Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:23])[CH2:19][C@H:18]4[CH:24]([CH3:26])[CH3:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:35](=[N:37][OH:38])[NH2:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:23])[CH2:19][C@H:18]4[CH:24]([CH3:25])[CH3:26])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]3[NH:36][C:39](=[O:40])[O:38][N:37]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-N′-hydroxy-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (79 mg, 0.146 mmol) and 1,1′-carbonyldiimidazole (26.1 mg, 0.161 mmol) dissolved in acetonitrile (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 mL, 0.585 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C29H36ClN7O3 [M+H]+ 566. found 566. 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.96 (d, J=1.8, 1H), 8.78 (d, J=2.4, 1H), 8.50 (t, J=2.1, 1H), 7.82 (s, 1H), 4.39-4.34 (m, 1H), 3.98 (s, 1H), 3.85-3.81 (m, 1H), 3.77 (s, 2H), 3.53 (dd, J=5.9, 15.1, 1H), 3.20 (s, 3H), 2.31-2.27 (m, 1H), 2.09-2.00 (m, 1H), 1.80-1.72 (m, 1H), 1.37 (d, J=10.5, 2H), 1.12-1.05 (m, 1H), 1.05-0.96 (m, 1H), 0.89 (d, J=7.0, 3H), 0.87 (s, 1H), 0.76 (d, J=6.8, 3H), 0.6 (d, J=6.5, 3H), 0.61-0.55 (m, 1H), 0.54-0.48 (m, 1H), 0.48-0.44 (m, 1H), 0.40-0.34 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].C(OCC)(=O)C>C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.34 g of t-butyl α-(6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl)acetate [prepared as described in Example 7(g) above] was N-alkylated with 0.45 g of butyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The resulting product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as the eluent. As a result, the title compound was separated into isomers A and B (resulting from the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5](I)=[N:4][C:3]=1[C:24]([O:26][CH3:27])=[O:25].[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[C:28]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:7]=2)[C:2]([OH:1])=[C:3]([C:24]([O:26][CH3:27])=[O:25])[N:4]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2cc(Oc3cccc4ccccc34)ccc2c1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Methyl 4-hydroxy-1-iodo-7-(naphthalen-1-yloxy)isoquinoline-3-carboxylate (130 mg, 0.28 mmol) and CuCN (49 mg, 0.55 mmol) were suspended in DMF (1.1 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 87 mg. MS: (−) m/z 369.31 (M−1).
Reaction SMILES: [CH:1]1([N:7]([O:14][CH3:15])[C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:20]([CH3:23])[CH:21]=O)(=O)C.C(O)C(C)C>[Fe].O>[CH3:15][O:14][N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([C:9]1[CH:21]=[C:20]([CH3:23])[O:11][C:10]=1[CH3:12])=[O:13]
Reactant: CC(=O)OC(C)C=O
Reactant: CON(C(=O)CC(C)=O)C1CCCCC1
Agent: [Fe]
Solvent: CC(C)CO
Solvent: O
Product: CON(C(=O)c1cc(C)oc1C)C1CCCCC1
Reaction time: 7.5 h

Procedure:
A mixture of 85.2 parts of N-cyclohexyl-N-methoxyacetoacetamide and 58.2 parts of 95.7% pure α-acetoxypropionaldehyde is added dropwise to a suspension of 19.4 parts of iron-III chloride in 100 parts of isobutanol at 40°-45° C. The mixture is then kept at 45° C. for 7.5 hours. Water is added to the reaction mixture, the batch is extracted with methylene chloride and the extract is evaporated. 104 parts of crude product are obtained; this can be distilled at 138°-145° C./0.3 mm Hg, to give 88.5 parts of pure O-methyl-N-cyclohexyl-2,5-dimethylfuran-3-hydroxamic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20].I[CH2:22][CH:23]([CH3:25])[CH3:24].NC1N=C(OC)C(C(=O)CCC2CCNCC2)=CC=1.ICCCC>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20]
Reactant: CC(C)CI
Reactant: COc1nc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Agent: COc1nc(N)ccc1C(=O)CCC1CCNCC1
Solvent: CCCCI
Product: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(CC(C)C)CC1

Procedure:
The title compound was prepared according to the procedure of step 2 in the example 13 using 1-(6-amino-5-chloro-2-methoxy-3-pyridinyl)-3-(4-piperidinyl)-1-propanone and 1-iodo-2-methylpropane, instead of 1-(6-amino-2-methoxy-3-pyridinyl)-3-(4-piperidinyl)-1-propanone and 1-iodobutane.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2C=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-N—Boc 3-amino pyrrolidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml). The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.27 (m, 1H) 1.28-1.47 (m, 2H) 1.52-1.71 (m, 4H) 1.71-1.89 (m, 4H) 1.89-2.04 (m, 1H) 2.64 (dd, J=11.12, 5.05 Hz, 1H) 2.75 (ddd, J=10.74, 7.96, 6.32 Hz, 1H) 2.83-3.03 (m, 2H) 3.31 (s, 3H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H) 4.22-4.36 (m, 1H) 4.38-4.54 (m, 1H) 7.47 (dd, J=8.46, 1.64 Hz, 1H) 7.51 (d, J=1.52 Hz, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.23 (d, J=7.07 Hz, 1H) 8.26 (d, J=8.34 Hz, 1H). Melting point: 195-198° C. [M+H] calc'd for C26H33F2N7O3 530. found 530.
Reaction SMILES: [CH2:1]([C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2].[Cl:12]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl>[Cl:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:11][C:3]([CH2:1][CH3:2])=[N:4][C:5]=12
Reactant: CCc1nc2cccnc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2c(Cl)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
2-Ethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 4.00 g, 27.2 mmol) was dissolved in chloroform (45 mL), and the solution was added with m-chloroperbenzoic acid (5.18 g, 29.9 mmol) followed by stirring at room temperature for 5 hr. The reaction mixture was concentrated, added with ethyl acetate and water, and partitioned between ethyl acetate and water. The aqueous layer was concentrated and the residue was dissolved in chloroform (8 mL). Phosphorus oxychloride (24 mL, 257 mmol) was added thereto and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured onto ice, neutralized with aqueous ammonia, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the residue and the precipitated solid was collected by filtration to give the title compound (3.32 g, 67%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:15]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH2:17].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH2:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:26])[O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=2)[CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH2:17]
Reactant: C=CCc1cccc(N=C=O)c1
Reactant: COC(COc1ccc(O)cc1)OC
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCc1cccc(NC(=O)Oc2ccc(OCC(OC)OC)cc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 3-Allylphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is stripped of solvent and unreacted isocyanate to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-3-allylphenylcarbamate as the residue.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[Br:27][C:28]1C(Cl)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1>C(Cl)Cl>[Br:27][C:28]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[CH2:12][CH2:11]2)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 58.9 %

Procedure:
tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.160 g, 0.56 mmol, 1.0 eq) was dissolved in DCM (1.8 mL) and the reaction mixture cooled in a ice-water bath before the dropwise addition of TFA (1.8 mL). Stirring was continued at this temperature for 1 h, the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.10 g, 0.56 mmol, 1.1 eq) was suspended in iPrOH (0.55 mL) and DIPEA (0.22 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.130 g, 0.51 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.120 g, 55%); 1H-NMR (500 MHz, DMSO-d6): δ 2.58 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.54 (br d, 1H, J=1.2 Hz, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H), 9.04 (d, 1H, J=1.7 Hz, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.83 min—398/400 [(M+H)+, Br isotopic pattern, 100%].
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:18]([OH:20])=[O:19])[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1)=O)(C)(C)C.[ClH:21].CCOCC>O1CCOCC1>[ClH:21].[NH2:8][CH2:9][C:10]1([C:18]([OH:20])=[O:19])[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCCC2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCC1(C(=O)O)CC12CCCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid (200 mg, 0.706 mmol) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3 mL). The reaction was stirred for 18 hours at room temperature. Ether (20 mL) was added and the precipitate was isolated by vacuum filtration. The solid was dried in a vacuum oven at 48° C. to give 133 mg (86%) of 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid hydrochloride as a white solid: mp 240–242° C.; 1H NMR (300 MHz, D2O) δ 0.92 (d, J=5.2 Hz, 1H), 1.40 (d, J=5.2 Hz, 1H), 1.4–1.6 (m, 10H), 3.12 (d, J=14.0 Hz, 1H), 3.61 (d, J=14.0 Hz, 1H); MS (APCI) m/z 184 [M+H]+. Anal. Calcd. For C10H17NO2—HCl: C, 54.67; H, 8.26; N, 6.38; Cl, 16.14. Found: C, 54.91; H, 8.36; N, 6.25; Cl, 15.99.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[NH2:21][N:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]1[CH3:33]>>[CH3:33][C:23]1[N:22]([NH:21][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1nc2ccccc2c(=O)n1N
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CNn2c(C)nc3ccccc3c2=O)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 3-amino-2-methylquinazolin-4(3H)-one. m/e+ 410 for C25H24N5O [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.22 (t, J=1.1 Hz, 1H), 7.71 (m, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.06 (dd, J=1.1, 9.1 Hz, 1H), 5.86 (t, J=4.8 Hz, 2H), 4.53 (bs, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 161.838, 155.787, 147.287, 146.870, 144.648, 137.968, 134.753, 131.113, 129.377, 128.399, 128.361, 127.246, 126.736, 126.457, 122.711, 121.779, 120.763, 117.161, 114.044, 43.949, 21.906, 21.459, 18.646 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH:12][C:13]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:9][CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[C:30]1[C:38]2[CH:37]=[C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]3=[CH:34][C:33]=2[C:32](=[O:43])[NH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:22]([O:21][C:19]([C:13]1([NH:12][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][N:31]2[C:32](=[O:43])[C:33]3[CH:34]=[C:35]4[CH:42]=[CH:41][CH:40]=[CH:39][C:36]4=[CH:37][C:38]=3[C:30]2=[O:29])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)C(CCO)NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCN1C(=O)c2cc3ccccc3cc2C1=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of benzyl 1-(1-tert-butoxycarbonyl-3-hydroxy-1-propylamino)cyclohexanecarboxylate (466 mg, 1.19 mmol) in dry tetrahydrofuran (12 mL) was added 1,3-dioxo-1,3-dihydrobenzo[f]isoindole (258 mg, 1.31 mmol), triphenylphosphine (344 mg, 1.31 mmol) and diethylazodicarboxylate (0.21 mL, 1.31 mmol). The resulting mixture was stirred at room temperature for 6 days. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel eluting first methylene chloride and then with 2% ethyl acetate in methylene chloride to afford 1-[1-tert-butoxycarbonyl-3-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)propylamino]cyclohexanecarboxylic acid benzyl ester as a white solid, 530 mg (78%).
Reaction SMILES: [CH:1]([O:14][N:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18](=[O:31])[CH:17]=[C:16]1[CH2:32]O)([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.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C>[CH:1]([O:14][N:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18](=[O:31])[CH:17]=[C:16]1[CH2:32][N:38]1[C:34](=[O:44])[C:35]2[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:37]1=[O:39])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CO)cc2=O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN3C(=O)c4ccccc4C3=O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 1-(benzhydryloxy)-2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one (Intermediate 291, 2 g, 4.51 mmol), phthalimide (0.664 g, 4.51 mmol) and triphenylphosphine (1.178 g, 4.51 mmol) in THF (20 mL) at room temperature was added diisopropyl azodicarboxylate (2.397 mL, 12.18 mmol). Reagents are insoluble. DMF (10 mL) was added. The reaction was stirred at room temperature overnight. The reaction mixture was filtered and concentrated onto silica gel. Silica gel chromatography (0%-4% methanol/dichloromethane) did not offer separation of desired product from impurities. Fractions were combined and repurified. Silica gel chromatography (0%-30% acetone/dichloromethane) afforded the title compound (1.66 g, 64.3%) as a light yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19]O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCCS(C)(=O)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cool (ice-bath) a mixture containing the product of Step C (21.8 gm-0.078 mol), 250 ml CH2Cl2 and 9.7 ml pyridine (0.12 mol), add in a dropwise fashion (20 minutes) mesylchloride (6.65 ml-0.086 mol) in 6.6 ml CH2Cl2 and allow the mixture to warm to room temperature, stirring the mixture for 2 hours. Pour the resulting mixture into 200 ml CH2Cl2, wash with 500 ml 0.5N HCl, saturated NaHCO3, dry over MgSO4, evaporate (in vacuo) and flash chromatograph eluting from the silica gel with 25% EtOAc/hexane to obtain 10.7 g of desired product, Rf is 0.36 (silica gel plates eluted with 25% EtOAc/hexane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18](N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl.CO.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1.28 Grams of 6-{(tert-butoxycarbonyl)amino}hexanoic acid was dissolved in a liquid mixture of 9 ml of chloroform and 3 ml of methanol. To the solution 1.27 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 7 mg of 4-dimethylaminopyridine were successively added at room temperature, followed by 2 hours' stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous ammonium chloride solution, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 1.03 g of the title compound was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:25]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
DIEA (137.5 mL, 0.766 mol) was added to a suspension of (5)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (75.0 g, 0.357 mol) in THF (900 mL), and the mixture was cooled to 0° C. (ice/water bath). Methyl chloroformate (29.0 mL, 0.375 mol) was added dropwise over 45 min, the cooling bath was removed and the heterogeneous mixture was stirred at ambient temperature for 3 h. The solvent was removed under diminished pressure and the residue partitioned between EtOAc and water (1 L each). The organic layer was washed with H2O (1 L) and brine (1 L), dried (MgSO4), filtered and concentrated under diminished pressure. The crude material was passed through a plug of silica gel (1 kg), eluting with hexanes (4 L) and 15:85 EtOAc/hexanes (4 L) to afford (S)-tert-butyl 2-(methoxycarbonylamino)-3-methylbutanoate as a clear oil (82.0 g, 99% yield). 1H-NMR (500 MHz, DMSO-d6, δ=2.5 ppm) 7.34 (d, J=8.6, 1 H), 3.77 (dd, J=8.6, 6.1, 1 H), 3.53 (s, 3 H), 1.94-2.05 (m, 1 H), 1.39 (s, 9 H), 0.83-0.92 (m, 6 H). 13C-NMR (126 MHz, DMSO-d6, δ=39.2 ppm) 170.92, 156.84, 80.38, 60.00, 51.34, 29.76, 27.62, 18.92, 17.95. LC/MS: [M+Na]+ 254.17.