Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH:52]1[CH2:57][CH2:56][S:55][CH2:54][CH2:53]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[C:26]([C:31]3[NH:35][C:34]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:33][CH:32]=3)[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].C([O-])([O-])=O.[Na+].[Na+].Cl[C:65]([O:67][CH3:68])=[O:66]>O>[CH3:68][O:67][C:65](=[O:66])[NH:1][C@@H:2]([CH:52]1[CH2:53][CH2:54][S:55][CH2:56][CH2:57]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:31]5[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:48][CH3:49])=[O:50])[CH:43]([CH3:44])[CH3:45])=[N:33][CH:32]=5)[CH:27]=4)[CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](N)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
To methyl (S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-amino-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (30 mg, 0.06 mmol) in water (0.3 mL) was add Na2CO3 (13 L, 0.09 mmol). The reaction mixture was cooled to 0° C. and methyl chloroformate (0.12 mmol) was added and then stirred for 2 hours. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (20 mg, 65%). MS (ESI) m/z 848 [M+H]+.
Reaction SMILES: CC(OC([NH:8][C:9]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([N:26]2[CH2:30][C@@H:29]([N:31]3[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][CH2:32]3)[CH2:28][C@H:27]2[C:41]([NH:43][C:44]2[CH:56]=[CH:55][C:47]([C:48]([O:50]C(C)(C)C)=[O:49])=[CH:46][CH:45]=2)=[O:42])=[O:25])[CH2:20][CH2:19]1)=[N:10]C(OC(C)(C)C)=O)=O)(C)C.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[C:9]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]([N:26]2[CH2:30][C@@H:29]([N:31]3[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][CH2:32]3)[CH2:28][C@H:27]2[C:41]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:48]([OH:50])=[O:49])=[CH:55][CH:56]=2)=[O:42])=[O:25])[CH2:22][CH2:23]1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)Nc3ccc(C(=O)O)cc3)N(C(=O)C3CCN(C(=N)N)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a solution of the compound prepared in Example 8 (0.11 g, 0.13 mmol) in dichloromethane (15 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). The reaction was warmed to room temperature and stirred for 18 h. The solvent and excess trifluoroacetic acid was removed under reduced pressure. The solid was dissolved in water and lyophilized to dryness to afford the title compound (0.030 g, 40%) as an off-white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](OC(C)(C)C)=[O:16])=[C:10]([CH3:22])[CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[C:10]([CH3:22])[CH:9]=1
Reactant: Cc1cc(Br)ccc1CC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CCO
Temperature: 25 °C

Procedure:
6.31 mL (6.31 mmol, 1M solution in THF) of lithium aluminum hydride was added at −5° C. to a solution of 4.00 g (6.31 mmol) of tert-butyl (4-bromo-2-methylphenyl)acetate in 50 mL of THF. The reaction mixture was heated to RT and stirred at this temperature until the reaction was complete. 0.3 mL of water, 0.3 mL of 15% aqueous sodium hydroxide solution, and 0.9 mL of water were added successively. After filtration, the organic phase was dried over magnesium sulfate and the solvent was eliminated in vacuo. Further purification was carried out by column chromatography on silica gel (PE/EtOAc 8:2). Yield: 1.02 g (75% of theoretical); C9H11BrO (M=215.087); calc.: molpeak (M)+:214/216 (Br); found: molpeak (M)+:214/216 (Br); Rf value: 0.59 (silica gel, PE/EtOAc 8:2).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:23][C@H:22]2[C@H:18]([CH2:19][CH2:20][CH2:21]2)[C@H:17]1[CH:24]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(=O)OCC.CCCCCCC>[C:9]([O:13][C:14]([N:16]1[CH2:23][C@H:22]2[C@H:18]([CH2:19][CH2:20][CH2:21]2)[C@H:17]1[CH2:24][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1CNCc1ccccc1
Reaction time: 2 h

Procedure:
Benzylamine (0.263 mL, 1.75 eq) was added to a solution of (1S,2S,5R)-2-formyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (330 mg, 1 eq) in chloroform (10 mL). After 15 min the mixture was treated with NaBH(OAc)3 (292.25 mg, 1 eq), stirred for 2 h and poured into a sat. aq NaHCO3 solution. The layers were separated and the aqueous layer was extracted twice with chloroform. The combined org. extracts were washed with sat. NaHCO3 solution, dried over anh. MgSO4, filtered and concentrated in vacuo to give a crude yellow oil. FC (EA/n-heptane: 3/7 to 7/3) gave the title compound as a colourless oil
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][C:26]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(Cl)s1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, and washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (72 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([OH:24])[C:12](=[NH:23])[NH:13][O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>COCCOCCOC.ClCCl>[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:12]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][N:13]=1)[OH:24]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Solvent: COCCOCCOC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(O)c1noc(-c2ccccc2)n1
Yield: 29.9 %

Procedure:
A solution of (3) (1.5 g, 4.3 mmol) in diglyme is heated at 150° C. in a microwave reactor (Smith Creator, S00219) for 40 minutes. Solvent evaporated under vacuum in Genevac Evaporator at 80° C. for 3hours to give a solid. This is taken in dichloromethane (40 mL) and treated with trifluoroacetic acid at room temperature for 2 hours. Solvent evaporated to dryness under reduced pressure, crude taken in water, washed with DCM, aqueous layer basified with 1M NaOH solution and extracted with dichloromethane. Organic layer dried over Na2SO4 and evaporated under reduced pressure to give 2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol (300 mg) as a solid.
Reaction SMILES: O1CCCC1.[OH:6][C:7]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH2:10][C:9](=[O:24])[C:8]=1[C:25](=O)[CH2:26][CH3:27].[CH3:29][O:30][NH2:31].C[O-].[Na+]>CO>[CH3:29][O:30][N:31]=[C:25]([C:8]1[C:9](=[O:24])[CH2:10][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=2)[CH2:12][C:7]=1[OH:6])[CH2:26][CH3:27]
Reactant: CON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=NOC)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reaction time: 15 h

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 1.2 g of 3-hydroxy-5-(4-methanesulfonamidophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution were added 0.6 g of methoxyamine hydrocholorate salt and 1.4 g of methanol containing 28% of sodium methylate. Then, the mixture was kept for 15 hours at room temperature and an insoluble material was filtered off from it and the resulting filtrate solution was concentrated under reduced pressure. Its residue was dissolved in chloroform and the solution was washed with a dilute hydrochloric acid solution and water, and it was dried with anhydrous magnesium sulfate. The chloroform was distilled off from it under a reduced pressure and ethyl ether was add in it. Thus, the crystal sedimented is collected with a filtering step and 1.2 g of the desired compound as colorless crystals having a melting point of 150°-151° C. was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.C([O:28][C:29](=[O:34])[C@H:30]([CH2:32][OH:33])[NH2:31])C.C(CCC(N[C:44](=[O:68])[CH2:45][C:46]1[CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([S:57]([CH3:60])(=[O:59])=[O:58])=[CH:53][CH:52]=2)[N:48]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:47]=1[CH3:67])CO)(O)=O.[OH-].[Na+].Cl>C(Cl)Cl.CCO>[OH:33][CH2:32][C@H:30]([NH:31][C:44](=[O:68])[CH2:45][C:46]1[CH:50]=[C:49]([C:51]2[CH:52]=[CH:53][C:54]([S:57]([CH3:60])(=[O:59])=[O:58])=[CH:55][CH:56]=2)[N:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:47]=1[CH3:67])[C:29]([OH:28])=[O:34]
Reactant: Cc1c(CC(=O)NC(CO)CCC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Reactant: CCOC(=O)[C@@H](N)CO
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CC(=O)N[C@@H](CO)C(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
The following are added, at 0° C., to acid 6a (0.8 mmol) in DCM (10 ml): DIPEA (2.43 mmol), EDC (1.63 mmol), HOBt (0.27 mmol) and L-serine ethyl ester dihydrochloride (0.8 mmol). It is stirred at RT for 12 hours, then it is washed with H2O, the organic phase is separated, dried and concentrated. The residue is purified by chromatography (silica, EtOAc/MeOH (9:1)) obtaining: N-[1-(carboxyethyl)-2-hydroxyethyl]-2-[1-phenyl-2-methyl-5-(4-methanesulphonylphenyl)-1H-pyrrol-3-yl]-acetamide. Oil, yield 77%. 1H NMR (CDCl3) ppm: 1.25 (t, 3H); 2.05 (s, 3H); 2.70 (broad t, 1H); 2.97 (s, 3H); 3.51 (s, 2H); 3.93 (m, 2H); 4.20 (m, 2H); 4.63 (m, 1H), 6.48 (s, 1H); 6.74 (broad d, 1H), 7.11-7.16 (m, 4H); 7.37-7.40 (m, 3H); 7.60-7.64 (m, 3H). The carboxyethyl derivative (0.55 mmol) is treated with NaOH (0.55 mmol) in EtOH (5 ml), at 0° C., for 1 hour. It is acidified with 3N HCl to pH 6; the solvent is evaporated and the residue is taken up in EtOAc. The organic phase is washed until neutral with NaCl s.s., dried and concentrated. The residue is treated with EtOAc/n-hexane to give the product, m.p. 80-83° C., yield 50%. 1H NMR (DMSO-d6) ppm: 1.97 (s, 3H); 3.11 (s, 3H); 3.34 (s, 2H); 3.55-3.75 (m, 2H); 4.23-4.31 (m, 1H); 4.95-5.04 (s broad, 1H); 6.54 (s, 1H); 7.10-7.22 (m, 4H); 7.40-7.49 (m, 2H); 7.59-7.66 (m, 2H); 8.06-8.10 (broad d, 1H); 12.59 (broad s, 1H). MS ESI: m/z 455 (M−H+); m/z 495 (M+K+).
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[CH:17]=[CH:16][N:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:14]=1[CH3:28])=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[CH:17]=[CH:16][N:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:14]=1[CH3:28])=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: Cc1c(C(=O)Cl)ccn1-c1ccc2ccccc2n1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: Cc1c(C(=O)NC(=N)N)ccn1-c1ccc2ccccc2n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
0.795 g (33.1 mmol) of sodium is added at 20° C. under an argon atmosphere to 30 mL of methanol. After complete dissolution, 2.97 g (31.2 mmol) of guanidine hydrochloride are added. After stirring at 20° C. for 0.5 hour, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue that is dissolved in 15 mL of 1,2-dimethoxyethane. 2 g of 3-chlorocarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole hydrochloride, suspended in 15 mL of 1,2-dimethoxyethane, are then added at 20° C. under an argon atmosphere. After stirring at 20° C. for 8 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue that is triturated in 100 mL of water for 16 hours. After filtering off and drying the solid residue under reduced pressure (2.7 kPa), a residue is obtained, which residue is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (86/7/7 by volume) and then dichloromethane/methanol/20% aqueous ammonia (96/24/2 by volume)]. After concentrating the fractions under reduced pressure, a beige-coloured solid is obtained, which solid is triturated in 100 mL of N hydrochloric acid for 15 hours. After filtration, the solid residue is recrystallised under hot conditions from 30 mL of methanol to give 0.82 g of 3-guanidinocarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole hydrochloride in the form of a pinkish solid melting at 250° C. Mass spectrum (EI): m/e 293 (M+.), m/e 206 (base peak).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24](O)=[O:25].[CH3:27][C:28]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:39]1[CH2:40][CH2:41][C:36]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[C:28]2[CH3:27])[CH2:37][CH2:38]1)=[O:25]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Reactant: CC1=Cc2ccccc2C12CCNCC2
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 64.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.100 g, 0.282 mmol) obtained in Example 88, step 2 and 2-methylspiro[inden-1,4′-piperidine] (0.062 g, 0.313 mmol), the title compound (0.098 g, 65%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])(O)=O.[Na+]>O1CCCC1>[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: C1CCONC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCNc1nc(NCCC)nc(N2CCCCO2)n1
Temperature: 100 °C
Yield: 89 %

Procedure:
An ACE® pressure tube was charged with 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.50 g, 6.53 mmol), N-ethyldiisopropylamine (19.59 mmol), 1,2-oxazinane hydrochloride (1.61 g, 13.06 mmol) and tetrahydrofuran. The reaction mixture was heated at 100° C. for 2 h, then cooled and poured into saturated NaHCO3 solution (50 mL). The suspension was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield 6-[1,2]oxazinan-2-yl-N,N′-di-n-propyl-[1,3,5]triazine-2,4-diamine (LVII) (1.63 g, 89%). ESI-MS (m/z): 281 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:33])([CH3:32])[C:13]([NH:15][C@H:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][C:26]3[C:31]([C:19]=2[CH2:18][CH2:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]1[CH:56]=[CH:55][C:54]([CH2:57]O)=[CH:53][CH:52]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:33])([CH3:32])[C:13]([NH:15][C@H:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][C:26]3[C:31]([C:19]=2[CH:18]([CH2:57][C:54]2[CH:53]=[CH:52][C:51]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[CH2:44][NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])=[CH:56][CH:55]=2)[CH2:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2c(ccc3ccccc23)NC1=O
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CC2C[C@@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)C(=O)Nc3ccc4ccccc4c32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]prop-anamide (Step A) in dry dimethylformamide under nitrogen at 0° C. is added of 60% sodium hydride/oil dispersion (1.05 eq.). After stirring for 15 minutes, a solution of 2′-[(t-butoxycarbonylamino)methyl]-1,1′-biphenyl-4-methanol, methanesulfonate ester (Step F) in dimethylformamide is added by cannula. The flask which originally contained the methanesulfonate ester is rinsed with dimethylformamide which is added to the reaction mixture. After stirring at 0° C. for 15 minutes, the reaction mixture is diluted with ethyl acetate and 50% saturated ammonium chloride. The mixture is transferred to a separatory funnel and the aqueous layer is separated. The organic layer is washed with 100 mL of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue is purified by flash chromatography on silica gel eluting with ethyl acetate/hexane to afford the product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.I[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CN(C=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:23][CH2:24][CH3:25])[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccncc2)(c2cccc(O)c2)N=C1N
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOc1cccc(C2(c3ccncc3)N=C(N)N(C)C2=O)c1
Yield: 97.2 %

Procedure:
To a stirred solution of 2-amino-5-(3-hydroxyphenyl)-3-methyl-5-pyridin-4-yl-3,5-dihydro-4H-imidazol-4-one (0.13 g, 0.46 mmol) in acetone (20 mL) and DMF (1 mL) is added 1-iodopropane (0.07 mL, 0.69 mmol) and Cs2CO3 (1.50 g, 4.60 mmo). After refluxed for 1 hour, the solvent is evaporated and the crude material was purified by chromatography (silica gel, EtOAc/2M methanolic NH3: 97/3) to give the title compound (0.145 g, 97%) as a solid. mp: 173-175° C.; MS(+) ES: 325 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:15][CH:14]([F:16])[C:12]1[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.8) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.035 g, 16%). MS (ISP) 443.3 [(M+H)+]; mp 191° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]3[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=3[CH2:24][O:23][C:22]=2[CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[C:27](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]5[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=5[CH2:24][O:23][C:22]=4[CH:38]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2c(C)cccc2[nH]1
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(CCl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)OCc1ccccc1C2=CC(=O)OCC
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
4-Methyl-2-propyl-1H-benzimidazole (464 mg) was dissolved in a mixture of 50 ml of DMF and 80 ml of toluene, and 106.4 mg of sodium hydride (60% oily) was added to the solution under ice cooling, followed by stirring for 30 minutes. To the mixture was added 732 mg of Compound 1-c, and the mixture was heated under reflux for 3 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate/triethylamine (20/5/1)] to give 629 mg (61%) of the product.