Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Yield: 38.2 %

Procedure:
5-Benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (9-03) (1.7 g, 38.16%) was synthesized as a dark liquid from 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (7-01) (3 g, 7.28 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl amine (8-b) (1.73 g, 8.01 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[N:8]=2)[CH2:4]1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.C(N(CC)CC)C.ClCCl>O1CCOCC1.O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([CH:5]3[CH2:6][N:3]([C:20]4[C:21]([Cl:25])=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=4)[CH2:4]3)=[N:8][C:9]=2[CH:15]=1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc2[nH]c(C3CN(c4nc(Cl)ncc4Cl)C3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-(Azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride, as prepared in preparation 5, (0.16 g, 0.57 mmol) was added to a solution of 2,4,5-trichloropyrimidine (0.11 g, 0.57 mmol) and triethylamine (0.28 mL, 2.00 mmol) in dioxane (2 mL) under argon. The mixture was stirred for 2 h at RT, then dichloromethane and water were added. The resulting layers were separated and the aqueous layer was extracted with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 5-chloro-2-(1-(2,5-dichloropyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.18 g, 0.51 mmol, 89% yield) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)c2n[nH]c3c(C(F)(F)F)cccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1cccc(O)c1)c1n[nH]c2c(C(F)(F)F)cccc12
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A solution of (3-methoxyphenyl)[7-(trifluoromethyl)-1H-indazol-3-yl]methanone (0.03 g, 0.094 mmol) in 2 mL of CH2Cl2 containing 0.2 mL cyclohexene was cooled to −78° C. under an argon atmosphere. Boron tribromide (0.035 mL, 0.375 mmol) was added in one portion and the reaction mixture was allowed to warm to ambient temperature. The reaction was quenched by the careful addition of methanol. The reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The solvents were removed in vacuo and the residue purified by flash chromatography to give 0.02 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:36]([N:38]([CH2:42][CH2:43]O)[CH:39]([CH3:41])[CH3:40])=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[C:24]([C:32]([F:33])([F:35])[F:34])[CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:43][CH2:42][N:38]([CH:39]([CH3:41])[CH3:40])[C:36](=[O:37])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O

Procedure:
9-(Benzyloxy)-6-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (465) was synthesized as a white solid from 5-(benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropylpyrimidine-4-carboxamide (464) following the procedure described for 9-benzyloxy-6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (247).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCN(CC)CC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([S:22]([NH:5][C:4]2[CH:3]=[C:2]([I:1])[CH:8]=[CH:7][CH:6]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(I)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cccc(I)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 3iodoaniline (5 g, 22.8 mmol), in CH2Cl2 (100 mL), were added at room temperature Et3N (6.97 mL) followed by benzenesulfonyl chloride (5.84 mL). The mixture was stirred 4 h then a white precipitate was formed. A saturated aqueous solution of NaHCO3 was added and the phases were separated. The aqueous layer was extracted several times with CH2Cl2 and the combined extracts were dried over (MgSO4) then evaporated. The crude mixture was dissolved in MeOH (100 mL) and NaOMe (6 g), was added and the mixture was heated 1 h at 60° C. The solution became clear with time and HCl (1N) was added. The solvent was evaporated under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated. The crude material was purified by flash chromatography using (100% CH2Cl2) as solvent yielding the title compound 21 (7.68g, 94%) as yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)(=[O:3])[NH2:2].O.[NH2:16]N.Cl.O>CN1CCCC1=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:9])[NH:16][NH:10][C:11]2=[O:12])(=[O:3])[NH2:2]
Reactant: NN
Reactant: NC(=O)c1ccc2c(c1)C(=O)NC2=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Carbamoylphthalimide (2.00 g, 0.011 mol) was suspended in 12 ml of N-methyl-2-pyrrolidinone, followed by the dropwise addition of 0.8 ml of hydrazine hydrate. The obtained mixture was stirred at room temperature for 30 minutes, followed by the addition of 5.5 ml of 3N hydrochloric acid and 50 ml of water. The crystals thus precipitated were recovered by filtration, washed with water and dried with hot air. The title compound (2.0 g) was obtained as a light brown crystal (yield: 94%).
Reaction SMILES: [Cl-].[Cl-].[Ca+2].FC1C=CC(N)=C(N)C=1.[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[N+:22]([O-])=O.FC1C(N)=C(N)C=CC=1.[OH-].[Na+]>CCO.Cl.[Zn].O>[NH2:22][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[NH2:13])[C:18]#[N:19]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: Nc1ccc(F)cc1N
Agent: Nc1cccc(F)c1N
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N)c(N)c1

Procedure:
3,4-Diaminobenzonitrile was prepared using an adaptation of the method of Tsuji et al. (Tsuji, Y. et al., J. Org. Chem. 55:580 (1990)). Zn powder (2.51 g, 38.3 mmol), CaCl2 (251 mg), H2O (3.0 mL) and 9.0 mL EtOH were combined and brought to reflux as described for 4-fluoro-1,2-diaminobenzene (Example 10) and to this mixture was added slowly dropwise a solution of 4-amino-3-nitrobenzonitrile (500 mg, 3.06 mmol) in 20 mL EtOH. Analysis and workup were described for 3-fluoro-1,2-diaminobenzene except that the reaction residue was dissolved in 20 mL 1N HCl . This solution was then made basic by the addition of 20 mL 1.5M NaOH. A precipitate separated as fine tan needles which were collected by vacuum filtration, rinsed with cold H2O and dried in a vacuum desiccator (0.5 torr, 25° C.) over CaSO4 to yield 275 mg (67%) of tan crystals. 1H NMR (CDCl3) δ3.42 (br, s, 2H, NH2), 3.86 (br s, 2H, NH2), 6.70 (d, J=8, 1H, ArH), 6.96 (d, J=1, 1H, ArH), 7.06 (dd, J=8, J=1, 1H, ArH).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.[O:39]1CCOCC1>O>[CH:14]1([CH:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([OH:39])[CH:11]=2)[OH:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1COCCO1
Reactant: OC(c1cc(Br)nc2ccccc12)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Product: Oc1cc(C(O)C2CCCCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of 2-bromo-α-cyclohexyl-4-quinolinemethanol (100 mg, 0.31 mmol) in dioxan (1 mL) was treated with 1-M HCl, stirred at room temperature for 16 h, refluxed for 24 h, cooled, diluted with water (5 mL), the resulting solid filtered and dried under vacuum to give the title compound (58 mg, 73%) as a white solid: mp>250° C.; IR νmax (Nujol)/cm−1 3451, 2956, 2924, 2854, 1649, 1546, 1437, 1103, 886 and 760; NMR δH (400 MHz, DMSO-d6) 1.07-1.29 (5H, m), 1.53-1.69 (6H, m), 4.77 (1H, t, J 4.5 Hz), 5.38 (1H, d, J 4.6 Hz), 6.50 (1H, s), 7.18 (1H, t, J 7.0 Hz), 7.34 (1H, d, J 7.6 Hz), 7.49 (1H, t, J 7.0 Hz), 7.84 (1H, d, J 7.6 Hz) and 11.64 (1H, s); M/Z 258 (M+H)+.
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].O.[NH2:13][NH2:14]>CO>[CH:2](=[N:13][NH2:14])[C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reactant: NN
Solvent: O
Solvent: CO
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=NN

Procedure:
A solution of 4.0 g of 6-deoxy-L-galactose in 10 ml of methanol and 10 ml of hydrazine hydrate was stirred overnight, then evaporated to dryness, giving 4.4 g of 6-deoxy-L-galactose hydrazone.
Reaction SMILES: C([O:8][C:9](=[O:23])[CH2:10][CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[CH3:24][Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C1(C)C=CC=CC=1>[C:19]([O:18][C:16]([NH:15][CH:11]([C:12]([O:14][CH3:24])=[O:13])[CH2:10][C:9]([OH:8])=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)OCc1ccccc1)C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C(CC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
2.0 g (6.18 mmol) of 4-(benzyloxy)-2-[(t-butoxycarbonyl)amino]-4-oxobutanoic acid was dissolved in a solvent mixture of 6 ml of methanol and 12 ml of toluene. 3.7 ml of 2 M trimethylsilyldiazomethane/hexane solution was added to the obtained solution and they were stirred for 3 hours. Additional 0.5 ml of 2 M trimethylsilyldiazomethane/hexane solution was added to the reaction mixture and they were stirred for 1 hour. The solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of ethanol. 2.0 g of palladium carbon (10% w/v) was added to the obtained solution, and they were stirred in hydrogen gas atmosphere for 19 hours. After the filtration, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.BrC1C=C(S(OC2C=CC(N3C(=O)CC(=O)NC4C5CCCCC=5C=CC3=4)=CC=2)(=O)=O)C=CC=1>>[N:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])=[CH:28][CH:29]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C1CC(=O)N(c2ccc(OS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3c(c2N1)CCCC3
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccncc3)cc2)c2ccc3ccccc3c2N1
Yield: 50.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), and isonicotinoyl chloride hydrochloride (71 mg, 0.4 mmol), 5-[4-[(pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (43 mg, yield 50%) was obtained as pale green crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:22]4)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH2:28][CH2:29][C:30]([O-:32])=[O:31])=[CH:22]4)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].[Na+:2]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CCC(=O)[O-])cc4c3)no2)cc1Cl
Reaction time: 0.5 h

Procedure:
Aqueous NaOH solution (2 N, 2 mL) was added to a solution of ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D33) (90 mg) in ethanol (20 mL) at RT. The resulting solution was stirred for 30 min. Ethanol was evaporated. Saturated aqueous sodium chloride solution (10 mL) was added. The mixture was extracted with EtOAc (2×50 mL). The organic fractions were combined. The combined solution was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was triturated with ether to afford sodium 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (E9) (80 mg) as a white solid. δH (CD3OD, 400 MHz): 1.44 (6H, d), 2.62 (2H, t), 3.08 (2H, t), 4.87 (1H, m), 6.33 (1H, d), 7.33 (1H, d), 7.41 (1H, d), 7.80 (1H, dd), 8.14 (1H, dd), 8.24 (2H, dd). MS (ES): C22H19ClN3O4Na requires 447; found 425.9 (M—Na++2H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].CO>ClCCl.C(OCC)(=O)C>[Cl:32][C:30]1[CH:29]=[CH:28][C:10]2[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:40](=[O:42])[CH3:41])[CH2:7][CH2:6]3)[C:9]=2[CH:31]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)NC1CCN(C2=NC(Cc3ccc4ccccc4c3)C(=O)N(C)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
5-(4-Aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.11 mmol) was dissolved in dichloromethane (0.5 mL) and triethylamine (31 μL, 0.22 mmol), acetic anhydride (11 μL, 0.11 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. To the solution was added silica and concentrated in vacuo. Column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes then 0-15% methanol in ethyl acetate provided N-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-yl)acetamide (30 mg, 55% yield). ESI m/z measured 489.2043 [M+H]+. calculated 489.2057.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](O)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Br)(Br)([Br:15])=O>C1(C)C=CC=CC=1>[Br:15][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]([NH2:1])[N:11]=1
Reactant: Nc1nc(O)c2c(n1)CCCC2
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: Nc1nc(Br)c2c(n1)CCCC2
Temperature: 95 °C
Yield: 74.5 %

Procedure:
To a suspension of 2-amino-5,6,7,8-tetrahydroquinazoline-4-ol (1.65 g, 10 mmol) in toluene (16.5 ml) was added phosphorous oxybromide (3 g) and the mixture was kept to warm in a bath (bath temperature 90-100° C.) for 2 hours. After confirming disappearance of the starting materials, the reaction mixture was poured into ice-water, and was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CHCl3) to give the object compound (1.7 g, 75%).
Reaction SMILES: [P:1]([O-:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[Na+].Cl[CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:15]([P:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6])[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]
Reactant: CCCCOP([O-])OCCCC
Reactant: CCOP(=O)(CCl)OCC
Agent: [Na+]
Product: CCCCOP(=O)(CP(=O)(OCC)OCC)OCCCC
Yield: 43 %

Procedure:
Dibutyl diethyl methylenediphosphonate was prepared in 43% yield by reacting sodium dibutyl phosphite with diethyl chloromethylphosphonate, bp=140° (0.05 mmHg), (Kugelrohr).
Reaction SMILES: [N+:1]([O-:7])([O:3][CH2:4][CH2:5][OH:6])=[O:2].[C:8]([NH:15][C@H:16]([C:20](O)=[O:21])[CH:17]([CH3:19])[CH3:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:8]([NH:15][C@H:16]([C:20]([O:6][CH2:5][CH2:4][O:3][N+:1]([O-:7])=[O:2])=[O:21])[CH:17]([CH3:18])[CH3:19])([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCO[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 5 h

Procedure:
To the reactor 2-hydroxyethyl nitrate (8 kg) was added, followed by dichloromethane (25 L). Then, boc-L-valine (12.5 kg) was added slowly under stirring, and the reaction mixture was cooled down to −10° C. Afterwards, DMAP (50 g) was added as the catalyst, and DCC (12.5 kg dissolved in 5 L of dichloromethane) was slowly added dropwise to the mixture under −10° C. The reaction was continued for another 5 hours at temperature between −10 and 0° C. under continuous stirring, while insoluble white solid was gradually formed. The reaction mixture was then warmed up slowly to room temperature, and the reaction was continued for another 12 hours at room temperature. At the end, the reaction mixture was filtered, and the filtrate was washed with water and dried to yield the crude nitrooxyethyl boc-valinate that was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39](I)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39]([C:2]4[CH:7]=[CH:6][C:5]([S:8]([N:11]5[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]5)(=[O:10])=[O:9])=[CH:4][CH:3]=4)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(C)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 45.2 %

Procedure:
A mixture of 1.12 g of 1-(4-bromo-benzene-sulfonyl)-4-methyl-piperazine, 0.978 g of bis-(pinacolato)-diboron, 0.06 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.077 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 1.03 g of potassium acetate in 40 ml of degassed dioxane are heated to 90° C. under N2 for 8 hours. To the resulting mixture 15 ml of degassed dioxane, 0.931 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.283 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.678 g of potassium carbonate and 0.208 g of lithium chloride in 15 ml of degassed water are added under N2. The mixture is heated to reflux under N2 for 16 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 15-10:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate gives 0.545 g of the title compound as a solid of m.p. 193-195° C. The mass spectrum shows the molecular peak MH+ at 493.4 Da.
Reaction SMILES: CS(O[CH:6]([CH:18]1[CH2:20][CH2:19]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=O)=O.C([O-])(C)(C)C.[K+].O>CN(C)C=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]1[CH2:7][CH:6]1[CH:18]1[CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Reaction time: 1 h
Yield: 84.9 %

Procedure:
1.18 g of 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate (3.94 mmol) is dissolved in 40 ml of dimethylformamide, 0.91 g of potassium tert-butanolate (97%, 7.88 mmol) are added and stirring is carried out for 1 hour at ambient temperature under a nitrogen atmosphere. Water is added to the reaction mixture. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:2). After removal of the eluant, 0.68 g of 2-(2-nitrophenyl)-bicyclopropane (85% of theory) is obtained in the form of an orange-coloured liquid (trans:cis ratio: 6.5:1).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:18]([NH:23][C:8](=[O:9])[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCN
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Product: CCCCCNC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=295 (M+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and pentylamine.