Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([CH3:20])[C:11]3=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]1([C:7]2[C:8]3[CH2:9][C:10]([CH3:20])=[CH:11][C:12]=3[CH:13]=[C:14]3[C:18]=2[CH2:17][CH2:16][CH2:15]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1Cc2c(cc3c(c2-c2ccccc2)CCC3)C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1=Cc2cc3c(c(-c4ccccc4)c2C1)CCC3
Temperature: 50 °C
Reaction time: 3 h

Procedure:
9.6 g (24.4 mmol) of 4-phenyl-2-methyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (2a) and 2.10 g (55 mmol) of sodium borohydride in 40 ml of toluene were placed in a reaction vessel. The solution was heated to 50° C. and 7 ml of methanol was added slowly and the reaction mixture was stirred at 50° C. for 3 hours. After cooling to room temperature 12 ml of water and 40 ml of 1 N sulfuric acid were added and the mixture was stirred for 30 minutes. After phase separation the water phase was extracted with toluene. Organic phase was evaporated and the residue was taken up in 100 ml of toluene and mixed with 100 mg of p-toluenesulfonic acid. Water was distilled off from this reaction mixture by refluxing for 2 hours on a water separator until reaction was complete. The reaction mixture was washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was dried in an oil pump vacuum. This gave 11.5 g of brawn oil. The crude product was purified by column chromatography (200 g of silica gel, 1 l of heptane: diethylether=9:1).
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@@H:9]2[C:14]3=[C:15](O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@](O)(C(C)=O)C2)C[C@H](N)[C@@H]1O.Cl.[CH2:40]([OH:47])[C:41]([NH2:46])([CH2:44][OH:45])[CH2:42]O.[CH2:48]([OH:55])[C:49]([NH2:54])([CH2:52]O)[CH2:50][OH:51].Cl>CO.O=O>[CH3:52][C:49]1([CH2:48][OH:55])[NH:54][C:14]([C:13]2([CH3:12])[NH:46][C:41]([CH2:40][OH:47])([CH3:42])[CH2:44][O:45][C:18]2=[O:19])([CH3:15])[C:9](=[O:8])[O:51][CH2:50]1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: O=O
Solvent: CO
Product: CC1(CO)COC(=O)C(C)(C2(C)NC(C)(CO)COC2=O)N1
Reaction time: 0.33 h

Procedure:
A test similar to that described for the same reaction in methanol solvent (vide supra) was run. Oxomorpholinyl dimer DHM3 (1.38 mg, 4.37×10-3 mmol) was dissolved in 0.5 ml of oxygen-free methanol and quickly transferred without delay into one compartment of the cell. The solvent was promptly removed under vacuum. Daunorubicin hydrochloride (11.9 mg) was dissolved in 100 ml of an aqueous solution of Tris (24.2 mg) and Tris hydrochloride (31.6 mg) and 2.6 ml of this solution (4.18×10-4 mmol of 6) was introduced into the other compartment of the cell. The sample was freeze-thaw degassed over three cycles as described above, sealed, and placed in a thermostatted cell holder at 10.0±0.1° C. for about 20 min prior to mixing. Full spectra between 320 and 800 nm were recorded every 10 sec for the first 125 sec, and then every 20 sec. From the absorbance change at 620 nm over the first 85 sec (50% reaction of daunorubicin), a non-linear least-squares treatment gave a first order rate constant for bond homolysis of DHM3 (k1) equal to 6×10-4 sec-1 and a first order rate constant for destruction of 7 (k2) equal to 2×10-2 sec-1. Treatment of the data obtained in the 164-225 sec interval gave k2 =2.8×10-2 sec-1.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][C:3]1=[O:18].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(O)(=O)C.[Na]>C(O)C.CO>[CH2:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][N:2]([NH:1][CH:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[CH2:30][CH2:29]2)[C:3](=[O:18])[CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCN(NC2CCN(c3ccncc3)CC2)C(=O)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A solution of 1-amino-4-benzyloxycarbonyl-2-piperazinone (21.92 g) and 1-(4-pyridyl)-4-piperidone (15.51 g) in ethanol (500 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 24 hours. The reaction mixture was concentrated to obtain a residue, which was dissolved in methanol (300 ml) and combined with acetic acid (18.26 g) with cooling on ice followed by sodium cycanoborohydride (7.16 g) and then stirred at 0° C. for 3 hours. The reaction mixture was concentrated, and the residue was combined with a 1N aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extract was washed with water and brine, dried and concentrated to obtain 4-benzyloxycarbonyl-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (25.29 g) as a pale yellow amorphous material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].CC(N(C)C)=O.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.[Cu]I>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:24]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (0.2 mL, 1.43 mmol) was stirred in a solvent of dimethylacetamide (10 mL). The reaction solution was added with 4-methyl-1H-imidazole (0.35 g, 4.26 mmol), K2CO3 (0.20 g, 5.23 mmol), Cu (0.022 g, 0.346 mmol) and CuI (0.068 g, 0.115 mmol), and stirred for about 2 days at 140° C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[CH:46]=[CH:45][C:29]2[NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:32][C:28]=2[CH:27]=1.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:25][C:26]2[CH:46]=[CH:45][C:29]3[NH:30][C:31]([C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[N:32][C:28]=3[CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CBr)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc2[nH]1
Reaction time: 2.5 h
Yield: 28.6 %

Procedure:
The product from Example 20A (0.530 g, 2.32 mmol) and K2CO3 (0.802 g, 5.81 mmol) were combined in dry DMF (20 mL) at room temperature, and nitrogen was bubbled through the solution for 10 min. The product from Example 7C (1.0 g, 2.63 mmol) was added in three equal portions in 20 min. intervals, and the reaction was stirred a total of 2.5 h. The mixture was poured into water, extracted into EtOAc, washed with brine. The organic was dried (MgSO4), filtered and evaporated. The product was purified by chromatography on silica gel, eluting with c 0-4% MeOH in CH2Cl2, and a second column eluting with 0-5% EtOAc in CH2Cl2 to give the title compound (0.350 g, 28.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:18])([CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16])[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:18])([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
Into a solution wherein 0.5 g of (R)-2-(2,4-difluorophenyl)-3-propionyloxy-1,2-propanediol obtained in Example 37 was dissolved in 5 ml of ethyl acetate was added dropwise 0.66 g of methanesulfonyl chloride at a temperature of 0° to 5° C., and thereto was added dropwise 0.46 g of pyridine at a temperature of 0° to 5° C. After dropping, the resulting liquid was stirred at room temperature for 16 hours. To the reaction mixture was added 20 ml of 1N hydrochloric acid and an organic layer separated. The organic layer was washed with saturated aqueous solution with sodium hydrogencarbonate and with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 0.53 g of oily (S)-2-(2,4-difluorophenyl)-1-propionyloxy-3-methanesulfonyloxy-2-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 24.3 minutes ((R)-form) and 26.9 minutes ((S)-form)).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:21]([O-])=[O:22])([CH3:20])[CH2:13][CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1.C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:21]([C:12]([CH3:20])([CH3:11])[CH2:13][CH2:14][CH:15]1[O:16][CH2:17][CH2:18][O:19]1)[O-:22]
Reactant: CC(C)(CCC1OCCO1)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CCC1OCCO1)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.7 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (290.6 mg, 2.04 mmol), 2-(3-methyl-3-nitrobutyl)-1,3-dioxolane (776.8 mg, 4.11 mmol) and zinc (402.7 mg, 6.16 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.69 ml, 12.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 10 hours and let stand overnight. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1-1/1) to give the title compound (419.4 mg; 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][CH:15]=[O:16].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].I[C:34]1[CH:35]=[CH:36][C:37]2[O:42][CH2:41][CH2:40][CH2:39][C:38]=2[CH:43]=1>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][CH2:40][CH2:39][C:38]=4[CH:43]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][CH:15]=[O:16]
Reactant: O=CNCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: Ic1ccc2c(c1)CCCO2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=CNCc1cc(-c2ccn(-c3ccc4c(c3)CCCO4)n2)ccc1Cl
Temperature: 110 °C

Procedure:
To a solution of N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]formamide (i.e. the product of Step D) (0.25 g, 1.1 mmol) in dioxane (2.5 mL) was added trans-N,N′-dimethylcyclohexane-1,2-diamine (0.06 mL, 0.43 mmol) followed copper(I) iodide (0.08 g, 0.43 mmol), potassium carbonate (0.87 g, 6.4 mmol) and 3,4-dihydro-6-iodo-2H-1-benzopyran (0.45 g, 1.7 mmol; prepared according to the procedure of Muraki et al., Tetrahedron Lett. 1996, 37, 2441). The reaction mixture was heated at 110° C. for 20 h and then cooled to ambient temperature. The solvent was evaporated, and the residue was taken up in chloroform, washed with water and brine, then dried (Na2SO4) and concentrated. The crude residue was then purified by preparative TLC (2% methanol in chloroform as eluant) to provide the title product, a compound of the present invention, as a solid (0.069 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([OH:8])[CH2:6][CH2:5][O:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@@H:3]2[C@@H:7]([OH:8])[CH2:6][CH2:5][O:4]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OC[C@H]1OCC[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2OCC[C@@H]2O)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
(2R,3S)-2-(hydroxymethyl)tetrahydrofuran-3-ol (1.59 g, 13.46 mmol) (prepared as described in Chenault, K. H.; Mandes, R. F. Tetrahedron, 1997, 53(32), 11033-11038) is dissolved in dry pyridine (15 mL) and the solution cooled to −40° C. in a dry ice/acetone bath for 30 min. p-Toluenesulfonyl chloride (2.58 g, 13.51 mmol) is added slowly over 5 min and the solution allowed to warm up to room temperature over 4 h. The solution is concentrated to provide 3.59 g (86%) of the title compound which is used without further purification. LC-ES/MS m/z 295.0 [M+Na]+, TR=1.76 min. (Symyx Draw 3.1 (IUPAC Name) provides the name for the compound of Preparation 12.)
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol) in N,N-dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102 mmol, 1.5 eq). The mixture was stirred for 30 min. A solution of methyl iodide (4.17 mL, 67.0 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to provide 10.2 g (92%) of methyl 2-amino-3-methylbenzoate, 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][O:41][CH2:42][CH2:43][C:44](Cl)=O>ClCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:31]=[C:44]1[CH2:43][CH2:42][O:41][CH3:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl{4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (28.62 g, 65.5 mmol) in dichloromethane (1 L) was cooled to ˜0° C.; triethylamine (10.0 mL, 72.1 mmol) was added. Methoxypropionyl chloride (8.57 mL, 78.6 mmol) was added dropwise, and the reaction was stirred at ambient temperature for two hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (840 mL). Triethylamine (33 mL) was added, and the reaction was heated at reflux overnight and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure to provide 30.77 g of tert-butyl{4-[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a brown oil, which was used without purification.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[N:30]=[N:31][N:32]([CH2:34][CH3:35])[N:33]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=3)[C:54](O)=[O:55])=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:22][CH2:23][N:24]([C:54]([C:53]6[CH:57]=[CH:58][CH:59]=[C:51]([C:45]7[C:46]8[CH:47]=[C:48]([O:49][CH3:50])[C:39]([O:38][CH2:36][CH3:37])=[CH:40][C:41]=8[C@H:42]8[CH2:63][S:62][CH2:61][CH2:60][C@H:43]8[N:44]=7)[CH:52]=6)=[O:55])[CH2:25][CH2:26]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[N:30]=[N:31][N:32]([CH2:34][CH3:35])[N:33]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc7c(c6)OCO7)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(1,3-benzodioxol-5-yl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (94 mg; compound B77) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (72 mg; compound C8) and HBTU (151 mg) in DCM/DMF (14 ml/1 ml) in the presence of DIPEA (188 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:17]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[CH:17]=2)[CH2:31][CH2:30]1
Reactant: O=C1NCCCc2cc(OCCCCl)ccc21
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C1NCCCc2cc(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)ccc21
Temperature: 150 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
A mixture consisting of 7-(chloropropoxy)-2,3,4,5-tetrahydro-1H-2-benzoazepin-1-one (0.507 g, 2 mmol) and 1-(2-quinolylmethyl)piperazine (1.81 g, 8 mmol) was stirred for 4 hours at a bath temperature of 150° C. under an argon gas stream. After the reaction mixture was allowed to cool down, chloroform was added to the reaction mixture to dissolve the same. The resulting solution was rendered basic with a dilute aqueous solution of sodium hydroxide. The thus-obtained solution was washed with water and then dried over anhydrous magnesium sulfate. After the resulting solution was purified by subjecting it to chromatography on a silica gel column (developer: chloroform/methanol=40/1), recrystallization was conducted from acetone. The title compound (0.613 g) was obtained as yellow leaflets (yield: 68.9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[NH:18]([C:20]([C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=O)[NH2:19]>O>[NH2:1][C:2]1[C:3]([C:16]2[NH:19][N:18]=[C:20]([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)[N:17]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NN)C1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2n[nH]c(-c3nc(-c4cccc(CO)c4)cnc3N)n2)C1
Temperature: 180 °C
Yield: 64.2 %

Procedure:
3-Amino-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carbonitrile (514.0 mg, 2.27 mmol) and 1,1-dimethylethyl (3S)-3-(hydrazinocarbonyl)piperidine-1-carboxylate (1.66g, 6.83 mmol) were combined together and heated to 180° C. for 1-2 h. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (2×35 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by MPLC to give 1,1-dimethylethyl (3R)-3-(5-{3-amino-6-[3-(hydroxymethyl)phenyl]pyrazin-2-yl }-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate. (655.0 mg, 64.2% yield): MS (EI) for C23H29N7O3: 452.29 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25](O)=[O:26])=[C:22]([CH3:28])[C:21]=3[CH:29]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.C[O:40][C:41](=[O:44])[CH2:42][NH2:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([NH:43][CH2:42][C:41]([OH:40])=[O:44])=[O:26])=[C:22]([CH3:28])[C:21]=3[CH:29]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)c(C)c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)c(C)c2c1
Yield: 66.6 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-benzofuran-2-carboxylic acid (520 mg, 1.154 mmol) in CH2Cl2 (10 mL) and DMAP (422 mg, 3.46 mmol), EDC (332 mg, 1.73 mmol), and glycine methyl ester hydrochloride (217 mg, 1.73 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (390 mg, 100%).