Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12]
Reactant: NCc1ccc(Cl)c(N)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1Cl
Reaction time: 3 h

Procedure:
3-Amino-2,4-dichloro-benzylamine (2.28 g, 11.9 mmol) was added to a mixture of 2,2-dimethyl-propionic acid chloride (1.47 mL, 11.9 mmol) and TEA (4.14 mL, 29.8 mmol) in THF (90 mL) and it was stirred for 3 h. The reaction mixture was concentrated, diluted with EtOAc, washed with 5% aq. NaHCO3 solution and water, dried with Na2SO4 filtered and concentrated to give the sub-title compound.
Reaction SMILES: [OH:1][CH:2]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([NH:43][CH3:44])=[O:42])[CH:36]=2)=[CH:31][CH:30]=1)[CH2:3][CH2:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.Cl>[C].[Pd]>[OH:1][CH:2]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([NH:43][CH3:44])=[O:42])[CH:36]=2)=[CH:33][CH:34]=1)[CH2:3][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: CNC(=O)c1cccc(-c2ccc(C(O)CCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c1
Agent: [Pd]
Agent: Cl
Product: CNC(=O)c1cccc(-c2ccc(C(O)CCc3c[nH]cn3)cc2)c1
Yield: 72.1 %

Procedure:
By the reaction in the same manner as in Example 41-(ii) using [4′-[1-hydroxy-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide (1.29 g), 10% palladium carbon (1.29 g)and 1N hydrochloric acid (2.23 ml), the colorless amorphous title compound (540 mg) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:18][Si:2]([CH3:1])([CH2:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: C[Si](C)(C)C#C[Si](C)(C)CCCCCCCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 15 (15.21 g, 0.0535 mol) and palladium hydroxide on charcoal (1.85 g, 1.60 mmol) in ethanol and ethyl acetate (120 ml, 1:1) was stirred under an atmosphere of hydrogen for 24 h at room temperature. The reaction mixture was filtered (celite) and the solvent roved in vacuo to yield a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][CH:21]1[CH2:24][NH:23][CH2:22]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:23]3[CH2:24][CH:21]([O:20][CH3:19])[CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: COC1CNC1
Agent: Cl
Product: COC1CN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3-methoxy-azetidine hydrochloride. Orange oil. MS (m/e): 305.4 ([M+H]+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[O:4].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CC#N.ClCCl.O>[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: N#Cc1ccc(C(=O)CCl)cc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C(=O)Cc2ncc[nH]2)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A stirred solution of 4-(2-chloroacetyl)benzenecarbonitrile (0.5 M) and imidazole (1.5 M) in CH3CN (200 ml) were heated for 14 hours at 60° C. The product was stripped of solvent under reduced pressure. The residue was diluted with dichloromethane (250 ml) and water (100 ml), and the mixture was stirred for 30 min. After filtering off a solid impurity, the aqueous layer was removed and discarded. The organic layer was washed sequentially with water (60 ml), sat. aq. NaHCO3 (60 ml), water (60 ml), brine (60 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The dark colored oil was dried overnight in vacuo giving 4-(2-imidazolylacetyl)benzenecarbonitrile in 90% yield.
Reaction SMILES: O=C1C=C(OCC[NH:11][C:12](N)=[NH:13])C2C=CC=CC=2O1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33](=[O:41])[CH:32]=1>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[O:41]=[C:33]1[CH:32]=[C:31]([O:30][CH2:29][CH2:28][CH2:27][NH:26][C:12]([NH2:13])=[NH:11])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34]1
Reactant: NCCCOc1cc(=O)oc2ccccc12
Reactant: N=C(N)NCCOc1cc(=O)oc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1cc(=O)oc2ccccc12

Procedure:
Is prepared according to the procedure for N-[2-(2-oxo-2H-1-benzopyran-4-yloxy)-ethyl]-guanidine from the trifluoroacetic acid salt of 4-(3-amino-propoxy)-1-benzopyran-2-one to afford the title compound as the trifluoroacetic acid salt after HPLC purification (40.0 mg, 35%). 1H NMR (DMSO-d6, 300 MHz) δ 7.88 (1H, dd, J=1.5, 8 Hz), 7.67 (2H, m), 7.39 (2H, m), 7.15 (3H, br s), 5.92 (1H, s ), 4.26 (2H, t, J=6 Hz), 3.32 (2H, buried under solvent peak), 2.03 (2H, m); MS (ESI, Pos.) calcd for C13H15N3O3 m/z [M+H]=262.1, found 262.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([CH:8]([C:19](=O)[CH3:20])[C:9]([O:11]CC2C=CC=CC=2)=O)[N:3]=1.[NH2:22][NH2:23]>CCO>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:19]([CH3:20])=[N:23][NH:22][C:9]=2[OH:11])[N:3]=1
Reactant: NN
Reactant: CC(=O)C(C(=O)OCc1ccccc1)n1nc(C)nc1C
Solvent: CCO
Product: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Temperature: 25 °C

Procedure:
A mixture comprising benzyl 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-oxobutanoate (step 2) (7.1 g, 24.71 mmol) and hydrazine (2.327 ml, 74.1 mmol) in EtOH (124 ml) were stirred at 50° C. for 3 hours. The reaction was allowed to cool to RT overnight. The resultant solid was then collected by filtration and washed with a small amount of cold EtOH to afford the title compound as a pale yellow solid; LC-MS Rt 0.61 mins; MS m/z 193.9 [M+H]+; Method=Method LowpH_v001.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([Br:35])[CH:29]=2)=[CH:24][CH:23]=1)[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:37][C:38]#[N:39])=[C:30]([Br:35])[CH:29]=2)=[CH:24][CH:23]=1)[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)N(Cc2ccccc2)Cc2ccc(-c3ccc(O)c(Br)c3)cc2)c2ccccc21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)N(Cc2ccccc2)Cc2ccc(-c3ccc(OCC#N)c(Br)c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 74.6 %

Procedure:
A mixture of N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (1.5 g, 2.85 mmol), prepared in the previous step, bromoacetonitrile (240 μL, 3.44 mmol) and potassium carbonate (1.95 g, 14.1 mmol) in 75 mL of DMF was stirred under nitrogen at room temperature for 23 h. The reaction was partitioned between methylene chloride and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-1-methyl-1H-indole-3-carboxamide (1.2 g, 75%) as a white solid, MS (ESI) m/z 564 [M+H]+. Elemental Analysis for C32H26BrN3O2: Calc'd: C, 68.09; H, 4.64; N, 7.44; Found: C, 66.78; H, 4.68; N, 7.19.
Reaction SMILES: [C:1]1([C:7](=[O:14])[C:8](=[N:12]O)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][O:17][C:18]([CH2:20][C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O)=[O:19].C([O-])(=O)C.[Na+]>[Zn].O.C(O)(=O)C>[C:7]([C:8]1[NH:12][C:21]([CH2:20][C:18]([O:17][CH2:16][CH3:15])=[O:19])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=1[CH3:10])(=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=NO)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1[nH]c(C(=O)c2ccccc2)c(C)c1C(=O)OCC
Temperature: 100 °C

Procedure:
A solution of 71 g. (0.37 mole) of 1-phenyl-1,2,3-butanetrione-2-oxime in 350 ml. glacial acetic acid and 50 ml. of water is added to 75.5 g. diethyl acetonedicarboxylate in 350 ml. of glacial acetic acid at 70° C. Concurrently, a mixture of 73 g. (1.12 mole) of zinc dust and 91.5 g. (1.12 mole) of anhydrous sodium acetate is added in portions at such a rate that the temperature is maintained near 100° C. After the additions are complete (about 45 minutes), the mixture is refluxed for one hour and poured into iced water. The resulting crude semisolid is collected by filtration and recrystallized twice from methanol to give ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate, m.p. 152-154° C. Analysis: Calcd. for C19H21NO5: C, 66.46; H, 6.16; N, 4.08%. Found: C, 66.50; H, 6.20; N, 4.17%.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][OH:5].Cl[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][N:15]=2)[N:12]=1.[H-].[Na+]>CN(C)C=O>[O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][N:15]=2)[N:12]=1
Reactant: OCC1CO1
Reactant: Clc1ccc2nncn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2nncn2nc1OCC1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
12.0 g of 2-oxiranylmethanol and 2.50 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine were dissolved in 40 ml of N,N-dimethylformamide; under ice cooling, 713 mg of 60% oily sodium hydride was added, followed by stirring at room temperature for 30 minutes. After cold saline was added, the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (10:1). The desired fraction was collected and concentrated under reduced pressure; the precipitated crystal was washed with diethyl ether and dried to yield 1.02 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:19][NH2:20].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1COCC1>[CH3:19][NH:20][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Intermediate D2 (4.57 g, 1 eq), methylamine (9.15 mL of a 2M solution in THF) and anhydrous magnesium sulphate (4.41 g, 2 eq) was stirred at room temperature for 16 h, filtered and the solid washed thoroughly with ethyl acetate. The combined filtrates were evaporated to a solid which was suspended in ethanol (90 mL) and sodium borohydride (1.01 g, 1.5 eq) added portionwise. The mixture stirred at room temperature for 3 h and the solvent removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with brine, dried and evaporated to give the title compound as a white solid. 1H-NMR (CDCl3) δ 7.68 (4H, m), 7.56-7.58 (2H, m), 7.43-7.45 (2H, m), 3.83 (2H, s), 2.50 (3H, s); MS(APCI+) found (M+1)=266, C15H14F3N requires 265.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][CH:30]4[CH2:32][CH2:31]4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and cyclopropanecarboaldehyde (0.3 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45 g) as yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][C:32]=2[NH2:33])[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[N:28]1([C:31]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:34][C:32]=2[NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=2[CH3:24])[CH2:29][CH2:30][O:25][CH2:26][CH2:27]1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (39.0 mg, 0.110 mmol) and 2,5-dimorpholinoaniline in toluene to give N-(2,5-di-4-morpholinylphenyl)-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.21 (2H, d, J=7.6 Hz), 7.78 (1H, t, J=7.6 Hz), 7.69 (1H, t, J=7.2 Hz), 7.47 (1H, d, J=9.2 Hz), 7.40 (1H, d, J=7.4 Hz), 6.98-7.09 (2H, m), 6.40 (1H, br. s.), 6.24 (1H, br. s.), 3.90 (4H, m), 3.78 (4H, m), 2.74-3.33 (8H, m), 1.95 (3H, m). Mass Spectrum (ESI) m/e=595.3 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([OH:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].CS(O[CH:35]1[CH2:49][C@@H:38]2[CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][C@@H:37]2[CH2:36]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.CO.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH:35]4[CH2:49][C@@H:38]5[CH2:39][N:40]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:41][C@@H:37]5[CH2:36]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(OS(C)(=O)=O)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1
Yield: 93.7 %

Procedure:
A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (0.22 g, 0.49 mmol), 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.15 g, 0.45 mmol), potassium carbonate (0.34 g, 2.50 mmol) in N,N-dimethylacetamide (5 mL) was heated in a sealed reaction tube at 90° C. for 12 h. The crude reaction mixture was diluted with 100 mL 10% methanol in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1×30 mL), water (1×30 mL) and brine (1×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO2, 3:2 hexanes:acetone) provided 1,1-dimethylethyl(3aR,6aS)-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy})hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.23 g, 98%). 1H NMR (400 MHz, d6-DMSO): 9.57 (s, 1H), 8.52 (s, 1H), 8.24 (d, 1H), 7.88 (dd, 1H), 7.78 (s, 1H), 7.62 (d, 1H), 7.13 (s, 1H), 5.15 (m, 1H), 3.96 (s, 3H), 3.42 (m, 2H), 3.36 (m, 2H), 2.80 (bs, 2H), 2.06 (m, 2H), 1.94 (m, 2H), 1.40 (s, 9H). MS (EI) for C27H30Cl2N4O4: 547 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:13]2[O:12][CH2:11][CH2:10][NH:9][C:8](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[C:13]2[O:12][CH2:11][CH2:10][NH:9][C:8](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCCNC2=O
Agent: Br
Product: O=C1NCCOc2c(O)cccc21
Temperature: 105 °C
Yield: 76.7 %

Procedure:
9-(Methyloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Preparation 57) (9.3 g, 48.1 mmol) in hydrobromic acid (120 ml, 2210 mmol) was stirred and heated at 105° C. for 5 hours. Evaporated to dryness, azeotroped with 200 ml of ethanol and biotage chromatographed twice in 3% methanol in EtOAc. Triturated with EtOAc and filtered off to give 6.61 g of white solid. MS (ES): C9H9NO3 requires 179; found 180 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH3:27])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])C1C=CC=CC=1>C1COCC1.CO.[Pd].[C]>[CH3:20][C:14]1([CH3:19])[CH2:13][CH:12]([N:21]([CH3:27])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: CCS(=O)(=O)N(C)C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)N(C)C1CC(C)(C)Oc2ccc(O)cc21

Procedure:
7.2 g (18.5 mmol) of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-methylethanesulfonamide were dissolved in 150 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pd/carbon. After absorption of hydrogen was complete, the catalyst was filtered off with suction, the filtrate was concentrated and the residue was crystallized using diisopropyl ether, 5.0 g, m.p. 160-162° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C)n2)C1=O
Yield: 87.4 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (655 mg) described in Preparation Example 247 and 1-acetylimidazolidin-2-one (259 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (642 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:8](=[O:20])[CH:7]=1.[Cl:26]N1C(=O)CCC1=O>CC(O)=O>[Cl:26][C:7]1[C:8](=[O:20])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1]
Reactant: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g, 0.4 mmol) in AcOH (3 mL) was added N-chlorosuccinimide (70 mg, 0.5 mmol), and the reaction mixture was heated at reflux for 10 min. The reaction mixture was cooled room temperature and the solvent was removed under reduced pressure. 1H NMR (300 MHz, CDCl3) δ 7.60-7.50 (m, 1H), 7.45-7.20 (m, 2H), 7.10-6.80 (m, 5H), 6.16 (d, J=8 Hz, 1H), 5.21 (s, 2H), 5.15 (s, 2H). ES HRMS m/z 380.0641 (M+H C19H14ClF3NO2 requires 480.0660).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:48])[C@@H:20]([NH:28][C:29](=[O:47])[C@H:30]([C:40]([S:43]([CH3:46])(=[O:45])=[O:44])([CH3:42])[CH3:41])[NH:31][C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]1(=[O:55])[O:54][C:52](=[O:53])[CH2:51][CH2:50]1>O1CCCC1>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([O:48][C:49](=[O:55])[CH2:50][CH2:51][C:52]([OH:54])=[O:53])[C@@H:20]([NH:28][C:29](=[O:47])[C@H:30]([C:40]([S:43]([CH3:46])(=[O:45])=[O:44])([CH3:42])[CH3:41])[NH:31][C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccnc1)C(C)(C)S(C)(=O)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](OC(=O)CCC(=O)O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccnc1)C(C)(C)S(C)(=O)=O
Yield: 67.6 %

Procedure:
A solution of 68 mg (0.1 mmol) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide (example 7) in 10 ml of tetrahydrofuran was treated with 10 mg (1 mmol) of succinic anhydride (Aldrich 23,960-0) and heated at reflux overnight. The volatiles were evaporated under reduced pressure and the residue chromatographed on silica eluting with dichloromethane/methanol (19:1) to give 53 mg of N-tert-butyl-2-[2(R)-(3-carboxypropionyloxy)-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valyl]amino]-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8a(S)decahydro-3(S)-isoquinolinecarboxamide as a foam, [M+H]+ 784.5.
Reaction SMILES: [CH2:1]([C@@H:8]1[O:10][C@@H:9]1[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.O.Cl>[CH2:1]([C@@H:8]1[O:10][C@@H:9]1[C:11]([OH:14])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCCCCCC[C@@H]1O[C@@H]1CO
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC[C@@H]1O[C@@H]1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 500 mg (2.50 mmole) of (2R-cis)-3-heptyloxiranemethanol in 50 ml of DMF was added 3.30 g (8.75 mmole) of pyridinium dichromate. The reaction was allowed to stir overnight under argon. The mixture was then diluted with 150 ml H2O and 20 ml 0.1 M HCl and washed three times with 50 ml of Et2O. The combined Et2O layers were dried over MgSO4, filtered and evaporated to afford a white powder. This residue was crystallized from petroleum ether to afford 39 mg of white power, mp 62-3° C. 1H NMR (CDCl3) δ 3.59 (d, 1, J=5 Hz), 3.24 (m, 1), 1.6-1.2 (m, 12), 0.88 (t, 3, J=7 Hz). Mass Spectra: M+(19.1)186.1, M-45(42.3)141.1, M(100)95.1.