm3 of N,N-dimethylformamide is stirred for about 3 hours at a temperature close to 20° C. A white precipitate forms. A solution of 5 g of 1-(2,6-dichlorophenyl)-ethanol in 72 cm3 of dichloromethane is added dropwise without exceeding 25° C. After about 48 hours at a temperature close to 20° C., the suspension is solubilized by adding 150 cm3 of dichloromethane. The solution obtained is washed five times with 40 cm3 of water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. After filtration of the residue on 100 cm3 of silica [eluent: cyclohexane/ethyl acetate (75/25 by volume)], we obtain 5.5 g of 1,3-dichloro-2-(1-chloroethyl)benzene in the form of a colorless oil, which has the following characteristics:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:20]1[CH2:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(OCC)C.C(N(CC)CC)C.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=C(O)CN1CCN(C(=O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 31.6 %

Procedure:
To (4-benzoylpiperazin-1-yl)acetic acid (2 g) was added N,N-dimethylformamide (80 ml) at room temperature, and then azetidine hydrochloride (1.51 g) and triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added thereto in this order, and the mixture was stirred at room temperature for 66 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) in this order and dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (10 ml). The solid was filtered off and dried under aeration to provide the titled compound (731.5 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][CH:9]([N:17]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:44][CH2:45][CH2:46][CH2:47][B:48]1[O:52][C:51]([CH3:54])([CH3:53])[C:50]([CH3:56])([CH3:55])[O:49]1.O>O1CCCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][C:9]([N:17]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:44][CH2:45][CH2:46][CH2:47][B:48]2[O:52][C:51]([CH3:54])([CH3:53])[C:50]([CH3:55])([CH3:56])[O:49]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
While under a nitrogen atmosphere, a solution of tert-butyl 4-(4-chlorophenoxy)-2-(diphenylmethyleneamino)butanoate (450 mg, 1.0 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (2.0 mL, 1.0 M in tetrahydrofuran, 2.0 mmol) in a dropwise manner. After the addition was complete, stirring was continued for 30 minutes and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (931 mg, 3.0 mmol) was slowly added to the reaction mixture. Stirring was continued for 2 more hours, and then slowly warmed to room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-15% ethyl acetate in heptane) gave tert-butyl 2-(2-(4-chlorophenoxy)ethyl)-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (486 mg. 77%); 1H NMR (CDCl3, 300 MHz) δH 7.54 (d, J=7 Hz, 2H), 7.36 (m, 4H), 7.18-7.32 (m, 6H), 6.82 (d, J=9 Hz, 2H), 4.19 (m, 1H), 4.04 (m, 1H), 2.39 (ddd, J=14 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 2.22 (ddd, J1=13.5 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 1.73 (m, 2H), 1.14-1.46 (m, 4H), 1.34 (s, 9H), 1.18 (s, 12H) and 0.76 (t, J=7 Hz, 2H); MS (+CI): m/z for C37H47BClNO5: expected 631.3. found 632.3 (M+H)+, 576.3 (M+H-isobutene)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:17].Cl.[NH2:19][CH2:20][CH2:21][O:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:17].[ClH:17].[NH2:19][CH2:20][CH2:21][O:22][N:23]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCON
Reactant: O=C(CCCn1ccnc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccccc1
Reaction time: 8 h
Yield: 217.5 %

Procedure:
A mixture of 4-(1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.50 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, overnight. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was combined with 5.0 g of crude, previously prepared material and purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol to give 6.3 g (58%) of product, mp 196°-198° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]3[CH:23]=2)=[CH:10][CH:9]=1)=[O:6].Cl.[CH3:29][NH:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:29][N:30]([CH3:31])[C:26]1[CH:25]=[CH:24][C:4]([C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]4[CH:23]=3)=[CH:12][CH:13]=2)=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: CNC
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3)cn2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)c(F)c4)cc3)cn2c1
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A stirred mixture of 3,4-difluoro-N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]benzamide (0.10 g, 0.275 mmol), dimethylamine hydrochloride (0.045 g, 0.551 mmol) and potassium carbonate (0.080 g, 0.577 mmol) in dry DMSO (3 ml) was heated at 100° C. for 18 h. After cooling to room temperature, the reaction mixture was added to water (100 ml) and the precipitate was collected by vacuum filtration, and washed with water (50 ml). The air-dried solid was then purified by flash chromatography (25:1 DCM/MeOH) to give the title compound (0.066 g, 62%) as a colourless solid.