Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([CH2:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[N:73]#[C:74][NH2:75]>CN(C=O)C>[C:74]([NH:75][C:37](=[O:38])[CH2:36][C:35]([CH3:41])([CH3:40])[CH2:34][CH2:33][C:20]1[C:21]([CH3:32])([CH3:31])[C@H:22]2[C@:17]([CH3:42])([CH2:18][CH:19]=1)[C@@H:16]1[C@:25]([CH3:30])([C@@:26]3([CH3:29])[C@H:13]([CH2:14][CH2:15]1)[C@H:12]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:11]1([NH:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][S:2](=[O:49])(=[O:1])[CH2:7][CH2:6]1)[CH2:28][CH2:27]3)[CH2:24][CH2:23]2)#[N:73]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: N#CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)NC#N)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
A solution of 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanoic acid (30 mg, 0.043 mmol) in DMF (1 mL) was treated with EDC (11.7 mg, 0.061 mmol) and HOBT (8.2 mg, 0.053 mmol). The reaction mixture was stirred at rt for 1 h. N,N-diisopropylethylamine (0.013 mL, 0.073 mmol) was added to the reaction mixture and after stirring 10 min, cyanamide (1.0 mg, 0.024 mmol) was then added. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the crude product was purified by prep HPLC (Method 12) to afford N-cyano-5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanamide (4.9 mg, 28% yield). LC/MS m/e 723.5 (M+H)+, 2.29 min (method 3). 1H NMR (500 MHz, DMSO-d6) δ 5.19 (d, J=5.9 Hz, 1H), 4.71 (s, 1H), 4.58 (s, 1H), 3.49 (t, J=4.8 Hz, 1H), 3.42 (t, J=5.5 Hz, 1H), 3.14-3.03 (m, 4H), 3.01-2.92 (m, 4H), 2.72-2.58 (m, 3H), 1.96-0.76 (m, 28H), 1.66 (s, 3H), 1.04 (s, 3H), 0.95 (s, 6H), 0.92 (s, 6H), 0.87 (s, 3H), 0.79 (s, 3H)
Reaction SMILES: Cl.C(O)C.[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[CH2:6][CH3:7].N>[Fe].O>[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH2:6][CH3:7]
Reactant: CCCOc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1N
Temperature: 30 °C
Yield: 73.8 %

Procedure:
Iron 60 mesh (134.5 g., 2.40 mole), concentrated HCl (37.4 cc), ethanol (630 cc), and water (570 cc) are stirred under nitrogen and the temperature of the mixture is raised to reflux. Then o-propoxynitrobenzene (12.5 g., 0.69 mole), is added at reflux over a period of 5 hrs. and refluxed for 3-4 hrs. Then the mixture is neutralized with concentrated ammonia to a pH of 8-9. The temperature is raised to 30° C., and the reaction mass filtered, 200 cc ether added, the organic layer separated. The product distilled at vapor temperature of 65°-67° C. at 0.05-0.03 mm. yielding 77 g of product (74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:29].[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:36]1([NH:41][C:33]([C:30]2([C:28]([NH:27][C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[O:17])[CH:10]=4)=[CH:7][C:2]=3[F:1])=[O:29])[CH2:32][CH2:31]2)=[O:34])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Reactant: NC1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)NC5CCCC5)CC4)c(F)c3)ccn2)CC1
Reaction time: 25 h
Yield: 51 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added cyclopentylamine (0.0163 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 25 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (23.2 mg, 51%).
Reaction SMILES: O=[C:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1.[CH:24]([O-:26])=O.[NH4+:27].C(=O)([O-])O.[Na+]>>[CH:24]([NH:27][CH:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:26]
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: CCOC(=O)COc1ccc(CCC(=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)COc1ccc(CCC(NC=O)c2cccnc2)cc1
Yield: 44.6 %

Procedure:
1.95 g of ethyl 4-[3-oxo-3-(3-pyridyl)propyl]phenoxyacetate and 5.00 g of ammonium formate were stirred at 165° C. for 1.5 hours. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, which was then extracted with ethyl acetate, and the organic phases combined were washed in saturated aqueous sodium chloride, dried over magnesium sulfate, and the solvent was then distilled off. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 0.95 g of ethyl 4-[3-formamido-3-(3-pyridyl)propyl]phenoxyacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH2:28])=[N:9]1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:23])([F:24])[F:25])[CH:16]=[C:15]([F:27])[CH:14]=2)=[CH:11][C:10]([NH:28][C:35]([C@H:32]2[CH2:31][C:30](=[O:29])[NH:34][CH2:33]2)=[O:36])=[N:9]1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccccc2F)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2F)c1)C(F)(F)F
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To a solution of 1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) prepared in the previous step in dimethylformamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared in Preparation 14 and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (32 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O.N1CCCCC1>C(O)C>[N:1]1([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[CH:17][C:19]4[NH:20][C:21]5[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=5[C:27]=4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2ccc(N3CCOCC3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(N4CCOCC4)ccc32)[nH]c2c1CCCC2
Yield: 36.4 %

Procedure:
A mixture of 4 g of 6-(morpholin-4-yl)-2-oxindole, 3.75 g of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid, and 1.8 mL of piperidine in ethanol (60 mL) was refluxed for 6 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid to pH 6. The precipitate was collected by filtration, washed once with water, twice with ethyl acetate and twice with methanol to give 2.6 g of 3-[2-(6-Morpholin-4-yl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]propionic acid as an orange solid (34% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9](NC2N=CC(C3C=CC(OC)=CC=3)=CN=2)[CH:10]=[CH:11][C:12]=1OC)[CH3:2].COC1C=CC([NH:40][C:41]2[N:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)=[CH:43][N:42]=2)=CC=1O.[C:56]([O-])([O-])=[O:57].[Cs+].[Cs+].ClCCN(CC)CC>CN(C=O)C>[CH2:30]([N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([O:57][CH3:56])[CH:10]=[CH:11][C:12]=1[N:42]1[CH:43]=[C:44]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)[CH:45]=[N:46][CH:41]1[NH2:40])[CH2:1][CH3:2])[CH3:31]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CCOc1cc(Nc2ncc(-c3ccc(OC)cc3)cn2)ccc1OC
Reactant: COc1ccc(-c2cnc(Nc3ccc(OC)c(O)c3)nc2)cc1
Agent: CCN(CC)CCCl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cc(OC)ccc1N1C=C(c2ccc(OC)cc2)C=NC1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
[3-(2-Diethylamino-ethoxy)-4-methoxy-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine can be synthesized by the following procedure. To a solution of 2-methoxy-5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenol (0.2 mmol) (from Example 5v) in anhydrous DMF (2 mL) is added Cs2CO3 (0.28 mmol) and (2-chloro-ethyl)-diethyl-amine (0.2 mmol). The reaction mixture stirred at 80° C. for 8 h and quenched with water followed by extraction with DCM (3×30 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated. Preparative LCMS purification affords the title compound (78%). MS (m/z) (M+1)+ 423.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])/[CH:4]=[CH:5]/I.C([Li:18])(C)(C)C>CCOCC.CCCCC>[Li:18]/[CH:5]=[CH:4]/[CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])[CH:2]([CH3:13])[CH3:1]
Reactant: [Li]C(C)(C)C
Reactant: CCOCCOC(/C=C/I)C(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: [Li]/C=C/C(OCCOCC)C(C)C
Temperature: -78 °C

Procedure:
2.50 g (8.40 mmol) of trans-4-methyl-3α-ethoxyethoxy-1 -iodopentene was dissolved in 57 ml of anhydrous ether and cooled to -78° C. with stirring under argon atmosphere. To this solution 13.7 ml of 1.23 N t-butyllithium in pentane was injected. The resulting solution was stirred for 2.75 hours at -78° C. under argon atmosphere, yielding the lithio-anion, 1-lithio-trans-4-methyl-3α-ethoxyethoxy-1-pentene. The lithio-anion was added to a solution of 0.44 g hexamethylenephosphorous triamide copper iodide in 50 ml of anhydrous ether at -78° C. under argon. This yellow mixture was stirred for 15 minutes at -78° C. Then 1.97 g (4.22 mmol) of 15α-ethoxyethoxy-PGA2 -methyl ester in 11.5 ml ether was added dropwise and the reaction mixture was stirred at -70° C. for 15 min. The mixture was then slowly warmed to 0° C. over a period of 1.5 hr. by use of an ice water and salt bath, and stirred for 0.5 hr. The mixture was then brought to 25° C. and stirred for an additional 0.5 hr. The mixture was then processed with a 20% aqueous NH4Cl/NH4OH solution and 3.35 g of an orange oil was obtained. NMR(CDCl3) analysis revealed: δ 3.65, singlet, CO2CH3 ; δ Ξ5.45, multiplet, olefinic-H; and no absorption due to olefinic protons on the cyclopen-tenone in the PGA2 starting material. The ethoxyethoxy groups were hydrolyzed by reacting with 70 ml of 65/35 acetic acid/water and 7.0 ml THF for 17 hours at 25° C. After processing, 3.30 g of an orange oil were obtained. NMR (CDCl3) analysis showed no absorption in the δ 4.80 region. The methyl ester was hydrolyzed by reaction with 22 ml of 1N NaOH and 22 ml of THF for 19 hours at 25° C. under argon atmosphere. After processing 3.28 g of a red oil was obtained chromatographed in Silicic Acid and Celite (15%). 1.227 g (65.6%) of (-)-11α-(trans-4'-methyl-3'-β -hydroxy-1-pentenyl-11 -desoxy-PGE2 was obtained. NMR(CDCl3) analysis: δ 3.95, multiplet, 2H, CHOH; δ 5.45, multiplet, 6H, CO2H, -OH. IR analysis: λmaxCHCl3 2.68μ5.75μ, 5.85μ. Optical rotation: [α]D 25° = 36.4 ± 02° (c = 1.0, CH3OH). Mass spectoscopy: 416 (P+ - 18).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH3:29][N:30]([CH2:32][CH2:33][CH2:34][Cl:35])[CH3:31].Cl>CN(C)C=O.O.C1(C)C=CC=CC=1>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:34][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CN(C)CCCCl
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In one portion 1.5 g (4.8 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.6 g (5.3 mmol) of potassium t-butoxide in 25 ml of dimethylformamide which was cooled to 0°. After stirring for 15 min, 5.2 ml (10.4 mmol) of a 2 M toluene solution of dimethylaminopropyl chloride was added. The mixture was warmed to room temperature and stirred for 4 hr. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. Purification of the residue by column chromatography (silica gel, 25 g; eluents, 4:1 ration of methylene chloride:ether followed by 1:2:7 ratio of methanol:ether:methylene chloride) gave a colorless oil. The oil was dissolved in an excess of methanolic hydrogen chloride and the solution was concentrated at reduced pressure. Crystallization of the residue from a mixture of isopropanol and ether gave an orange solid, mp 258°-260°.
Reaction SMILES: [F-].[K+].Br[CH2:4][C:5](=[O:23])[C@@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]([O:29][CH2:4][C:5](=[O:23])[C@@H:6]([NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:28]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)COC(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium fluoride (0.326 g, 5.61 mmol) was added to a mixture of the tert-butyl (S)-3-bromo-2-oxo-1-phenethylpropylcarbamate (1.00 g, 2.81 mmol) and 2,5-dichlorobenzoic acid (1.07 g, 5.61 mmol) in DMF (10 mL). The mixture was stirred for 2 hours at room temperature and then ethyl acetate (75 mL) was added. The solution was washed with 1M hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (MgSO4), filtered, and evaporated to dryness to provide crude (S)-3-tert-butoxycarbonylamino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([NH2:22])[N:15]=2)[N:6]=1.I[CH2:28][CH3:29].[O:30]1CCC[CH2:31]1>C(OCC)(=O)C>[NH2:20][C:18]1[N:19]=[C:14]([N:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])=[N:6]2)[N:15]=[C:16]2[C:17]=1[N:21]([CH2:28][CH3:29])[C:31](=[O:30])[NH:22]2
Reactant: CCI
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc(N)c1N
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(=O)[nH]c2nc(-n3nc(Cc4ccccc4F)c4ncccc43)nc(N)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.392 mmol) of 2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidine-4,5,6-triamine (example 2A) were initially charged in tetrahydrofuran (11.1 ml) and the suspension was cooled to 0° C. Subsequently, 0.43 ml (0.43 mmol) of bis(trimethylsilyl)sodium amide solution (1.0 M in tetrahydrofuran) was added and the mixture was stirred at 0° C. for a further 30 min Thereafter, 31.3 μl (0.392 mmol) of iodoethane were added dropwise and the reaction mixture was stirred at RT overnight. The reaction mixture was cooled again to 0° C. and a further 0.47 ml (0.47 mmol) of bis(trimethylsilyl)sodium amide solution was added. Thereafter, the reaction mixture was stirred at RT overnight and heated to reflux for a further 2 days. Subsequently, the reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. The crude product was extracted by stirring in methyl tert-butyl ether, and the solids were filtered off and dried under high vacuum. This gave 4.6 mg (2.9% of theory) of the title compound in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=1.C(OO)(=[O:19])C.C(O)(=O)C.[OH2:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=1)(=[O:19])=[O:26]
Reactant: CC(=O)OO
Reactant: O=c1ccc(Sc2ccc(Cl)cc2Cl)n[nH]1
Reactant: O
Solvent: CC(=O)O
Product: O=c1ccc(S(=O)(=O)c2ccc(Cl)cc2Cl)n[nH]1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 37 %

Procedure:
A mixture of 6-(2,4-dichloro-phenylsulfanyl)-2H-pyridazin-3-one (418 mg), peracetic acid (3.2 mL) and acetic acid (3.2 mL) was prepared and stirred for 2.5 hours at 80° C. The reaction mixture was then cooled to room temperature and poured into water (50 mL). The resulting white solid was collected and dried to obtain the title product, 6-(2,4-dichloro-benzenesulfonyl)-2H-pyridazin-3-one, (37%, 173 mg); mp, 202-203° C.; NMR 7.15 (d, 1H), 7.81 (dd, 1H), 8.03 (m, 2H), 8.25 (d, 1H), 13.88 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].[N:27]1([C:32]2[N:37]=[C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[CH:35]=[C:34]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[N:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1.P([O-])(O)(O)=O.[Na+]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:9]1[CH2:10][O:11][C:15]([N:41]1[CH2:42][CH2:43][N:38]([C:36]2[CH:35]=[C:34]([N:44]3[CH2:45][CH2:46][CH2:47][CH2:48]3)[N:33]=[C:32]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:37]=2)[CH2:39][CH2:40]1)=[O:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(=O)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
A solution of 3 g of BOC-(L)-prolinol in 100 ml of anhydrous THF, cooled at 0° C. with water/ice, under stirring and inert gas atmosphere, is added with 2.9 g of carbonyldiimidazole in portions, then the reaction mixture is warmed to room temperature and stirring is continued for 3 hours. Said solution is added with 4.5 g of N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine in portions and stirring is continued for 18 hours. The reaction mixture is added with 400 ml of an aqueous saturated solution of sodium dihydrogen phosphate and extracted with ethyl acetate (3×100 ml). The combined organic extracts are dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue (7.5 g) is purified by silica gel chromatography (eluent hexane/ethyl acetate 7:3), to obtain 5.5 g of (-)-N'-[(1-(tertbutoxycarbonyl) pyrrolidin-2-yl) methyloxycarbonyl]-N-[2,6-bis(pyrrolidin -1-yl)pyrimidin -4 -yl]piperazine, m.p. 147° C., [(α]D-32'(c=0.25 in EtOH).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[C:18]2[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH2:22])[N:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:8][C:9]1[C:18]2[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:22][C:5](=[O:7])[CH3:6])[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)cc2c([N+](=O)[O-])cccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc2c([N+](=O)[O-])cccc2c(C)n1
Reaction time: 3.5 h
Yield: 32.6 %

Procedure:
Acetic anhydride (1.4 mL, 15 mmol) was added to a suspension of Example 141C (5 mmol) and triethylamine (0.76 mL, 5.5 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred for 3.5 hours, then the volatiles were removed under reduced pressure. The residue was chased with toluene (3×25 mL) and concentrated under reduced pressure to afford the title compound (0.40 g, 33% yield over three steps). MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[C:3]1=[O:24].[CH2:25](I)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:25]([N:7]1[C:6]2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])[C:3](=[O:24])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[CH3:26]
Reactant: CCI
Reactant: CCOP(=O)(CCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2CC)n(C)c1=O)OCC
Temperature: 60 °C

Procedure:
7.2 g (0.02 mol) of diethyl [4-(3-methylxanthin-1-yl)-butyl]phosphonate were suspended in 100 ml of DMF, treated with 4.7 g (0.03 mol) of ethyl iodide and 4.1 g (0.03 mol) of activated potassium carbonate and heated at 60° C. for 4 hours. The solid was filtered off, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate, filtered again and crystallized from diisopropyl ether.