Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:8]2[CH2:9][C:10](=O)[CH2:11]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1>C(O)C>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:8]2[CH2:9][C:10](=[N:20][OH:21])[CH2:11]3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN2C3CCCC2CC(=O)C3)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(CN2C3CCCC2CC(=NO)C3)cc1
Yield: 75.4 %

Procedure:
A solution of N-(4-methylbenzyl)-9-aza-bicyclo-[3.3.1]-nonan-3-one (5 g), hydroxylamine hydrochloride (1.5 g) and pyridine (0.75 ml) in ethanol (100 ml) was heated at reflux for 1 hour. The solution was evaporated and the residue dissolved in ethyl acetate and water. It was basified with potassium carbonate and the ethyl acetate extract was separated, dried and evaporated to give the crude oxime. Recrystallisation from ethyl acetate/light petroleum gave the oxime (4 g, 77%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([OH:33])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:35])([F:34])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:37]1[C:46]([CH2:47][CH3:48])=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1.CN(C=O)C.CCC([O-])(C)C.[Na+]>CC#N.Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:37]3[C:46]([CH2:47][CH3:48])=[N:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([OH:33])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:35])([F:34])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1nc2ccccc2nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2nc1O[C@@H]1C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.5 %

Procedure:
To (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (Example 7j, 87.4 mg, 0.174 mmol) was added 2-chloro-3-ethylquinoxaline (47.7 mg, 0.247 mmol) and DMF (868 μl). To this solution was added sodium tert-pentoxide (48.9 mg, 0.444 mmol) at room temperature, and the mixture turned dark purple (slightly exothermic). The reaction mixture was stirred at room temperature for 17 h. Additional 2-chloro-3-ethylquinoxaline (18.1 mg, 0.094 mmol) and sodium tert-pentoxide (24.2 mg, 0.202 mmol) were added, and the reaction mixture was stirred for 22 h. The reaction mixture was diluted with CH3CN and neutralized with HCl (1 N, 0.7 ml) and evaporated under reduced pressure. The residue was purified by reverse phase HPLC (CH3CN/H2O (0.1%TFA), gradient=20/80-85/15) to provide the title compound as a light brown solid, (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (66 mg, 57% yield).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10](Cl)[CH2:11][CH2:12][C:13](=[O:16])[O:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C.ClCCl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:10](=[O:9])[CH2:11][CH2:12][C:13]([O:14][CH3:15])=[O:16])=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thioanisole (12.4 g) and 1,4-dioxo-4-methoxybutyl chloride (16.5 g) in dichloroethane (100 ml) were cooled to 0° C. and aluminum chloride (16 g) was added, followed by another equivalent (16 g) and the reaction mixture was stirred at 0° C. for 2 hours. Ice was added, followed by 1N HCl. Dichloromethane (100 ml) was then added and the organic layer was separated, washed with water and then brine and dried with Na2SO4. Removal of the solvents yielded the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH2:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:3]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(CCN)[nH]c2ccccc12
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)C(=O)NCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 2-(3-methylindol-2-yl)ethylamine 1.74 g) in tetrahydrofuran (200 ml) at room temperature was added 1,1'-carbonyldiimidazole (1.6 g) in small portions. After one hour of stirring, the reaction mixture was evaporated in vacuo. The residue was dissolved in toluene and the solution was evaporated in vacuo. The oil obtained was heated at 100° C. for 40 minutes and then cooled. Purification of the residue with silica gel column chromatography (chloroform) gave 3,4-dihydro-5-methylpyrimido[1,6-a]indol-1(2H)-one (0.8 g).
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[OH:36][C:37]1[CH:45]=[CH:44][C:40]([C@H:41]([NH2:43])[CH3:42])=[CH:39][CH:38]=1>C(Cl)Cl.CCOC(C)=O>[C:14]([NH:13][C@@H:12]([C:11]([NH:43][C@@H:41]([C:40]1[CH:44]=[CH:45][C:37]([OH:36])=[CH:38][CH:39]=1)[CH3:42])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: C[C@@H](N)c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (33 g; 66.8 mmol; from step (a) above) and (R)-4-hydroxy-α-methylbenzylamine (9.3 g; 68.2 mmol) were combined in CH2Cl2 (600 mL). The resulting yellow solution was stirred at room temperature for 4 hours. When the coupling was complete, as determined by TLC, the solution was concentrated under vacuum to give the crude product. The crude material was dissolved in EtOAc, washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL), dried over Na2SO4, filtered and concentrated to yield 30.1 g (61.9 mmol; 93%) of the sub-title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:36].C(N(CC)C(C)C)(C)C.[C:46]([O:50][C:51](=[O:59])[NH:52][CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:46]([O:50][C:51](=[O:59])[NH:52][CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:34]=[CH:35][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:7]([Cl:36])[CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:33][CH:32]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 100 mL round-bottom flask charged with the 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid prepared above (13.0 mmol) was added CH2Cl2 (65 mL), and then N,N-diisopropylethylamine (7.95 mL, 45.5 mmol). The flask was cooled with a 0° C. bath. To the solution was added tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (3.16 g, 15.6 mmol), and then 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 6.43 g, 16.9 mmol). The bath was removed and the solution was allowed to warm to room temperature with stirring for 1 h. The solution was transferred to a 1 L separatory funnel and was diluted with EtOAc (500 mL). The solution was washed with aq. 2M HCl (2×100 mL), and then with sat. aq. NaHCO3 (100 mL), and then with sat. aq. NaCl (100 mL). The organic solution was dried over MgSO4; filtered; and then concentrated in vacuo. The resulting solid residue was subjected to SiO2 chromatography (hexanes:EtOAc, 1:1) to afford tert-butyl(3-(4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate as a colorless solid (8.77 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.5 Hz, 2H), 7.76-7.66 (m, 1H), 7.62 (dd, J=15.6, 8.5 Hz, 2H), 7.35 (s, 1H), 7.22-7.15 (m, 1H), 6.96-6.89 (m, 1H), 5.16-5.04 (m, 1H), 4.73 (dq, J=12.2, 8.4 Hz, 2H), 4.57 (d, J=5.3 Hz, 2H), 4.19-4.14 (m, 2H), 3.69-3.61 (m, 2H), 3.28-3.18 (m, 2H), 3.00-2.92 (m, 2H), 2.36 (sxt, J=5.8 Hz, 2H), 1.46 (d, J=2.0 Hz, 9H), 0.91 (d, J=3.3 Hz, 6H); MS m/z=774.25 (M+1)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:24][CH:25]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4cccnc4)ccc3n2C)cc1
Yield: 35 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 35% of theory, C36H45N7O5 (655.8) Rf value: 0.28 (silica gel; dichloromethane/ethanol=19:1) ##EQU87##
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].O>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CNc2ccccc2Cl)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (5 g) and 2-chloroaniline (2.5 mL) in toluene (60 mL) is heated at reflux under a Dean and Stark water trap for 3 hours. After concentration, the residue is dissolved in methanol (60 mL) and the stirred solution is treated at 0° C. with sodium cyanoborohydride (2.1 g). The temperature is allowed to rise to room temperature, and the stirring is continued for 2 hours, before dilution with ethyl acetate (100 mL) and washing with saline (100 mL). The organic layer is dried and concentrated, to give a brown oil. This oil is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1:4 v/v), to give N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine (0.64 g), in the form of an oil. [Elemental analysis: C, 69.5; H, 6.8; N, 4.1; Cl, 10.6%; calculated: C, 68.8; H, 6.7; N, 3.2; Cl, 10.7%].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22][NH2:23]>CO>[NH:22]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:23]
Reactant: NN
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (Aldrich, 300 mg, 1.07 mmol) in MeOH (5.4 mL) was added hydrazine hydrate (170 μL, 3.44 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated with hexanes (2×) and then from a minimal amount of 2:3 hexanes/MeOH (2×) to give the title compound (195 mg, 65%) as a white solid. 1H NMR (CDCl3) δ 7.41-7.25 (m, 3H), 7.20 (d, J=6.8 Hz, 2H), 4.39-4.21 (m, 1H), 3.07 (d, J=7.0 Hz, 2H), 1.42 (s, 9H); MS (ESI+) m/z 280.3 (M+H)+.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH:10]([N:12]([CH3:21])[C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH3:11])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH:10]([N:12]([CH3:21])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:11]
Reactant: Cc1cccc(C)c1N(C)C(C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1N(C)C(C)CN
Reaction time: 1 h
Yield: 74.4 %

Procedure:
2.5 ml of a 90% hydrazine hydrate are added to a solution of 3.0 g (9.3 mmoles) of 1-phthalimido-2-[N-methyl-N-(2,6-dimethylphenyl)-amino]-propane in 30 ml of ethanol, and the mixture is boiled for one hour. Next day the mixture is processed as described in Example 11, and the crude product is distilled under reduced pressure. 1.33 g (74.5%) of 1-amino-2-[N-methyl-N-(2,6-dimethylphenyl)-amino]-propane are obtained; b.p.: 97°-99° C./53.3 Pa. The monohydrochloride of the product, prepared as described in Example 1, melts at 158°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[N:7]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH:27]1([CH2:33][NH:34][C:16]2[O:17][C:13]3[CH:12]=[C:11]([CH2:10][N:7]4[C:6]5[CH:23]=[C:24]([O:25][CH3:26])[C:3]([O:2][CH3:1])=[CH:4][C:5]=5[N:9]=[CH:8]4)[CH:22]=[CH:21][C:14]=3[N:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2cc1OC
Reactant: NCC1CCCCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(NCC5CCCCC5)oc4c3)c2cc1OC
Temperature: 90 °C
Yield: 29.4 %

Procedure:
A stirred mixture of 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (60 mg, 0.162 mmol), cyclohexylmethylamine (36 mg, 0.323 mmol), and DIEA (63 mg, 0.485 mmol) in anhydrous DMA (2 mL) was heated at 90° C. for 15 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford N-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-amine (20 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 7.37 (s, 1H), 7.11-7.24 (m, 4H), 5.42 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.11 (t, J=6.2 Hz, 2H), 1.50-1.79 (m, 7H), 1.07-1.26 (m, 2H), 0.81-1.00 (m, 2H). LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([C:13]1[N:14]([CH2:27][CH3:28])[C:15](=[O:26])[N:16](COC)[C:17](=[O:22])[C:18]=1[CH:19]([CH3:21])[CH3:20])[C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8])#[N:2].CSSC>ClCCl>[C:1]([CH:3]([C:13]1[N:14]([CH2:27][CH3:28])[C:15](=[O:26])[NH:16][C:17](=[O:22])[C:18]=1[CH:19]([CH3:21])[CH3:20])[C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8])#[N:2]
Reactant: CCn1c(C(C#N)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)n(COC)c1=O
Solvent: ClCCl
Solvent: CSSC
Product: CCn1c(C(C#N)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 72 h
Yield: 89.2 %

Procedure:
To a stirred solution of 3-[cyano-(3-ethyl-5-isopropyl-1-methoxymethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-methyl]-5-methyl-benzonitrile (190 mg, 0.5 mmol) in dichloromethane (5 mL) at room temperature, were added dimethyl disulfide (804 μL, 10 mmol) and boron trifluoride-diethyl etherate (300 μL, 2.37 mmol). After stirring for 3 days, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to give 150 mg (89%) of 3-[cyano-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-methyl]-5-methyl-benzonitrile as a white solid. The product was recrystallized from chloroform-methanol-ether. m.p. 260-261° C.; 1H-NMR (200 MHz, DMSO-d6) δ 0.77 (3H, d, J=6.6 Hz), 1.07 (3H, t, J=7.0 Hz), 1.19 (3H, d, J=6.6 Hz), 2.41 (3H, s), 2.49 (1H, m), 3.68 (1H, m), 4.00 (1H, m), 6.22 (1H, s), 7.59 (1H, s), 7.71 (1H, s), 7.73 (1H, s), 11.45 (1H, s); m/z (EI) 336 (M+).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].[OH-].[Na+]>C(O)C.O>[CH2:28]([O:30][NH:31][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])[CH2:2][CH2:3][CH3:4])[CH3:29]
Reactant: CCCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.6 Gram of 2-butyryl-5-[2-(5-trifluoromethyl-2-pyridylthio)ethyl]cyclohexane-1,3-dione was dissolved in a mixed solvent of 10 ml of ethanol and 1 ml of water, and 0.2 g of ethoxyamine hydrochloride and 0.07 g of sodium hydroxide were added to the resulting solution which was then stirred at room temperature for 2.5 hours. The reaction solution was poured into water, weakly acidified and extracted with ethyl acetate. After removing ethyl acetate, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.45 g of 2-(1-ethoxyaminobutylidene)-5-[2-(5-trifluoromethyl-2-pyridylthio)-ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].CO>C1COCC1>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: ClCCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
Anhydrous THF (25 mL) was cooled in an ice bath. After NaH (1.40 g, 35 mmol, 60%) was added to the THF in one portion, the mixture was stirred at rt for 30 min and cooled in an ice bath. Then a solution of 1H-imidazole (2.00 g, 30 mmol) in anhydrous THF (6 mL) was added dropwise. The reaction mixture was then warmed to rt and stirred at rt for 1.5 h. To the mixture was added 1-bromo-3-chloropropane (4.60 g, 30 mmol) dropwise, and stirred at rt overnight. To the resulting mixture was added MeOH (5 mL) in one portion. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30:1) to give the title compound as pale yellow oil (3.10 g, 73%).
Reaction SMILES: [NH2:1][CH:2]([C:32]#[N:33])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.C(N(CC)CC)C.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>ClCCl>[C:26]([O:25][C:24]([N:23]([CH3:31])[CH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH:2]([NH:1][C:42](=[O:43])[O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:32]#[N:33])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)C#N)CC4)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)NC(=O)OCc2ccccc2)CC4)CC1
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(2-amino-2-cyanoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (800 mg, 1.70 mmol, 1.00 equiv) and triethylamine (340 mg, 3.36 mmol, 2.00 equiv) in dichloromethane (50 mL) was added dropwise a solution of benzyl chloroformate (320 mg, 1.88 mmol, 1.10 equiv) in 10 mL of DCM at 0° C. The resulting solution was stirred for 30 min at this temperature and then quenched with water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5) to give benzyl N-[2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]-1-cyano ethyl]carbamate (0.5 g, 49%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OCCN2CCCC2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (2.15 g, 10.42 mmol) and triethylamine (3.27 mL, 23.4 mmol) in 100 mL methylene chloride at 0° C. was added cyclohexanecarbonyl chloride (1.46 mL, 10.94 mmol), dropwise. The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with 50 mL methylene chloride. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated to afford the title compound of Step A. MS 317.2 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][O:24][CH2:23]1)#[CH:21]>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:21]#[C:20][C:22]1([OH:27])[CH2:26][CH2:25][O:24][CH2:23]1)[N:5]=2
Reactant: C#CC1(O)CCOC1
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC3(O)CCOC3)nc21

Procedure:
A suspension of 0.3 g (2.24 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 17 ml of a dimethylformamide/triethylamine mixture (V/V; 2/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.319 g (2.79 mmol) of (±)-3-ethynyltetrahydro-3-furanol, 0.043 g of CuI (0.23 mmol) and 0.079 g of bis(triphenylphosphine) palladium(II)dichloride (0.11 mmol) are successively added.