Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C1([N:34]=C=NC2CCCCC2)CCCCC1.N>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([NH2:34])=[O:21])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Agent: N
Solvent: ClCCl
Product: NC(=O)CCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.9 %

Procedure:
0.50 g (1.29 mmol) of 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]butanoic acid obtained in Example 28 was dissolved in 5 ml of dichloromethane, and 0.32 g (1.55 mmol) of dicyclohexylcarbodiimide was added to the reaction mixture on an ice bath. Then, 10 ml of ammonia gas dissolved dichloromethane solution was added, and the mixture was stirred at room temperature for 10 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a mixture of chloroform, methanol and conc. ammonia water (conc. 25% by weight) in the volume ratio 90:9:1 as the eluent. The desired fraction was concentrated under reduced pressure to give 0.38 g (76%) of 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]butanamide as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([O:25]CC)=O)=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][O:20][S:21][NH2:22])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[OH-].[NH4+:31]>CO>[NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([NH2:31])=[O:25])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([O:19][O:20][S:21][NH2:22])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc(N)cc1-2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Reaction time: 3 h

Procedure:
The product of Example 4a (968 mg), conc. ammonium hydroxide (10 mL), and methanol (5 mL) were heated at 95° C. in a sealed pressure bottle for 16 h. The mixture was allowed to cool and let stand for 3 h. The resulting amber solid was collected by filtration to yield the title compound (630 mg).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)=[NH:6])C.[CH2:34](N)[CH2:35][NH2:36]>C(O)C>[NH:6]1[CH2:34][CH2:35][N:36]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C4=NCCN4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a solution of N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (200 mg) in ethanol (4 ml) was added ethylenediamine (0.09 ml). The resulting mixture was stirred at room temperature overnight, was then concentrated and was mixed with an aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate/tetrahydrofuran, and the extract was washed with an aqueous solution of sodium chloride. The extract was dried (anhydrous magnesium sulfate) and was then concentrated, and the residue was recrystallized from ethyl acetate/methanol to obtain N-[4-(2-imidazolin-2-yl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 92) (60 mg) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([CH2:30][C:31]([NH:33][C:34]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:12]3[N:11]=[CH:10][N:9]=[C:8]4[C:13]=3[N:14]=[CH:15][N:7]4[CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:18][CH:19]=2)=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-[9-(Tetrahydro-pyran-2-yl)-9H-purin-6-yloxy]-phenylamine (1.1 g, 3.60 mmol, 1.0 eq.), DCM (10 ml) and phenyl-acetyl isothiocyanate (0.643 g, 3.60 mmol, 1 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was purified by flash column chromatography on silica gel to give 2-phenyl-N-{[(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)amino]-carbonothioyl}acetamide as a white solid (400 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 12.40 (s, 1H), 8.80 (s; 1H), 8.60 (s, 1H), 8.30 (s, 1H), 7.80 (m, 2H), 7.20 (m, 7H), 5.9 (m, 1H), 4.20 (m, 1H), 3.8 (m, 2H), 2.20 (m, 3H), 1.80 (m, 4H). MS (ESI) for C25H24N6O3S: 489 (MH+).
Reaction SMILES: [CH:1]1([C:5]2[C:14](I)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:16][CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:14]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]([CH2:16][CH3:17])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:19]
Reactant: CCc1cc(C2CCC2)c(I)cc1C(=O)OC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(C2CCC2)c(C#N)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 5.50 g, 16.0 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). Zinc cyanide (2.78 g, 23.7 mmol, 1.50 equiv) and Pd(PPh3)4 (1.83 g, 1.59 mmol, 0.10 equiv) were added to the reaction mixture. The resulting solution was stirred at 100° C. for 15 h under nitrogen. After cooling to ambient temperature, the reaction was carefully quenched with 300 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×300 mL of ethyl acetate. The combined organic layers were washed with 2×300 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:50) as eluent to furnish 3.20 g (82%) of methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[NH2:32][C:33]1[CH:34]=[C:35]([C:25]2[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:29])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])=[N:21][C:22]([S:27][CH3:28])=[N:23][CH:24]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Nc1cc(B(O)O)ccc1F
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CSc1ncc(-c2ccc(F)c(N)c2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of the Intermediate 45 (2.0 g, 3.77 mmol), 3-amino-4-fluoro phenylboronic acid (0.92 g, 5.94 mmol), Na2CO3 (0.88 g, 8.3 mmol) and catalytic amount of Pd(PPh3)4 in a mixture of toluene/EtOH/water (4:2:1) (28 mL) was stirred at 80° C. for 1 h. The mixture was cooled, and the solvents were removed. Water (5 mL) was added and the mixture was extracted with dichloromethane (3×5 mL). The combined organic fractions were washed with brine (5 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/isohexane to give the title compound as a yellow gum. 1H NMR (CDCl3, 500 MHz) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.77 (s, 2H), 7.10 (dd, J=11, 8 Hz, 1H), 6.77 (dd, J=8.5, 2.5 Hz, 1H), 6.64 (m, 1H), 5.72 (d, J=8.5 Hz, 1H), 4.98 (d, J=17.5 Hz, 1H), 4.40 (m, 1H), 4.10 (d, J=17.5 Hz, 1H), 2.64 (s, 3H), 0.74 (d, J=6.5 Hz, 3H). LCMS=561.5 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6]([O:8][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: CC(C)CCC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)CCC(=O)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of 5-methyl-2-oxohexanoic acid (0.288 g.) in methylene chloride (1 ml.) was added during 15 minutes to a stirred solution of dicyclohexylcarbodiimide (0.412 g.) and benzyl alcohol (0.432 g.) in methylene chloride (10 ml.) which was cooled to -15° C., and the mixture was stirred at that temperature for 1 hour, then at laboratory temperature for 30 minutes, and was then evaporated to dryness. Water (1 ml.), diethyl ether (2 ml.) and acetic acid (0.01 ml.) were added and the mixture was kept at laboratory temperature for 12 hours and then evaporated to dryness. The residue was purified by chromatography on a silica gel column using toluene as eluant and there was thus obtained benzyl 5-methyl-2-oxohexanoate as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2c(s1)C(Sc1ccccc1)=CCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cccc(Sc3ccccc3)c2s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a mixture of N-ethyl-N′-[7-(phenylsulfanyl)-4,5-dihydro-1,3-benzothiazol-2-yl]urea (crude product from the previous reaction, 1.59 mmol) in toluene (35.0 mL) was added DDQ (500 mg, 2.17 mmol). The reaction mixture was stirred at about 20° C. for about 2 hrs. The toluene was removed in vacuo and the crude material was taken up in CH2Cl2. The organic phase was washed with 0.5 M NaOH (2 times) and dried over MgSO4. The crude oil was purified by flash chromatography on SiO2 (EtOAc/CH2Cl2 5/95). 445 mg (85%, 2 steps) of pure product was isolated. LC/MS 330 (MH+); RP-HPLC RT 17.56 min.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[CH3:3].[NH2:26][C:27]1[N:32]=[C:31](Cl)[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1.C(N(CC)CC)C>CS(C)=O>[NH2:26][C:27]1[N:32]=[C:31]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15]2)[CH3:3])[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 85 °C

Procedure:
To a 25 mL pear flask were added the mixture of diastereomers of tert-butyl 3-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidine-1-carboxylate (0.057 g, 0.17 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.042 g, 0.25 mmol) in DMSO (1 mL). Triethylamine (0.069 mL, 0.50 mmol) was added and the mixture was heated to 85° C. for 14 hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by liquid chromatography (SiO2, 25-100% EtOAc/hexanes). The product-containing fractions from two different peaks were pooled separately and concentrated in vacuo to give the title diastereomers. Peak 1 (shorter retention time, 19 mg, 24%): 1H NMR (400 MHz, CDCl3) δ ppm 0.69-0.85 (m, 5H), 1.32-1.51 (m, 22H), 2.15-2.40 (m, 8H), 3.33-3.49 (m, 2H), 3.52-3.86 (m, 8H), 4.70 (dd, J=10.74, 7.45 Hz, 1H), 5.27 (br s, 1H), 5.62-5.75 (m, 1H), 5.82-5.96 (m, 2H), 6.60 (br s, 2H), 6.73 (d, J=8.84 Hz, 1H), 7.19 (s, 2H), 7.33-7.45 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477. Peak 2 (longer retention time, 41 mg, 52%): 1H NMR (400 MHz, CDCl3) δ ppm 0.66-0.90 (m, 3H), 1.39-1.52 (m, 15H), 1.88-2.07 (m, 3H), 2.21-2.40 (m, 5H), 3.30-3.89 (m, 10H), 5.02-5.20 (m, 2H), 5.65 (t, J=6.44 Hz, 1H), 6.61 (d, J=3.03 Hz, 1H), 7.14-7.24 (m, 2H), 7.28-7.46 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([NH:17][C:18]1[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[CH:21]3)[CH2:13]2)[CH2:7][CH3:8].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH2:6]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]([C:18]1[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[CH:21]3)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13]2)[CH2:7][CH3:8]
Reactant: CCCN1C2CCC1CC(Nc1ccc3c(cnn3C3CCCCO3)c1)C2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCN1C2CCC1CC(N(c1ccc3c(cnn3C3CCCCO3)c1)S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
Methanesulfonyl chloride (0.10 ml, 1.29 mmol) was added to a solution of N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (37 mg, 0.100 mmol) in pyridine (1 ml), and the resulting mixture was stirred at room temperature for 3 days. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a preparative thin-layer chromatography (200×200×0.5 mm, 2 plates, eluent: chloroform/methanol=20/1) to obtain N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-methanesulfonamide (20 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].O[NH:13][C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[NH:15]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[O:6][N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[N:13]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: COC(=O)CCCCC(=N)NO
Solvent: c1ccncc1
Product: COC(=O)CCCCc1noc(-c2ccccc2OC)n1
Yield: 34.4 %

Procedure:
Add 2-methoxybenzoyl chloride (5.20 g, 35 mmol) to a solution of methyl 5-(N-hydroxycarbamimidoyl)pentanoate (5.3 g, 34 mmol) in pyridine (50 mL) under nitrogen at 0° C. and then heat the mixture at reflux for 6 h. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate and wash with 1 N HCl. Wash the combined organic extracts with brine, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:4), to afford methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.4 g, 33% over two steps): 1H NMR (CDCl3) δ 1.7-1.85 (m, 2H), 1.85-2.00 (m, 2H), 2.35 (t, 2H), 2.95 (t, 2H), 3.65 (s, 3H), 3.95 (s, 3H), 7.00 (m, 2H), 7.45 (t, 1H), 8.00 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=O)[C:6]=2[CH:18]=1.B>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[CH2:7][C:6]=2[CH:18]=1
Reactant: CN1C(=O)C2CCCN2C(=O)c2cc(Cl)ccc21
Agent: B
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2cc(Cl)ccc21

Procedure:
If 7-chloro-1,2,3,11a-tetrahydro-10-methyl-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11(10H)-dione (prepared as described in Example 1 from DL-proline and 5 -chloro-N-methylisatoic anhydride) is treated with 1M borane in tetrahydrofuran as described in Example 1, the above compound is obtained. The hydrochloride salt melts at 243°-245°C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([N:29]=[C:30](OC)[CH2:31][CH3:32])#[N:28]>C(#N)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:30](=[N:29][C:27]#[N:28])[CH2:31][CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=NC#N)OC
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Solvent: CC#N
Product: CCC(=NC#N)NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Yield: 14.2 %

Procedure:
There were dissolved 4.0 g (0.0106 mol) of N-[4-[3-(piperidinomethyl) phenoxy]-cis-2-butenyl]-2-(2-aminoethylthio)acetamide and 2.01 g (0.0159 mol) of methyl N-cyanopropioimidate in 40 ml of acetonitrile, and after reflux with heating for 18 hours the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethanol=10:1) to give 0.69 g of the titled compound as oily matter.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCc2ccccc2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and benzyl alcohol by the method of Example 10 (b).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]#[N:8])[N:4]([CH3:9])[C:3]=1[C:10]1[CH:11]=[CH:12][C:13]2[N:18](C(OC(C)(C)C)=O)[C:17](=[O:26])[O:16][C:15]([CH3:28])([CH3:27])[C:14]=2[CH:29]=1.[O-]CC.[Na+]>C1COCC1.C(O)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]#[N:8])[N:4]([CH3:9])[C:3]=1[C:10]1[CH:11]=[CH:12][C:13]2[NH:18][C:17](=[O:26])[O:16][C:15]([CH3:27])([CH3:28])[C:14]=2[CH:29]=1
Reactant: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2C(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 80 °C
Yield: 54.2 %

Procedure:
A solution of tert-butyl 6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate (1 eq, 0.4 g, 0.87 mmol) in THF was added to a solution of sodium ethoxide (3 eq, 0.18 g, 2.6 mmol) in ethanol (10 mL). The solution was heated at 80° C. for 1 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in THF (10 mL) and 4N HCl (10 mL) was added. After heating to 60° C. for 16 h the solution was cooled, poured into water and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The product, 4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.17 g, 54%) was obtained by crystallization from 20% ethyl acetate/hexane. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 3.62 (s, 3H), 7.02 (d, 1H, J=8.2 Hz), 7.34 (s, 1H), 7.35 (dd, 1H, J=1.3, 8.2 Hz), 7.40 (s, 1H), 10.47 (s, 1H). MS (ESI (−)) m/z 358/360 (M−H)−. Anal. calcd for C16H14N3O2Br, C, 53.4, H, 3.92, N, 11.7. Found, C, 52.6, H, 3.82, N, 11.2.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:15])([C:9]#[C:10][CH2:11]N(C)C)[CH3:8].[OH-].[Na+].C(OCC)C>O1CCCC1.C1C=CC=CC=1.CCCCC>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:15])([CH:9]=[C:10]=[CH2:11])[CH3:8]
Reactant: CN(C)CC#CC(C)(O)c1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C=CC(C)(O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 507 g of the crude (foam) methiodide of 2-(p-biphenylyl)-5-dimethylamino-3-pentyn-2-ol obtained by step (b) above, in 4 liters of dry tetrahydrofuran, is added dropwise over a period of one hour, with cooling(to keep at room temperature), 478 g of a solution of sodium dihydrobis (2-methoxyethoxy) aluminate 70% w/w in benzene in 800 ml of dry tetrahydrofuran. The resulting mixture is then stirred at room temperature for 2 hours. The mixture is then cooled to 10° and dropwise there is added 3 liters of 2N sodium hydroxide, with stirring and cooling to 10° to 20°. 10 liters of diethyl ether are then added, in one portion, to the mixture. Solids present (inorganic salts) are removed by filtration on Celite. The filtrate is then extracted twice with 5 liter portions of water, the water washes then being washed three times with 5 liters of diethyl ether each time. The combined ether phases are washed once with 3 liters of aqueous saturated brine solution. The combined organic phases are dried over sodium sulfate, filtered, and the filtrate evaporated by rotary evaporation at 40° to obtain the crude product as an oil. The oil is taken up in 7 liters pentane (heated) and then the resulting pentane solution chilled until a precipitate forms. The precipitate is collected by filtration and washed with pentane. The precipitate is crystallized from pentane five times, then dried in a vacuum oven at room temperature for 12 hours to yield the title product, m.p. 65°-66°.
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[O:14][CH2:13][CH2:12][O:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].O>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[O:14][CH2:13][CH2:12][O:11]2)[C:7]1=[O:18]
Reactant: NO
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)OCCO3
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)OCCO4
Yield: 97 %

Procedure:
To a solution of 70 mg (0.27 mmol) of 9H,10H-5,8,11-trioxabenzo[de]anthracene-4,6-dione (from Example R3) in 4 mL pyridine was added 80 mg (1.16 mmol) of hydroxylamine hydrochloride and the reaction mixture refluxed for 1.5 hours and poured into 20 mL water while hot. The precipitate was isolated after 24 hours, washed with water, 1% HCl, water, and dried to yield 71 mg of the title compound, mp 344-347° C.