Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([F:13])=[CH:8][C:7]=1[Cl:14])([CH3:3])[CH3:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:14][C:7]1[C:6]([C:5](=[O:15])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:11][C:10]([NH:12][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[C:9]([F:13])[CH:8]=1
Reactant: CC(C)NC(=O)c1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1cc(C(=O)NC(C)C)c(Cl)cc1F

Procedure:
Analogously to the procedure described in Example 65, starting from N-isopropyl-5-amino-2-chloro-4-fluorobenzamide and ethyl chloroformate there is obtained ethyl 4-chloro-2-fluoro-5-(N-isopropylcarbamoyl)-carbanilate, m.p. 127°-130° C., used as the starting material in Example 2.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(O)[CH2:6]2.C(O)(=O)C.Cl.[C:22]([OH:28])(=[O:27])[CH2:23][C:24]([OH:26])=[O:25]>C(O)C>[C:22]([OH:28])(=[O:27])[CH2:23][C:24]([OH:26])=[O:25].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:6]2
Reactant: CN1C2CCC1CC(O)(c1ccccc1)C2
Agent: Cl
Agent: O=C(O)CC(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CN1C2C=C(c3ccccc3)CC1CC2
Reaction time: 2 h
Yield: 100 %

Procedure:
The title compound was prepared from 8-methyl-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (8 g, 37 mmol), glacial acetic acid (25 mL) and concentrated hydrochloric acid (8 mL). The free base of the title compound (7.4 g, 37 mmol) was dissolved in absolute ethanol (20 mL) and added malonic acid (3.9 g, 37.5 mmol), the solution was heated at reflux for a couple of minutes, some impurities was removed by filtration while the solution was still hot, the solution was cooled and kept at 5° C. for at while, then seeded with a crystal and precipitation of the title compound began, after 2 hours at 5° C., the title compound was isolated by filtration, the crystals was washed with cold absolute ethanol (10 mL). Yield 5.9 g (53%), m.p. 131-131.8° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:38])[C@H:26]([C@@H:35]([CH3:37])[OH:36])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(Cl)Cl>[C:31]([O:30][C:28]([NH:27][C@@H:26]([C:35](=[O:36])[CH3:37])[C:25]([O:24][CH3:23])=[O:38])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of Dess-Martin periodinane (2.84 g, 6.69 mmol) in DCM (50 mL) was added to a solution of Boc-L-threonine methyl ester (1.3 g, 5.57 mmol) in DCM (20 mL) at room temperature and under a nitrogen atmosphere. The white suspension was stirred at room temperature for 3 hours. The resulting mixture was diluted with DCM (50 mL) and quenched by the addition of saturated NaHCO3 (aq) (50 mL) containing 0.5 M of sodium sulfite (6.2 g). The phases were separated and the organic layer was washed with saturated NaHCO3 (aq) (50 mL) and water, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 10-50% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:20][O:21][Si](C(C)(C)C)(C)C)([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1.CCCCCC>[P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:20][OH:21])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methylbenzyl phosphate (6.02 g, 14.1 mmol) obtained from Example 22-(3) in tetrahydrofuran (50 ml) was added tetrabutylammonium fluoride (1 mol/l tetrahydrofuran solution; 17.6 ml, 17.6 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added thereto, and the product was extracted with ethyl acetate. The solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (75 g) column (eluent; ethyl acetate:hexane=3:1) to afford the title compound (3.84 g, 87% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2)OC1(C)C
Reactant: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccncc2)=C(c2ccc(OCc3ccccc3)cc2)C1=O
Yield: 60.1 %

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (10.0 g, 37.2 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g, 44.7 mmol), and Cs2CO3 (36.27 g, 111.6 mmol) in toluene (100 mL) and water (50 mL) was degassed. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (2.7 g, 3.7 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 3 h and monitored by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organic layer was then washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexanes on 230-400 mesh silica gel to afford 4-(4-(benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (8.3 g, 60.2%) as a light orange color solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.2 (d, 2H), 7.85 (d, 2H), 7.6 (d, 4H), 7.4 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 5.1 (s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC: (97.5%, Column: Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]=[O:10].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][OH:10]
Reactant: COc1ccncc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccncc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of 4-methoxy-pyridine-3-carbaldehyde (2.1 g, 14.9 mmol) in MeOH (70 mL) cooled to 0° C. was added sodium borohydride (0.67 g, 17.7 mmol) as a solid in one portion. The reaction was allowed to slowly warm to room temperature and stirred for 2 h. Excess hydride was consumed by the addition of water and the reaction mixture was concentrated under reduced pressure. The residue was taken back up in EtOAc and washed with water. The aqueous phase was back extracted with EtOAc and the combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography using a 95:5 CH2Cl2:MeOH as an eluent to provide, after concentration, to give 1.1 g (55%) of (4-methoxy-pyridin-3-yl)-methanol as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[C:35]([NH:37][CH3:38])[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[C:35]([NH:37][CH3:38])[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CNc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(O)c1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 2-(2-hydroxy-4-(methylamino)benzamido)-4-phenylbenzoate (0.027 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue, followed by adjusting the pH to 6 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the solid substance was collected by filtration to obtain 0.014 g of 2-(2-hydroxy-4-(methylamino)benzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH3:15].[Cl:16][CH2:17][C:18](Cl)=[O:19].Cl>ClCCCl.[Cl-].[Cl-].[Zn+2]>[CH3:14][O:13][C:11]1[CH:12]=[C:7]([O:6][CH3:5])[C:8]([CH3:15])=[CH:9][C:10]=1[C:18](=[O:19])[CH2:17][Cl:16]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C)c(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(OC)c(C(=O)CCl)cc1C
Temperature: 0 °C

Procedure:
A suspension of 5.24 g of AlCl3 and 0.52 g of ZnCl2 in 40 ml of 1,2-dichloroethane is cooled to 0° C., and a solution of 5.0 g of 2,4-dimethoxytoluene in 20 ml of 1,2-dichloroethane is added dropwise. The mixture is then cooled to -10° C., and a solution of 2.9 ml of chloroacetyl chloride in 1.5 ml of 1,2-dichloroethane is added dropwise while the temperature of the reaction medium is maintained at between -10° C. and -7° C. The mixture is left stirring while the temperature is allowed to rise to r.t., the reaction medium is poured into a mixture of ice and concentrated HCl, the resulting mixture is extracted with DCM, the combined organic phases are washed with water and dried over magnesium sulphate and the solvents are evaporated off under vacuum. The residue is taken up in heptane and the precipitate formed is filtered off. 3.0 g of the expected product, m.p.=166°-167° C., are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[N:3]=1.C([Sn](CCCC)CCCC)CCC.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>[Pd]>[N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[NH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[N:3]=1
Reactant: Brc1cccc(-c2nc3ccccc3[nH]2)n1
Reactant: c1ccncc1
Agent: [Pd]
Agent: CCCC[Sn](CCCC)CCCC
Product: c1ccc(-c2cccc(-c3nc4ccccc4[nH]3)n2)nc1

Procedure:
In Scheme 3, the starting material is 2-bromo-6-carboxyl pyridine 7. Addition of an ortho-substituted aniline derivative 2 using BOP chemistry generates 2-bromo-6-benzimidazolyl pyridine 8. A tributyl-tin activated pyridine 11 is added to 8 in the presence of a palladium catalyst to yield 2-benzimidazolyl-6-pyridyl pyridine 6.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[NH:21]1[CH2:26][CH:25]([CH:27]2[CH2:32][CH2:31][CH2:30][N:28]2[CH3:29])[CH2:24][CH2:23][CH2:22]1>C(OCC)(=O)C>[CH3:29][N:28]1[CH2:30][CH2:31][CH2:32][CH:27]1[CH:25]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:26]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: CN1CCCC1C1CCCNC1
Solvent: CCOC(C)=O
Product: CN1CCCC1C1CCCN(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)C1

Procedure:
The title compound is prepared analogously to Example 35 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and hexahydronicotine to give colorless crystals, mp. 161°-163° C. (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][C:11]2[C:12](=[O:27])[N:13]([CH3:26])[CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[CH:5]=1.Cl[C:29]1[C:34]([CH:35]=[O:36])=[C:33]([N:37]2[CH2:49][CH2:48][C:47]3[N:46]4[C:41]([CH2:42][CH2:43][CH2:44][CH2:45]4)=[CH:40][C:39]=3[C:38]2=[O:50])[N:32]=[CH:31][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][C:11]2[C:12](=[O:27])[N:13]([CH3:26])[CH:14]=[C:15]([C:29]3[C:34]([CH:35]=[O:36])=[C:33]([N:37]4[CH2:49][CH2:48][C:47]5[N:46]6[C:41]([CH2:42][CH2:43][CH2:44][CH2:45]6)=[CH:40][C:39]=5[C:38]4=[O:50])[N:32]=[CH:31][CH:30]=3)[CH:16]=2)[CH:5]=1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Reactant: COCc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCc1cc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nn1C
Temperature: 95 °C
Yield: 22.5 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 336d (368 mg, 0.98 mmol), 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (270 mg, 0.82 mmol), PdCl2(dppf) (60 mg, 0.082 mmol), K3PO4 (348 mg, 1.64 mmol)), sodium acetate (135 mg, 1.65 mmol), acetonitrile (15 mL), and water (0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 95° C. for 3 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 ethyl acetate/methanol to afford 336e (100 mg, 22%). MS-ESI: [M+H]+ 542.2
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)[CH3:36])[CH3:32]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccco1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccco1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 55 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-3-(furan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-28) 64 mg (0.15 mmol) to obtain the title compound 24 mg (27%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CCNCCO
Product: CCN(CC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)CCO

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and 2-ethylaminoethanol were converted to yield 2-(Ethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol as light brown oil, MS: 405 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH:16]([N:29]1[CH2:34][C@H:33]([CH3:35])[NH:32][C@H:31]([CH3:36])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[CH:16]([N:29]1[CH2:30][C@@H:31]([CH3:36])[N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[C@@H:33]([CH3:35])[CH2:34]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1CCCN1C(=O)c2ccccc2C1=O

Procedure:
N-(3-Bromopropyl)phthalimide (2.50 g, 9.33 mmol) is added to a stirred solution of benzhydryl-3,5-cis-dimethylpiperazine (2.61 g, 9.33 mmol) and diisopropylethylamine (1.81 g, 14.0 mmol) in N,N-dimethylacetamide (25 mL). The resultant mixture is heated at 120° C. for 48 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 0-1%, 2-[3-(4-benzhydryl-2,6-cis-dimethylpiperazin-1-yl)-propyl]-isoindole-1,3-dione is obtained as a brown oil (1.98 g, 45% yield).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH:7]=[CH:8][C:9]1[CH:20]=[N:19][C:12]2[NH:13][CH2:14][C:15](=[O:18])[NH:16][CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[O:18]=[C:15]1[CH2:14][NH:13][C:12]2[N:19]=[CH:20][C:9]([CH:8]=[CH:7][C:6]([OH:21])=[O:5])=[CH:10][C:11]=2[CH2:17][NH:16]1
Reactant: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)CNC(=O)CN2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=Cc1cnc2c(c1)CNC(=O)CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
3-(3-Oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid tert-butyl ester (96 mg, 0.31 mmol) was dissolved into 1:1 CH2Cl2/TFA (2 mL) and stirred at room temperature for 30 min. The solvents were removed in vacuo to afford the title compound as a brown solid (44 mg, 61%) and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) 8.18 (t, J=5.7 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.37 (d, J=15.8 Hz, 1H), 7.35 (t, J=5.3 Hz, 1H), 6.24 (d, J=15.8 Hz, 1H), 4.28 (d, J=5.7 Hz, 2H), 3.98 (d, J=5.1 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15]/C=C2\C(=O)NC(=O)C3C\2=CC(N2C=CC=C2)=CC=3)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.BrC1C=C2C(=CC=1)C(=O)NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(-n5cccc5)cc43)cc2F)CC1
Agent: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CN1CCN(c2ccc(N)cc2F)CC1

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.28 g of tan solid is obtained from 0.2 g (0.746 mmol) of (4E)-4-(methoxy-8.42 g (methylene)-6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione and 0.187 g (0.895 mmol) of [3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amine: mp 206-207° C.; MS (ESI) m/z 446.2 (M+H)+1
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH3:10].[C:17]([C:20]1[C:21]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>C1COCC1>[OH:19][C:17]([C:20]1[C:21]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:18])[CH2:10][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C)(O)c1cccnc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 9.5 mL (2.1 eq) of LDA in 15 mL THF at −78° C. was added 2.0 mL of t-butyl acetate (2.1 eq.). The resulting mixture was stirred at −78° C. for 30 minutes after which a solution of N-(3-acetylpyridin-2-yl)pivalamide (1.52 g, 6.90 mmol) in THF was added in a dropwise fashion. The resulting reaction mixture was then stirred at −78° C. for 30 minutes and was brought up to room temperature. The reaction mixture was then quenched with saturated NH4Cl. The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with H2O (2×20 mL), brine (lx 20 mL), dried over MgSO4 and concentrated to give the title compound (1.40 g, 61%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.33 (s, 9 H) 1.44 (s, 9 H) 1.58 (s, 3 H) 2.65 (d, J=16.70 Hz, 1 H) 3.06 (d, J=16.70 Hz, 1 H) 5.54 (s, 1 H) 6.96 (dd, J=7.76, 4.83 Hz, 1 H) 7.43 (dd, J=7.91, 1.76 Hz, 1 H) 8.45 (dd, J=4.98, 1.76 Hz, 1 H) 10.29 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[CH:7][C:6]=2[CH:12]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][CH2:10][CH2:9][N:8]=[CH:7][C:6]=3[CH:12]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1ccc2c(c1)C=NCCN2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=NCCNc2ccc(-c3ccncc3)cc21
Temperature: 160 °C

Procedure:
A 20 mL microwave tube was charged 7-bromo-2,3-dihydro-1H-1,4-benzodiazepine (115 mg), 4-pyridylboronic acid (2 equiv), potassium carbonate (2 equiv), dichlorobis(triphenyl-phosphine)palladium(II) (10 mol %), DMF (3.5 mL) and water (0.7 mL) then heated to 160° C. for 360 s using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water then extracted with ethyl acetate/tetrahydrofuran (3:1). The organic extracts were combined and dried over sodium sulfate. The drying salts were removed by filtration and the filtrate was concentrated. The residue was triturated with diethyl ether and the resulting solids were collected on filter. Recrystallization from hot tetrahydrofuran provided 7-(4-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepine as a tan powder (9 mg). H1 NMR (d6-dmso): 8.49 (d, 2H), 8.23 (s, 1H), 7.85 (d, 1H), 7.62 (m, 3H), 7.29 (br t, 1H), 6.80 (d, 1H), 3.85 (m, 2H), 3.25 (m, 2H). Mass (ES+)=224.2 (100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:22]([NH:24][N:25]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:26][CH2:27][N:28]1C(=O)C2=CC=CC=C2C1=O)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.NN>CO>[NH2:28][CH2:27][CH2:26][N:25]([S:39]([CH3:42])(=[O:41])=[O:40])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:43][CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)C[C@@H](C(=O)NN(CCN1C(=O)c2ccccc2C1=O)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CCN)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A suspension of 0.926 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-(2-phthalimidoethyl)valerohydrazide in 10 ml of methanol was treated with 0.25 ml of hydrazine hydrate. The mixture was stirred at room temperature overnight. The suspended white solid was filtered off, the filtrate was concentrated and the residue was purified by chromatography on silica gel using 5% methanol in dichloromethane for the elution. There was obtained 0.23 g of (E)-2′-(2-aminoethyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl)-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid after trituration of the product with ether.