Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH-].[CH3:8][N+:9]([CH3:12])([CH3:11])[CH3:10]>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:8][N+:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)C(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: CC(C)C(=O)[O-]

Procedure:
To a 20 L round bottom flask was added isobutyric acid (1300 mL, 14 mol), and an aqueous solution of 25% tetramethylammonium hydroxide (5 L, 14 mol). The water was removed under reduced pressure, and azeotroped with toluene (2×2 L) to leave the product (15) as an amber liquid, which was used without further purification.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH2:25][CH:24]1[C:33]([O-:35])=O.[Li+].C(N(CC)CC)C.[CH3:44][C:45]1[N:49]=[C:48]([CH2:50][NH2:51])[O:47][N:46]=1>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH3:44][C:45]1[N:49]=[C:48]([CH2:50][NH:51][C:33]([CH:24]2[O:23][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][CH2:25]2)=[O:35])[O:47][N:46]=1
Reactant: O=C([O-])C1CNc2ccccc2O1
Reactant: Cc1noc(CN)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(CNC(=O)C2CNc3ccccc3O2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
HOBT (1.0 g, 6.5 mmol) and WSC.HCl (1.1 g, 5.8 mmol) were added to a solution of lithium benzomorpholine-2-carboxylate (900 mg, 5.0 mmol) in dichloromethane (25 ml) and DMF (4.0 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 45 min. Triethylamine (0.73 ml, 530 mg, 5.2 mmol) and a solution of 3-methyl-1,2,4-oxadiazol-5-ylmethylamine (590 mg, 5.2 mmol, prepared according to H. Biere et al., Liebigs Ann. Chem. 1749 (1986)) in dichloromethane (5.0 ml) were added and the mixture was stirred for 18 h. The mixture was reduced, taken up in ethyl acetate and washed with 0.3N potassium hydrogen sulphate, saturated sodium hydrogen carbonate and brine. The organic phase was dried and reduced. Chromatography (80% ethyl acetate/20% 60-80 petroleum ether) afforded N-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorpholine-2-carboxamide (900 mg, 65%) as a brown gum.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH:23]([OH:48])[C:24]2(O)[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23](=[O:48])[CH:24]2[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(O)C2(O)CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(=O)C2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 51.4 %

Procedure:
A solution of 5-t-butyldiphenylsilyloxy-1,2-dihydroxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene (2.0 g) and p-toluenesulfonic acid (20 mg) in toluene (40 ml) was stirred for 30 minutes under reflux. The mixture was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyldiphenylsilyloxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-2-oxo-1,2,3,4-tetrahydronaphthalene (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Cl.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C:45](Cl)=[O:46]>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:45]([C@@H:41]4[CH2:42][CH2:43][CH2:44][NH:40]4)=[O:46])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)[C@@H]1CCCN1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCNCC1
Agent: Cl
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(C(=O)[C@@H]2CCCN2)CC1

Procedure:
Prepared according to the method of Example 1 by replacing N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine with 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine and replacing 2-(dimethylamino)acetyl chloride hydrochloride with (S)-pyrrolidine-2-carbonyl chloride hydrochloride. Product was obtained. MS (ES+): 655.28 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)[C:10]=2[O:9]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3ccc(C)cc3)c2O1

Procedure:
The title compound was prepared (0.071 g, 34%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-methylphenylboronic acid (0.168 g, 1.24 mmol). mp 210-213° C.
Reaction SMILES: [NH2:1][C:2](=NO)[C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.C(#[N:30])C>[Pd]>[NH2:30][N:1]=[CH:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC#N
Reactant: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C(N)=NO)c2)cc1
Agent: [Pd]
Product: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C=NN)c2)cc1

Procedure:
The compound of Example 13 (0.49 g, 1.3 mmol) was dissolved in ACOH and hydrogenated with 4% Pd/C (53% wet, 0.050 g) in a Parr Shaker (60 psi, 60C). The catalyst was filtered off and the filtrate concentrated in vacuo to give a white solid. The solid was slurried with acetonitrile and the resulting white solid was collected by vacuum filtration (0.423 g).
Reaction SMILES: [ClH:1].CO[N:4]=[CH:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[NH:8][CH:7]=1.C(OCC)C>[Pd].CO>[ClH:1].[ClH:1].[NH2:4][CH2:5][C:6]1[C:10]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[NH:8][CH:7]=1
Reactant: CON=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
10 ml of 10% hydrochloric acid and 0.50 g of 10% palladium on carbon were added to a solution of 497 mg (1.68 mmol) of 5-(4-fluorophenyl)-4-(pyridin-4-yl)-1H-pyrrole-3-carboxaldehyde O-methyloxime [which was prepared as described in step 5(i) above] in 10 ml of methanol. The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. At the end of this time, the reaction mixture was filtered and the filtrate thus obtained was concentrated by evaporation under reduced pressure. The residue was washed with diisopropylether and then with diethylether to give 391 mg (yield 68%) of the title compound as a yellowish orange powder.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.C1CCN2C(=NCCC2)CC1.CO>CCOC(C)=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:3]2[CH:1]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:5][C:4]=2[CH:12]=1
Reactant: CCOC(=O)COc1cc(OC)ccc1C=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2ccc(OC)cc2o1
Temperature: 160 °C
Yield: 93.9 %

Procedure:
A mixture of the product of Step A (1.28 g, 5.37 mmol) and DBU (0.3 ml) was heated for 3 h at 160° C. with stirring, cooled to room temperature and dissolved in EtOAc:MeOH mixture (99:1). The mixture was filtered through the silica bead and the filtrate was evaporated to give the title compound (1.11 g; 77%), as colourless solid. 1H-NMR (CDCl3) 1.40 (tr, 3H, J=7.13 Hz); 3.85 (s, 3H); 4.40 (q, 2H, J=7.13, 14.25 Hz); 4.45 (s, 1H); 6.91 (dd, 1H, J=2.25, 8.68 Hz); 7.04 (d, 1H, J—1.87 Hz); 7.51 (d, 1H, J=5.17 Hz),
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:5]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:7]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.N[C@H](C(O)=O)CCSC.[OH-].[NH4+].[Cl-]>CS(O)(=O)=O>[ClH:1].[OH:3][C:4]1[C:5]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:7]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1
Reactant: COc1cc2c(cc1Sc1ccccc1)CCN(C)CC2c1ccccc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: Cl
Product: CN1CCc2cc(Sc3ccccc3)c(O)cc2C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-Methoxy-3-methyl-1-phenyl-7-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (4.5 g, 0.011 m) dissolved in methanesulfonic acid (165 ml) was treated with methionine (8.3 g, 0.055 m) and stirred for 16 hours at 25° C. The mixture was poured into ice water, basified with ammonium hydroxide and extracted with ethyl acetate. The organic phase was concentrated in vacuo and the residue purified by chromatography on silica eluted with methanol-methylene chloride (1:50) to give 8-hydroxy-3-methyl-1-phenyl-7-phenylthio-2,3,4,5-tetrahydro-1H-3-benzepine which was treated with hydrooen chloride to give 8-hydroxy-3-methyl-1-phenyl-7-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1.CO.[BH4-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1
Reactant: Fc1ccccc1C1=NCCNc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccccc1C1NCCNc2ccc(Br)cc21
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A round bottomed flask was charged with 7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (47 mg), methanol (5 mL) and acetic acid (1 mL). The resulting mixture was treated with sodium borohydride in small portions while stirring at room temperature. The addition of sodium borohydride was continued until the starting material was consumed. The reaction was then concentrated to dryness and taken up in a saturated solution of sodium bicarbonate. The aqueous mixture was stirred for 10 minutes then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to an oil. Silica gel purification provided 7-bromo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (30 mg) as a colorless oil. H1 NMR (d6-dmso): 7.47 (t, 1H), 7.34 (q, 1H), 7.10-7.25 (m, 3H), 6.88 (d, 1H), 6.40 (s, 1H), 5.66 (d, 1H), 5.04 (br s, 1H), 3.20 (m, 1H), 2.95 (m, 1H), 2.76 (m, 2H), 2.60 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH3:20]>CCCCCC>[CH:12](=[C:11]1[C:2]([CH3:19])([CH3:1])[CH2:3][C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C#Cc1ccccc1)C#Cc1ccccc1
Reactant: N
Solvent: CCCCCC
Product: CC1(C)CC(c2ccccc2)=NC1=Cc1ccccc1
Yield: 88 %

Procedure:
2-benzylidene-3,3-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrole was prepared by reacting (3,3-dimethylpenta-1,4-diyne-1,5-diyl)dibenzene with ammonia in the presence of 10 mol % of catalyst E (165° C., 18 h). Compound 6f was the major product of the reaction (60%) which had a yield of 88%. Single crystals suitable for an X-ray diffraction study were obtained by slow evaporation of a hexane solution. mp: 101-103° C. (n-hexane) an Ortep diagram is shown in FIG. 6; 1H NMR (300 MHz, CDCl3) δ=1.37 (6H, s, CH3), 2.99 (2H, s, CH2), 5.98 (1H, s, CH), 7.24 (1H, t, J=7.4 Hz, CH), 7.41 (2H, t, J=7.7 Hz, CH), 7.49 (1H, d, J=1.3 Hz, CH), 7.51 (2H, d, J=2.3 Hz, CH), 8.05-8.10 (4H, m, CH); 13C NMR (75 MHz, CDCl3) δ=29.6 (CH3), 41.9 (Cq), 49.3 (CH2), 115.6 (CH), 126.5 (CH), 128.4 (CH), 128.4 (CH), 129.6 (CH), 131.3 (CH), 134.8 (Cq), 137.6 (Cq), 165.9 (NCqCH), 174.4 (N═CqCH2); HRMS (ESI): 262.1594 [(M+H)+, 262.1596 (C19H20N)].
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CCO>[Cl:9][C:6]1[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:7]=1[CH3:8]
Reactant: C1COCCN1
Reactant: Cc1c(Cl)nc(N2CCOCC2)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(Cl)nc(N2CCOCC2)nc1N1CCOCC1
Temperature: 125 °C
Yield: 96 %

Procedure:
To a solution of 4-(4,6-dichloro-5-methylpyrimidin-2-yl)morpholine in EtOH (0.15 M) was added morpholine (2.0 equiv.) followed by triethylamine (4.00 equiv.). The resulting mixture was heated under microwave irradiation at 125° C. for 50 min (2×25 min). The reaction mixture was then concentrated in vacuo to yield 4,4′-(6-chloro-5-methylpyrimidine-2,4-diyl)dimorpholine as a white solid in 96% yield which was utilized without further purification in the subsequent reaction. LCMS (m/z) (M+H)=299.1, Rt=0.85 min.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[C:42]([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([NH:53][CH3:54])[N:47]=[CH:46]3)=[C:41]([CH3:55])[CH:40]=[CH:39][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[CH:30]=1)=O>C1(C)C=CC=CC=1>[F:23][C:24]1[C:42]([C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([NH:53][CH3:54])[N:47]=[CH:46]3)=[C:41]([CH3:55])[CH:40]=[CH:39][C:25]=1[C:26](=[S:10])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[CH:30]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNc1ncc2cc(-c3c(C)ccc(C(=O)Nc4cccc(OC(C)C)c4)c3F)ccc2n1
Solvent: Cc1ccccc1
Product: CNc1ncc2cc(-c3c(C)ccc(C(=S)Nc4cccc(OC(C)C)c4)c3F)ccc2n1

Procedure:
A mixture of Lawesson's reagent (47 mg, 115 μmol) and 2-fluoro-N-(3-isopropoxyphenyl)-4-methyl-3-(2-(methylamino)quinazolin-6-yl)benzamide (93 mg, 209 μmol) in toluene (8 mL) was heatred at reflux for 16 h. Solvent was removed in vacuo and the residue was purified by flash chromatography (25-70% EtOAc/hexane) to give the title compound. MS (M+H)+ 461.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:40]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[O:30][CH2:31][C:32](=[O:39])[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.[C:50](Cl)(=[O:52])[CH3:51]>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:50]([N:36]1[CH2:37][CH2:38][N:33]([C:32](=[O:39])[CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[NH:26][C:27]4[N:28]=[C:12]([NH:13][C:14]5[CH:15]=[CH:16][CH:17]=[C:18]([CH:40]=5)[CH2:19][CH2:20][C:21]=2[CH:29]=3)[N:11]=[CH:10][C:9]=4[Cl:8])[CH2:34][CH2:35]1)(=[O:52])[CH3:51]
Reactant: CC(=O)Cl
Reactant: O=C(COc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 46 %

Procedure:
6-Chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (11.1 mg, 0.019 mmol) was stirred in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (17 μL, 0.096 mmol), and acetyl chloride (1.5 μL, 0.021 mmol) was added. Purification by preparative LCMS (pH 2) gave the desired compound (46%). LCMS for C26H28ClN6O3 (M+H)+: m/z=507.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:26]([CH3:27])=[CH:25][S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:26]([CH3:27])=[CH:25][S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1csc2nc(-c3ccno3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([C:4]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[CH:13][N:12]=2)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C=C(c1cc(OC)ncn1)C1CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1cc(OC)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
A zinc powder (11.5 g) was added to a solution of ethyl 3-cyclopropyl-3-(6-methoxypyrimidin-4-yl)acrylate (5.57 g) in acetic acid (60 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure to give a crude product of the title compound (5.68 g) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [Na].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[CH3:7][C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12].O>CO.C(OCC)C>[CH3:12][C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[C:2]2[C:3]=1[CH:4]=[CH:5][CH2:6]2
Reactant: CC(=O)CCC(C)=O
Reactant: C1=CCC=C1
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C)c2c1C=CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
34.4 g (1.50 mol) of sodium were dissolved in 300 ml of absolute methanol. A mixture of 53.8 ml (43.6 g, 0.66 mol) of cyclopentadiene and 67.3 g (0.59 mol) of 2,5-hexanedione was slowly added dropwise at 0° C. When the addition had ended, the mixture was stirred at 0° C. for a further hour and then at room temperature for a further two hours. 200 ml of water and 300 ml of diethyl ether were added to the reaction mixture. The organic phase was separated off in a separating funnel and the aqueous phase was washed twice with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 50 ml of water each time and then dried over sodium sulfate. The solvent was removed in vacuo and the oily residue was subjected to fractional distillation (48°-52° C., 0.1 torr). Yield 48.8 g (56 %). For the NMR data, see Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH3:24])[CH:10]([O:25]CC(OC(C)(C)C)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[OH:5][C:1]([CH3:4])([CH3:3])[CH2:2][O:25][C@H:10]1[C@H:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH3:24])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1
Reactant: Cc1ccc2c(c1)nc(C)n2C1CCN(C(=O)OC(C)(C)C)CC1OCC(=O)OC(C)(C)C
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1OCC(C)(C)O
Reaction time: 1 h

Procedure:
Racemic 3-tert-butoxycarbonylmethoxy-4-(2,5-dimethyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (470 mg; 1.02 mmol) in THF (10 mL) was treated with CH3MgBr (1.0 M in THF; 3 mL, 3 mmol). The reaction mixture was allowed to stir for 1 h and then poured into saturated NH4Cl and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure yielded crude product. trans-3-[2-Hydroxy-2-methylpropoxy]-4-[2,5-dimethylbenzimidazol-1yl]-N-Boc-piperidine was isolated by flash chromatography as an oil (324 mg; 78%).
Reaction SMILES: [C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([O:26][CH2:27][C:28]#[N:29])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:30]1[C:28]([CH2:27][O:26][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C:8]2[O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=2[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:25]=[CH:24]3)=[N:29][N:32]=[N:31]1
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 6 of Example 1, the title compound was prepared from 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile (0.350 g, 0.913 mmol), sodium azide (0.297 g, 4.56 mmol), and ammonium chloride (0.246 g, 4.60) mmol) in DMF (6 mL). Crystallization from acetonitrile (also using charcoal), and drying of the product for 16 hours at 84° C. yielded a light yellow solid (0.0978 g), mp 150-151° C. Mass spectrum (+APCl, [M+H]+) m/z427; 1HNMR (400 MHz, DMSO-d6): δ16.8-17.1 (br, 1H), 8.4 (d, 1H, J=1.2 Hz), 8.0-8.05 (m, 3H), 7.85 (dd, 1H, J=8.5 Hz and 1.7 Hz), 7.7 (d, 1H, J=7.5 Hz), 7.65 (d, 1H, J=2.4 Hz) 7.45 (m, 3H), 5.65 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2(m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C25H22N4O3: Calculated: C, 70.41;H, 5.20; N, 13.14. Found: C, 70.21;H, 5.14; N, 13.23.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:21]#[N:22])[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)(=O)=O)=CC=1>C(#N)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:11]([C:21]#[N:22])[CH2:12][N:13]=2)[CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)CNc2ccc(Br)cn2)cc1
Solvent: CC#N
Product: N#CC1CN=C2C=CC(Br)=CN21
Yield: 88.7 %

Procedure:
7.64 g of 2-(5-bromo-2-pyridinylamino)-1-cyanoethyl toluene-4-sulfonate was dissolved in 76 mL acetonitrile, and the mixture was heated for 15 hours under reflux. After the solvent was removed, an aqueous saturated sodium bicarbonate was poured into the reaction product which was then extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered through NH silica gel. The solvent was removed, whereby 3.83 g of the title compound (yellow solid) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[C:21]([N+:27]([O-])=O)[CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10]>CO.[Pd]>[NH2:27][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH:25][CH3:26])[O:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][N:4]2[CH2:5][CH2:6][CH2:7][CH:3]2[CH2:2][OH:1])[CH:17]=1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CN3CCCC3CO)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(NC(=O)CN3CCCC3CO)c2)cc1N

Procedure:
2-(2-Hydroxymethyl-pyrrolidin-1-yl)-N-[4-(4-methylamino-3-nitro-phenoxy)-pyridin-2-yl]-acetamide was hydrogenated in methanol in the presence of Pd C for 4 hours. The catalyst was removed via filtration through Celite and filtrate was concentrated to give N-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-2-(2-hydroxymethyl-pyrrolidin-1-yl)-acetamide. MS: MH+=372.4.