Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[CH:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[CH3:1])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)NC(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To flame-dried flask under N2 was charged 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 mL of dry THF. The solution was cooled to −78° C. and 1.63 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium in hexanes added. The resulting mixture was brought to 0° C. and stirred for 10 min. After cooling the mixture again to −78° C., a solution of 1.0 g (3.40 mmol) of crude product from Method C in 10 mL of dry THF was added over a 10 min period. The resulting mixture was stirred for 1 h, at which time, 0.28 mL (4.50 mmol) of iodomethane were added. The reaction mixture was stirred for 2 h, quenched with a saturated solution of NH4Cl and warmed to room temperature. The mixture was stirred for 5 min., diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (M+2).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[CH:10]1([CH2:13]O)[CH2:12][CH2:11]1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH2:13][CH:10]1[CH2:12][CH2:11]1)=[O:4]
Reactant: OCC1CC1
Reactant: CCCCC(C)C(=O)O
Product: CCCCC(C)C(=O)OCC1CC1

Procedure:
Prepared from 2-methylhexanoic acid and cyclopropanemethanol according to the ester preparation method A described above.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.O.NN>C(O)C>[NH2:22][CH2:21][C@H:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CN)C1
Yield: 70 %

Procedure:
Into a 200 mL round bottom flask was added 15R (6.66 g, 15.3 mmol) and 110 mL of 10:1 dichloromethane:ethanol. Hydrazine hydrate (7.66 g, 10 equiv.) was added and the reaction was heated to reflux for three hours. The precipitate which had formed was removed by filtration through Celite. The filtrate was concentrated under high vacuum and temperature (to remove hydrazine). The residue was resuspended in dichloromethane and the resultant precipitate was removed by filtration through a Buchner funnel. The filtrate was concentrated to leave a clear oil 15S (3.27 g, 73%) which was analytically pure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[C:11]([Cu])#[N:12]>CN(C=O)C>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[N:12])([CH3:10])[CH3:9]
Reactant: N#C[Cu]
Reactant: CC(C)c1ccccc1Br
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1C#N
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a dry, N2 purged 100 mL round bottom flask attached with condenser was added 1-bromo-2-isopropylbenzene (10.0 g, 50.2 mmol), anhydrous DMF (26 mL), and CuCN (5.85 g, 653 mmol) The reaction slurry was stirred at reflux under N2 for 4 hrs prior to analysis by GCMS. The reaction mixture was cooled to room temperature and poured into an ice/aq NH4Cl solution. The resulting precipitates were removed by vacuum filtration through a Buchner funnel. The aqueous filtrate was extracted with EtOAc (150 mL×3). The combined organic phase was dried over Na2SO4, filtered and concentrated on the Rotavapor to afford 5.97 g (82% yield) of 2-isopropylbenzonitrile. The product was used in the next step without further purification. GCMS m/z=145 [M+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]3)(=[O:13])=[O:12])[CH2:6][CH2:5]2.[O:24]=[C:25]1[C:30]2=[CH:31][NH:32][C:33]([CH:34]=O)=[C:29]2[CH2:28][CH2:27][O:26]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]3=[CH:34][C:33]1[NH:32][CH:31]=[C:30]3[C:25](=[O:24])[O:26][CH2:27][CH2:28][C:29]=13)(=[O:12])=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4cc(Br)ccc43)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4cc(Br)ccc43)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(5-Bromo-2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26](O)([C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:27].C(N(CC)CC)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:26]([C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])=[CH2:27]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(C)(O)C(C)(C)C)c2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a solution of 2-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-3,3-dimethylbutan-2-ol (182 mg) and triethylamine (0.12 mL) in toluene (5 mL) was added thionyl chloride (60 μL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (153 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:30]I>C1COCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:30])[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1
Reactant: CI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)cc(-c2cccc(I)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.8 %

Procedure:
6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one (63 g, 130 mMol) was dissolved in THF (500 mL) under an atmosphere of dry N2. To this solution, was added a 10 N aqueous NaOH (550 mL), benzyltriethylammonium chloride (13.8 g, 60.5 mMol) and methyl iodide (13.5 mL, 212.0 mMol). The reaction mixture was stirred at ambient temperature for 15 hours after which time it was partitioned between DCM and water. The DCM layer was successively washed with water (4 times) and then brine. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give 51.2 g of a yellow solid as the titled compound which was used without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][C:20]1([CH3:24])[CH2:21][CH2:22][C@H:18]([O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:9])=[O:8])=[C:11]([F:31])[CH:12]=2)[C@H:19]1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC(C)(C)[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@@H]1[C@@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)CCC1(C)C
Yield: 89.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-3,3-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (263 Mg, 0.429 mmol) prepared in Example 99d, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (178 mg, 90%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[N:12][N:11](COCC[Si](C)(C)C)[C:10]=2[C:23]2[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=2)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.COC.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[N:12][NH:11][C:10]=2[C:23]2[CH:28]=[N:27][C:26]([NH2:29])=[N:25][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c(C)nn(COCC[Si](C)(C)C)c2-c2cnc(N)nc2)cc1
Agent: COC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc(-c2c(C)n[nH]c2-c2cnc(N)nc2)cc1
Reaction time: 2 h

Procedure:
5-[4-(4-Methoxy-phenyl)-5-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-pyrimidin-2-ylamine was dissolved in anhydrous dichloromethane under nitrogen. 2M borontrichloride.dimethylether in dichloromethane (7 eq) was added dropwise, and all was stirred for 2 hours. The reaction mixture was added dropwise to sat. NaHCO3(aq) and extracted into dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC/MS to give 5-[4-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-yl]-pyrimidin-2-ylamine as a solid.
Reaction SMILES: Br(O)(=O)=O.[O:5]1[CH2:10][CH2:9][N:8]([C:11]([NH2:13])=[NH:12])[CH2:7][CH2:6]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[C:19]([CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26])=O.CC(C)([O-])C.[Na+]>C(O)(C)(C)C>[OH:23][CH2:24][CH2:25][C:21]1[C:22]([OH:26])=[N:12][C:11]([N:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)=[N:13][C:19]=1[C:18]1[CH:27]=[CH:28][CH:29]=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: N=C(N)N1CCOCC1
Reactant: COc1cccc(C(=O)C2CCOC2=O)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [O-][Br+2]([O-])O
Solvent: CC(C)(C)O
Product: COc1cccc(-c2nc(N3CCOCC3)nc(O)c2CCO)c1

Procedure:
Morpholinoformamidine bromate salt (200 mg, 0.952 mmol), 3-(3-methoxybenzoyl)-dihydrofuran-2-one (419 mg, 1.904 mmol) and sodium t-butoxide (183 mg, 1.904 mmol) were added into a microwave reaction tube, followed by being dissolved in t-butanol (3 ml). After irradiation of microwave (200 W, 120° C.) for 1 hour, the solvent was removed under reduced pressure, to obtain a crude product as a brown solid. The crude was purified by silica gel column chromatography (DCM/MeOH=95/5), to obtain 5-(2-hydroxyethyl)-6-(3-methoxyphenyl)-2-(morpholin-4-yl)-pyrimidin-4-ol, and 4-(3-methoxyphenyl)-2-(morpholin-4-yl)-5,6-furo[2,3-d]pyrimidine as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([CH3:38])[CH:37]=1)[C:33]#[N:34])#[N:28].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH:29]([C:27]#[N:28])[C:30]2[CH:31]=[C:32]([CH:35]=[C:36]([CH3:38])[CH:37]=2)[C:33]#[N:34])[C:12]([CH:23]([CH3:25])[CH3:24])=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(CC#N)c1
Reactant: CC(C)c1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(C#N)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2,4-bis(benzyloxy)-6-chloro-5-isopropylpyrimidine (45.4 g, 0.123 M) and 3-(cyanomethyl)-5-methylbenzonitrile (18.3 g, 0.117 M) were dissolved in anhydrous DMF (200 mL). After cooling the mixture in an ice bath under nitrogen atmosphere, 60% sodium hydride (9.38 g, 0.235 M) was added portionwise (addition time ca. 1.5 hr.). The mixture was stirred for further 1 hr. in an ice bath and stirred for ca. 20 hr. at room temperature. The reaction mixture was then cooled in an ice bath and sat. aqueous ammonium chloride solution was added thoroughly. The crude product was extracted with ether, washed with water twice, dried with magnesium sulfate, filtered, and evaporated in vacuo to give a light brown syrup, which was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:9)) to afford 53.46 g (94%) of 3-((2,6-bis(benzyloxy)-5-isopropylpyrimidin-4-yl) (cyano)methyl)-5-methylbenzonitrile as a light brown syrup. λmax (film) 2236 (nitrile) cm−1, 1H NMR (200 MHz, CDCl3) δ 1.10 (3H, d, J=6.9 Hz), 1.12 (3H, d, J=6.9 Hz), 2.36 (3H, s), 2.96 (1H, m), 5.37 (1H, s), 5.44 (4H, s), 7.32-7.55 (13H, m).
Reaction SMILES: [Cl-].[NH4+:2].[F:3][C:4]1[C:9]([S:10](Cl)(=[O:12])=[O:11])=[C:8]([F:14])[C:7]([F:15])=[C:6]([F:16])[C:5]=1[F:17].[OH-].[Na+]>CC(C)=O>[F:3][C:4]1[C:9]([S:10]([NH2:2])(=[O:12])=[O:11])=[C:8]([F:14])[C:7]([F:15])=[C:6]([F:16])[C:5]=1[F:17]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
To an aqueous solution of ammonium chloride was added dropwise an acetone solution of pentafluorobenzenesulfonyl chloride at room temperature. During addition, pH was adjusted to 7 by an aqueous sodium hydroxide solution. Precipitated product was filtered and recrystallized from toluene to give pentafluorobenzenesulfonamide. The structure was confirmed by 1H-NMR, 19F-NMR and IR.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[CH:10]1[CH:15]=[C:14]2[CH:16]([CH2:23][O:24][C:25](Cl)=[O:26])[C:17]3[C:22]([C:13]2=[CH:12][CH:11]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3.Cl>C(=O)(O)[O-].[Na+].CC(C)=O.[Cl-].[Na+].O>[C:25]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])([O:24][CH2:23][CH:16]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:10][CH:15]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:26]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CNCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Iminodiacetic acid (2.19 g, 16.5 mmol, Sigma Chemical Co., St. Louis, Mo.) was dissolved in a mixture of 1 M sodium bicarbonate (40 ml) and acetone (30 ml). 9-Fluorenemethyl chloroformate (2.0 g, 7.7 mmol) was dissolved in acetone (10 ml) and added to the above solution. After 6 hours reaction, the mixture was treated with brine, acidified with 1N HCl, and extracted with ethyl acetate. The yield was 2.38 g (87%), mp 213°-215.5° C. The mass spectrum (CI-NH3) showed a peak at 373 corresponding to m+1+NH3. Analysis (C19H17N06): calc. 64.22% C, 4.82% H, 3.94% N; found 64.15% C, 4.83% H, 3.909% N.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.[Mn]([O-])(=O)(=O)=[O:23].[K+]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([OH:23])[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3=[N:14][CH2:13][CH2:12][N:11]23)=[CH:8][CH:9]=1
Reactant: Clc1ccc(C2NCCNCc3ccccc32)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCN21

Procedure:
Two grams of 1-(p-chlorophenyl)-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine dihydrochloride are dissolved in 50 ml. of water. A solution of 1 g. of potassium permanganate in 50 ml. of water is added dropwise over a period of one-half hour. The mixture is filtered to remove inorganic salts and the filtrate is made basic with sodium carbonate solution. The precipitated solid is separated and washed with water. On recrystallization from ethanol there is obtained 5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo [2,1-a]isoindol-5-ol which has the same physical characteristics as the identical compound of Example X.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH3:12].CC(C)([O-])C.[K+].[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=1.CCOCC>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([I:19])[CH:21]=2)([CH3:9])[CH3:10])=[CH:4][C:3]=1[CH3:12]
Reactant: Ic1cccc(I)c1
Reactant: Cc1cc(C(C)(C)N)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: Cc1cc(C(C)(C)Nc2cccc(I)c2)ccc1Cl
Temperature: 25 °C

Procedure:
A suspension of amine INT 22 (2.8 g, 15.24 mmol) and potassium tert-butoxide (5.99 g, 53.4 mmol) in DME (25 mL) was purged with argon for 5 minutes. Then, PEPPSI-IPr® (207 mg, 0.305 mmol) and 1,3-diiodobenzene (5.03 g, 15.24 mmol) were added and the flask was closed. The mixture was stirred at room temperature over the weekend. The crude reaction mixture was treated with Et2O (50 mL) and filtered. The residue was washed with more Et2O (30 mL) and the combined filtrates were concentrated. The crude was purified by chromatography on silica gel (cyclohexane/CH2Cl2).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([C:5]([NH:30][C:31]([O:33][CH3:34])=[O:32])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)C(OCC)=O)[CH3:4].Cl.O>O1CCCC1>[CH2:3]([C:5]1([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[CH2:34][O:33][C:31](=[O:32])[NH:30]1)[CH3:4]
Reactant: CCOC(=O)C(CC)(CCc1ccc(OCCCCc2ccccc2)cc1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CCc2ccc(OCCCCc3ccccc3)cc2)COC(=O)N1
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Lithium borohydride (0.83 g) was added to a solution of ethyl 2-ethyl-2-methoxycarbonylamino-4-(4(4-phenylbutyloxy)phenyl)butanoate (5.6 g) in tetrahydrofuran (130 ml) and the mixture was refluxed under heating for 4 hours and allowed to stand at room temperature overnight. 2M Hydrochloric acid (11 ml) and water (400 ml) were added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the subject compound (3.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.[C:15]([CH2:17][CH2:18][NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)#[N:16]>>[Cl:34][C:33]1[C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:19][CH2:18][CH2:17][C:15]#[N:16])=[O:36])=[N:29][C:30]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:31][CH:32]=1
Reactant: N#CCCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: CC1(C)CCCOc2c(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCC#N)n3)cccc21

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and N-(2-cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-benzamide in an analogous manner to Example 179. Product was isolated as a golden brown solid (50 mg, 50%). LCMS (m/e) 491 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 8.69 (d, 1H, J=8.6 Hz), 8.25 (d, 1H, J=7.8 Hz), 8.12 (s, 1H), 7.80 (s, 1H), 7.53 (m, 2H), 7.12 (t, 1H, J=7.8 Hz), 6.95 (m, 2H), 6.74 (m, 1H), 4.01 (t, 2H, J=5 Hz), 3.73 (dd, 2H, J=6, 12 Hz), 2.76 (t, 2H, J=6 Hz), 2.08 (m, 2H), 1.69 (t, 2H, J=6 Hz), 1.40 (s, 6H).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][NH2:16])[C:8]([O:10][CH3:11])=[O:9].O>N1C=CC=CC=1>[S:3]=[C:1]1[NH:16][CH2:15][C:14]2[C:5](=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[NH:4]1
Reactant: COC(=O)c1ccc(CN)c(N)c1
Reactant: S=C=S
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)NC(=S)NC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Carbon disulfide (1.36 mL, 22.6 mmol) was added to a solution of methyl 3-amino-4-(aminomethyl)benzoate (2.0 g, 11.3 mmol) in pyridine (10 mL) and the resultant reaction mixture was stirred at 60° C. overnight. After cooling, water was added to the reaction mixture. The solid formed was filtrated to afford methyl 2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (2.2 g) which was carried to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O[Na])(C)(C)C.O>COCCOCCOC>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: COc1ccccc1Br
Reactant: C1CNCCN1
Agent: CC(C)(C)O[Na]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccccc1N1CCNCC1
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a solution of 1-bromo-2-methoxybenzene (0.623 mL, 5.0 mmol) and piperazine (1722.8 mg, 20.0 mmol) in diglyme (5 mL) was added t-BuONa. The resulting mixture was stirred at rt for a few minutes before the addition of dichlorobis(tri-β-tolyphosphine)palladium (235.8 mg, 0.3 mmol). The resulting mixture was then stirred at 170° C. under microwave irradiation for 30 min. Water was added and the mixture was extracted with EtOAc. The combined organic layers were dried, concentrated, and purified by ISCO to give 1-(2-methoxyphenyl)piperazine (intermediate 65) (758 mg, 79%) as an off-white solid. HPLC: 95%, RT 2.641 min. MS (ESI) m/z 193.10 [M+H]+.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18](O)=[O:19])=[O:8])=[CH:3][CH:2]=1.O[N:28]=[C:29]([NH2:31])[CH3:30].CC(C)N=C=NC(C)C>ClCCl>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([CH2:17][C:18]2[O:19][N:31]=[C:29]([CH3:30])[N:28]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(N)=NO
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CON=C1C[C@@H](Cc2nc(C)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 102.4 %

Procedure:
To a solution of [(2S,4EZ)-1-biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 50 mg, 0.14 mmol) in dichloromethane (3 ml) was added N′-hydroxyethanimidamide (12 mg, 0.16 mmol) followed by DIC (36 mg, 0.28 mmol). The reaction mixture was stirred 1 h30. The precipitate was filtered and the solution was concentrated in vacuo. Pyridine (1 ml) was added and the reaction mixture was stirred at reflux overnight The solvent was removed and dichloromethane was added. The organic phase was washed with HCl 1N then NaHCO3. The organic phase was dried (MgSO4), concentrated and purified on silica gel column chromatography (Ethyl acetate/cyclohexane, 40:60) to afford (3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-[(3-methyl-1,2,4oxadiazol-5-yl)methyl]pyrrolidin-3-one O-methyloxime (56 mg). Yield: 91%. HPLC purity: 90%