Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[O:15][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]=2[CH:8]=1)[CH3:5].[C:16]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:5][N:4]([CH3:3])[CH2:6][C:7]1[O:15][C:10]2[CH2:11][N:12]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:25]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CN(C)Cc1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1cccc(C(=O)c3ccccc3)c1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.228 g (0.900 mmol) of the above N,N-dimethyl-(4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-ylmethyl)amine dihydrochloride, 0.26 g (1.1 mmol) of 3-benzoylbenzoic acid and 0.53 ml (3.8 mmol) of triethylamine in 30 ml of dichloromethane, 0.23 g (1.43 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (chloroform to chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17]OS(C1C=CC(Cl)=CC=1)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.[K].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][N:33]1[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]2[C:29]1=[O:39])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 60.8 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-p-chlorobenzenesulfonyloxymethyl-4-methanesulfonyloxypyrrolidine (23.7 g: ca. 50 mmole) in dimethylformamide (50 ml), potassium phthalimide (10.2 g: 55 mmole) is added in a nitrogen atmosphere, and the mixture is stirred at 60° C. for 3.5 hours. The reaction mixture is poured into a stirring mixture of ice water (500 ml) and ethyl acetate (500 ml). The organic layer is successively washed with water (4 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from a mixture of n-hexane and toluene. The solid is filtered off and the filtrate is purified by silica gel chromatography (toluene-ethyl acetate) to give crude (2S,4R)-1-allyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (12.41 g). Yield: 61%. Colorless oil.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:52])[C@H:4]([NH:47][C:48](=[O:51])[O:49][CH3:50])[C:5]([N:7]1[C@@H:11]([CH3:12])[CH2:10][CH2:9][C@H:8]1[C:13]1[NH:17][C:16]2[C:18]3[C:23]([CH:24]=[CH:25][C:15]=2[N:14]=1)=[CH:22][C:21]1[C:26]2[C:31]([CH2:32][O:33][C:20]=1[CH:19]=3)=[CH:30][C:29]([C:34]1[NH:38][C:37]([C@@H:39]3[CH2:43][C@H:42]([CH2:44][O:45][CH3:46])[CH2:41][NH:40]3)=[N:36][CH:35]=1)=[CH:28][CH:27]=2)=[O:6].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([CH:62]([CH3:64])[CH3:63])[C:59](O)=[O:60])=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C@H:3]([CH3:52])[C@H:4]([NH:47][C:48]([O:49][CH3:50])=[O:51])[C:5]([N:7]1[C@@H:11]([CH3:12])[CH2:10][CH2:9][C@H:8]1[C:13]1[NH:17][C:16]2[C:18]3[C:23]([CH:24]=[CH:25][C:15]=2[N:14]=1)=[CH:22][C:21]1[C:26]2[C:31]([CH2:32][O:33][C:20]=1[CH:19]=3)=[CH:30][C:29]([C:34]1[NH:38][C:37]([C@@H:39]3[CH2:43][C@H:42]([CH2:44][O:45][CH3:46])[CH2:41][N:40]3[C:59](=[O:60])[C@@H:58]([NH:57][C:55](=[O:56])[O:54][CH3:53])[CH:62]([CH3:64])[CH3:63])=[N:36][CH:35]=1)=[CH:28][CH:27]=2)=[O:6]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)cc3-4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl {(2S,3R)-3-methoxy-1-[(2S,5S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate (74.6 mg, 0.105 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (18.5 mg, 0.105 mmol), HATU (44 mg, 0.116 mmol) and 0.6 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. (48.1 mg)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.C(N=C=NCCCN(C)C)C.[CH3:25][N:26]([CH3:31])[S:27]([NH2:30])(=[O:29])=[O:28]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:30][S:27](=[O:29])(=[O:28])[N:26]([CH3:31])[CH3:25])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.2 %

Procedure:
To a mixture of 5-chloro-2,4-difluorobenzoic acid (3.48 g, 18.1 mmol) in anhydrous dichloromethane (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.20 g, 27.1 mmol), N,N-dimethylpyridin-4-amine (5.04 g, 41.3 mmol), and N,N-dimethylsulfamide (3.37 g, 27.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 24 h. The mixture was then cooled to 0° C. and quenched with hydrochloride acid (1N, 100 mL) followed by extraction with dichloromethane (2×200 mL). The organic layer was washed with ammonium chloride solution (3×30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the crude product was crystallized from ethyl acetate and hexanes to afford the title compound as a white solid (1.20 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.98-7.93 (m, 1H), 7.74-7.68 (m, 1H), 2.89 (s, 6H); MS (ES−) m/z 297.1, 299.1 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]=2[N:3]=1
Reactant: CC(C)CCBr
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC(C)C
Temperature: 50 °C

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.6 mmol) in DMF (40 ml) was treated with sodium carbonate (0.9 g, 8.5 mmol) and 1-bromo-3-methylbutane (1.04 g, 6.9 mmol). The stirred mixture was heated at 50° C. for 18 hours then cooled and evaporated to dryness. The residue was treated with water (60 ml) and extracted with ethyl acetate (3×80 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with a mixture of diethyl ether and cyclohexane to reveal the product as a white solid which was filtered off and dried. This gave the title compound as a white solid m/z 297[MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH2:14][C:15]([F:16])([F:17])[F:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66])=[O:8]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(CC(F)(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate (250 mg, 0.63 mmol) in dry DMF (3.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (288 mg, 0.76 mmol) and DIPEA (220 μl, 1.3 mmol) dropwise. The resulting solution was stirred for 5 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 119 mg, 0.69 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then stirred at room temperature for 16.5 hours. The reaction mixture was treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (30 mg). Stirring was continued for further 23 hours and the reaction mixture was then partitioned between water (30 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×20 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (50 ml), water (60 ml), brine (2×40 ml), dried over MgSO4, filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-10% MeOH/CH2Cl2) and triturated from ether (10 ml) with sonication. The resulting precipitate was collected by filtration and dried in-vacuo to give the title compound (249 mg, 74%) as a white solid. LC-MS 100%, 4.08 min (7 minute LC-MS method), m/z=530.0, 531.0, 532.0, 533.0; 1H NMR (500 MHz, Acetone) δ 10.67 (s, 1H), 7.55 (d, J=1.8 Hz, 2H), 7.27 (d, J=1.9 Hz, 1H), 5.90 (s, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.90 (dd, J=11.2, 4.6 Hz, 4H), 3.28 (t, J=11.6 Hz, 2H), 3.07-2.97 (m, 1H), 2.32 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.76 (dd, J=12.3, 1.6 Hz, 2H), 1.61 (qd, J=12.0, 4.5 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.CN(C)C=O.[OH-].[NH4+]>O>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: c1nc[nH]n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2c(-n3cncn3)ccnc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A mixture of 1.98 g of 4,7-dichloro-quinoline, 1.38 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 6 hours, whereupon the reaction mixture is poured into 100 ml of water and neutralized with 1 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered and recrystallized from ethanol. Thus 1.61 g of the desired product are obtained, yield 70%, Mp.: 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@H:12]([CH3:13])[C@H:11]([OH:14])[C:10]([F:16])([F:15])[C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.[I:18]N1C(=O)CCC1=O>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@H:12]([CH3:13])[C@H:11]([OH:14])[C:10]([F:15])([F:16])[C:9]2=[O:17])[CH:5]=[CH:6][C:7]=1[I:18]
Reactant: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(I)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of (4S,5S)-1-(3-chlorophenyl)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (110.5 mg) and N-iodosuccinimide (130 mg) in acetic acid (3 mL) was added dropwise conc. sulfuric acid (3 drops), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/2) to give the title compound as a pale-yellow oil (yield: 113 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCOC(=O)CC(C)=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
5 g (26.57 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 3.4 ml (26.57 mmol) of ethyl 3-oxobutanoate, 1.9 ml (33.21 mmol) of acetic acid and 263 μl (2.66 mmol) of piperidine in 50 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the solution is diluted with dichloromethane (50 ml) and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from isopropanol. 7.63 g (91% of theory) of the title compound are obtained as an E/Z mixture.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[NH:13][CH:12]=[CH:11]2.Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH:12]=[CH:11]2
Reactant: BrCC1CC1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=c1c2ccc(Br)cc2ccn1CC1CC1
Temperature: 50 °C

Procedure:
Cesium carbonate (2.62 g), intermediate 1 (1.5 g) and (bromomethyl)cyclopropane (0.8 mL) were stirred and heated at 50° C. for 4 hours. The mixture was allowed to cool then poured into water and extracted with ethyl acetate. The organic extracts were combined dried and evaporated under reduced pressure. The residue was triturated with ether and the sub-titled compound isolated by filtration (1.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([NH:6][C@@H:7]1[C:13]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=2[C:11]2[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:10]=2[CH2:9][CH2:8]1)(=[O:5])=[O:4].Cl[C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C>C(#N)C>[C:31](=[O:32])([O:33][CH3:34])[O:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:6][S:3]([N:2]([CH3:1])[CH3:29])(=[O:5])=[O:4])[C:13]=2[CH:14]=1
Reactant: COC(=O)Cl
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1[C@@H](NS(=O)(=O)N(C)C)CC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Oc1ccc2c(c1)[C@@H](NS(=O)(=O)N(C)C)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 32 %

Procedure:
A solution of (5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ol (1) (0.9; 0.71 mmol), methyl chloroformate (0.061 ml; 0.782 mmol) and triethylamine (0.109 ml; 0.782 mmol) in acetonitrile (8 ml) was stirred under argon atmosphere at 40° C. for 4 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with ethanol/dichloromethane (2/98) to give (5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl carbonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH:32]=5)=[N:23][N:22]=4)=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(C5=CCN(C(=O)OC(C)(C)C)CC5)c5ccccc45)cc3)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc2c(Sc3ccc(Nc4nnc(C5=CCNCC5)c5ccccc45)cc3)ccnc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a 20 mL sealed tube was dissolved tert-butyl 4-(4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.200 g, 0.337 mmol) in DCM (1.00 mL). To the mixture was added TFA (0.130 mL, 1.69 mmol). The mixture was stirred at 50° C. for 3 hours, then cooled to RT and concentrated. The crude material was purified on an Isco silica gel chromatography using 0-100% CH2Cl2:MeOH:NH4OH (90:10:1)/CH2Cl2. The product fractions were concentrated to yield N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phthalazin-1-amine as a light yellow solid. MS: [N+H]=493.0; Calc'd 492.6 for C28H24N6OS.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[Cl:12][Si](Cl)(C)C.N(OCCC(C)C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CCCCCCC>[Cl:12][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCCCCCC
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 55 °C
Reaction time: 17 h
Yield: 66 %

Procedure:
2-Amino-6-chloropurine (5.00 g, 29.5 mmol), dichlorodimethylsilane (11.42 g, 88.5 mmol), benzyltriethylammonium chloride (0.40 g, 1.8 mmol) and isoamyl nitrite (5.18 g, 44.2 mmol) were added to heptane (25 ml), and the mixture was heated to 50-60° C. and stirred for 17 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (25 ml) and adjusted to pH 4-5 with a 2M aqueous sodium hydroxide solution. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were recrystallized from methanol. The mixture was dried under reduced pressure at 60° C. to give 2,6-dichloropurine as a white powder (3.68 g, yield 66.1%). The properties of the obtained compound were the same as in Example 1(2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29]Cl.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[O:10][CH2:29][O:25]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: ClCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3cncn3)OCOC2c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Yield: 54.4 %

Procedure:
To a solution of 500 mg of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol in 5 ml of dry dimethylformamide is added 180 mg of 50% mineral oil dispersion of sodium hydride under ice cooling. Five minutes later 490 mg of bromochloromethane is added to the mixture, which is allowed to react at a temperature of 50° C. for 1 hour. The reaction mixture is mixed with ice water and shaken with ether. The ethereal layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica-gel, which is eluted with 3% methanol-methylene chloride. The eluate is concentrated and the residue is crystallized from ethyl acetate to give 280 mg of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals melting at 201 ° to 203° C. The yield is 54%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17](=[O:49])[C@@H:18]([NH:25][C:26](=[O:48])[CH:27]([C:38](=[O:47])[NH:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[NH:37])[NH2:36])=[CH:31][CH:30]=2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].ClCCl>>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[CH2:40]([NH:39][C:38](=[O:47])[CH:27]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:36])[NH2:37])=[CH:33][CH:34]=1)[C:26]([NH:25][C@@H:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:17](=[O:49])[NH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:48])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNC(=O)[C@@H](NC(=O)C(Cc2ccc(C(=N)N)cc2)C(=O)NCc2ccccc2)C2CCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)c1ccc(CC(C(=O)NCc2ccccc2)C(=O)N[C@H](C(=O)NCCN2CCNCC2)C2CCCCC2)cc1
Reaction time: 20 h

Procedure:
4-(2-{2-(S)-[2-(R,S)-Benzylcarbamoyl-3-(4-carbamimidoyl-phenyl)-propionylamino]-2-cyclohexyl-acetylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol, example 6b) was treated with a mixture of trifluoroacetic acid/dichloromethane (1/1, 0.5 ml) and stirred for 20 hours. The solvent was evaporated in vacuo and the residue lyophilized to give the desired product. mp.: 196° C. (dc), MS (FAB) m/z: 576.3 ((M+H)+, 100%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].F[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26].ClC1C=CC(SC)=CC=1[N+]([O-])=O>CN(C=O)C.O>[CH3:3][O:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: CONS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1ccc(F)c([N+](=O)[O-])c1
Agent: CSc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc(SC)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1

Procedure:
To a suspension of sodium hydride (60%, 0.33 g (8.17 mmol)) in DMF (10.0 ml), N-methoxy-p-toluenesulfonamide (1.63 g (8.17 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after 15 minutes' stirring at room temperature, a 3:2 mixture of 2-fluoro-5-(methylthio)nitrobenzene and 2-chloro-5-(methylthio)nitrobenzene (1.39 g) was added. The mixture was stirred overnight at room temperature, poured into water and extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:6 to 1:4) as eluent. The eluted substance was recrystallized from ethyl acetate-hexane to give 0.60 g of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]1[CH2:38]OC[CH2:35]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH:19]([CH2:35][CH2:34][CH3:38])[C:20]([O:22][CH3:23])=[O:21]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Yield: 75.2 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.395 g; 1.206 mmol), LHMDS 1N in THF (1.327 mL; 1.327 mmol), 1-iodopropane (0.177 mL; 1.810 mmol) in DMF (4.8 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.335 g (75%) of the title compound as a yellow oil.