Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[C:32]([F:38])[CH:31]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][C:32]=3[F:38])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: C#Cc1ccc(Cl)cc1F
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4ccc(Cl)cc4F)cc3F)[nH]c2=O)c1)C1CC1
Yield: 47.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 4-chloro-1-ethynyl-2-fluorobenzene (Intermediate-49, 0.022 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.025 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65-0.68 (m, 4H), 1.60 (m, 1H), 4.32 (d, J=6.0 Hz, 2H), 7.33-7.52 (m, 3H), 7.55-7.74 (m, 5H), 7.90 (m, 1H), 8.68 (m, 1H), 12.0 (br s, 1H).; MS (m/z): 539.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])N.[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:12]([N:11]([CH3:10])[C:15](=[O:16])[CH:14]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN1C(=O)C=CC1=O
Product: CN1C(=O)C=C(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
A 162 g portion of 3,4-dichloroaniline was reacted with 111 g of N-methylmaleimide as described in Example 6, giving 112 g of 2-(3,4-dichlorophenyl)-N-methylmaleimide.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1[CH:11]=[CH:10][CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cccnc1-c1ccncc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of ethyl 2-chloronicotinate (16.2 g), pyridine-4-boronic acid (12.9 g), sodium carbonate (27.8 g), tetrakis(triphenylphosphine)palladium(0) (5.04 g), water (50.0 mL) and DME (250 mL) was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (14.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:9]([O-:12])(=[O:11])=[O:10])[N:3]=1.[Na+:13]
Reactant: O=S([O-])[O-]
Reactant: Fc1cccc(F)n1
Agent: [Na+]
Product: O=S(=O)([O-])c1cccc(F)n1
Yield: 10.5 %

Procedure:
In the same manner as in Example 1, 1.725 g (15 mmol) of 2,6-difluoropyridine and 2.27 g (18 mmol) of sodium sulfite were reacted at 170° C. for 5 hours. By conducting the same post-treatment as in Example 1, 0.315 g (10.5%) of sodium 2-fluoropyridine-6-sulfonate was obtained.
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C1COCC1>[Br:30][CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CO)o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
5-Hydoxymethylfuran-2-carbononitrile (1.12 g, 9.1 mmol) is dissolved in THF (75 mL), treated with triphenylphosphine (2.9 g, 11.06 mmol), carbon tetrabromide (3.78 g, 11.4 mmol) and stirred at room temperature for 18 hours. Standard workup yields the title compound (1.45 g, 7.8 mmol).
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([O:27]C)=[O:26])[CH:6]=1)[CH2:3][OH:4].C1COCC1.O[Li].O>O>[OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([OH:27])=[O:26])[CH:6]=1)[CH2:3][OH:4]
Reactant: COC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 8 h

Procedure:
To the crude (S)-methyl 4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinate (assume 0.884 mmol) in 5 mL of a 5:1 mixture of THF and water was added LiOH.H2O (0.084 g, 2.00 mmol). The reaction was stirred overnight then evaporated in vacuo. The residue was dissolved in 5 mL water, filtered and acidified with 2.00 mL 1N HCl. The mixture was evaporated in vacuo to give the product (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid mixed with lithium chloride (LC/MS: m/z=370.2 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:16]=[C:17]([OH:23])[CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(F)n1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(O)n1

Procedure:
The title compound, light yellow solid, MS: m/e=310.1, 312.0 (M+H), was prepared in accordance with the general method of example 1a from 2-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-6-fluoro-pyridine and KOH in tert-butanol.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCBr
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (273 mg, 1.08 mmol) and 1-bromododecane (671 mg, 2.69 mmol), alcohol 31 was obtained as a colorless oil (195 mg, 43% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:24][N:45]1[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]2[C:49]1=[O:50])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, V., and Buenger, G. S., Org. Prep. Procedures Int., 22:57 (1990) in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to OIC and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ0.05 [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2' CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-15 4.35 (m, 1, 4'H), 5.0 (m,1,3'H), 6.15 (m, 1, 1'H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H31N3O7Si: C, 57.46;H , 6.23; N, 8.37. found : C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH3:17])=[CH:15][C:14](=[O:18])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]=[CH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:15][C:14](=[O:18])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1cc(=O)c(C(=O)O)cn1-c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(C=Cc2ccncc2)cc1=O
Yield: 44.1 %

Procedure:
To 0.7 g of 1-(4-fluorophenyl)-6-methyl-4-oxo-1,4-dihydronicotinic acid was added 0.33 g of isonicotinaldehyde and 0.61 g of acetic anhydride, and they were refluxed for 5 hours. After completion of the reaction, 30 ml of water was added to the reaction mixture, and the mixture was successively extracted with three 30-ml portions of chloroform. The chloroform layer was separated, washed with 20 ml of a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 0.42 g of 1-(4-fluorophenyl)-6-[2-(pyridin-4-yl)ethenyl]-4-oxo-1,4-dihydronicotinic acid having a melting point of 205°-215° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([N:16]=[C:17]=[S:18])=[CH:10][C:9]=2[F:19])[CH:7]=1>>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([NH:16][C:17]([NH2:1])=[S:18])=[CH:10][C:9]=2[F:19])[CH:7]=1
Reactant: COc1cc(N=C=S)cc(F)c1-n1cnc(Cl)c1
Reactant: N
Product: COc1cc(NC(N)=S)cc(F)c1-n1cnc(Cl)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
Step M (8): Methanolic ammonia (2.0 M, 5 mL, 10 mmol) was added to a flask charged with 4-chloro-1-(2-fluoro-4-isothiocyanato-6-methoxyphenyl)-1H-imidazole (230 mg, 0.811 mmol). After 2 h, the reaction mixture was concentrated in vacuo to afford 1-(4-(4-chloro-1H-imidazol-1-yl)-3-fluoro-5-methoxyphenyl)thiourea (244 mg, 100% yield). LC-MS (M+H)+ 301.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=[O:9].C(O)(C(F)(F)F)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])(=[O:9])=[O:28]
Reactant: CS(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1Cl
Reactant: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)O)cc1Cl

Procedure:
A solution of the product from step d) (73 mg) in TFA (3 ml) was stirred for 2 h. The solvent was removed in vacuo, water was added and the mixture was extracted with dichloromethane (three times). The organic extracts were dried (MgSO4), evaporated and triturated with ether to give the title compound (46 mg) as a white solid. M.p. 140-2° C.
Reaction SMILES: Br[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[F:11]
Reactant: N#Cc1cccc(F)c1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1cccc(F)c1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 2 to give 6,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (400 z, CDCl3) 7.40-7.44 (1H, m), 7.47-7.52 (1H, m), 7.59-7.67 (2H, m), 8.37-8.44 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[CH:7]=[CH:6][C:5]=1[Cl:12].C[Si]([N:18]=[N+:19]=[N-:20])(C)C>C(O)CCC>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:20][NH:19][N:18]=2)[CH:7]=[CH:6][C:5]=1[Cl:12]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)c(C(=O)OC)c1
Solvent: CCCCO
Product: COC(=O)c1cc(-c2cn[nH]n2)ccc1Cl
Yield: 43.5 %

Procedure:
A mixture of 2-chloro-5-ethynyl-benzoic acid methyl ester (0.18 g, 0.92 mmol) and trimethylsilyl azide (0.16 g, 1.39 mmol) in n-butanol was heated to reflux for 16 h. A second portion of trimethylsilyl azide (0.16 g, 1.39 mmol) was added and the mixture was refluxed for a further 16 h. A third portion of trimethylsilyl azide (0.16 g, 1.39 mmol) was added and the mixture was refluxed for a further 16 h. Silica gel was added and the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexanes-ethyl acetate) to afford the title compound (0.095 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[CH3:31][C@H:32]1[NH:37][C@@H:36]([CH3:38])[CH2:35][N:34]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:33]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:37]3[C@H:36]([CH3:38])[CH2:35][N:34]([C:39]4[CH:48]=[CH:47][C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=4)[CH2:33][C@@H:32]3[CH3:31])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(CNC(=O)C2(CCCCN3[C@H](C)CN(c4ccc5ccccc5n4)C[C@@H]3C)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[N:10]=1)=[O:8]>>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:3])[N:10]=1)=[O:8]
Reactant: COC(=O)c1cccc(CO)n1
Reactant: O=S(Cl)Cl
Product: COC(=O)c1cccc(CCl)n1
Reaction time: 1 h

Procedure:
5 ml of thionyl chloride is slowly added to 2.50 g of 6-(hydroxymethyl)-2-pyridinecarboxylic acid methyl ester at 0° C. under nitrogen and stirred for 1 hour. The reaction mixture is concentrated by evaporation in a vacuum. The thus obtained residue is mixed with 15 ml of saturated sodium bicarbonate solution and extracted three times with 25 ml of toluene each. After the drying on sodium sulfate and filtration, it is concentrated by evaporation in a vacuum. 2.37 g of the title compound is obtained, which is further used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:31])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:31])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:3]1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1

Procedure:
The title compound was produced in analogy to example 3, steps 1 and 2. Thus, reaction of (R)-6-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-2-methylpyridazin-3(2H)-one (example 25, step 1) with (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide produced 4-{4-[(R)-3-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester, which after cleavage of the tert-butoxycarbonyl group led to (R)-2-methyl-6-(3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropanoyl)pyridazin-3(2H)-one. This compound was then reacted with methanesulfonyl chloride to afford the title compound. White solid, MS: 494.3 [M+H]+.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:14][O:15][C:16]1([O:33][CH3:34])[C@H:29]([OH:30])[C:28]2[C:19](=[CH:20][N:21]=[C:22]3[C:27]=2[CH:26]=[C:25]([OH:31])[CH:24]=[CH:23]3)[C@@H:18]([CH3:32])[CH2:17]1>CN(C)C=O>[O:31]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[C:28]3[C:19](=[CH:20][N:21]=2)[C@@H:18]([CH3:32])[CH2:17][C:16]([O:15][CH3:14])([O:33][CH3:34])[C@@H:29]3[OH:30])[CH:26]=1)[Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: COC1(OC)C[C@H](C)c2cnc3ccc(O)cc3c2[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC1(OC)C[C@H](C)c2cnc3ccc(O[Si](C)(C)C(C)(C)C)cc3c2[C@H]1O
Temperature: 23 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Imidazole (1.01 g, 14.8 mmol, 2.60 equiv) and t-butyldimethylsilyl chloride (1.11 g, 7.39 mmol, 1.30 equiv) were added sequentially to a solution of (7S, 10R)-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-2,10-phenanthridinediol (16, 1.64 g, 5.69 mmol, 1 equiv) in N,N-dimethylformamide (10 mL) at 23° C. After stirring for 1 h at 23° C., the reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was separated and extracted further with two 100-mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by flash column chromatography (30% ethyl acetate-hexanes) to afford (7S,10R)-2-(tert-butyldimethylsiloxy)-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-10-phenanthridinol (17) as a light yellow foam (2.10 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH:8]=[CH:7]1.CN1CCOCC1>CCOC(C)=O>[CH3:1][O:2][C:3]([N:10]1[C:6](=[O:12])[CH:7]=[CH:8][C:9]1=[O:11])=[O:4]
Reactant: COC(=O)Cl
Reactant: O=C1C=CC(=O)N1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)N1C(=O)C=CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
Methylchloroformate (4.4 mL, 56.7 mmol, 1 eq) was added to a solution of maleimide (5.5 g, 56.7 mmol, 1 eq) and NMM (6.2 mL, 56.7 mmol, 1 eq) in 200 mL of EtOAc at 0° C. The suspension was stirred at 0° C. for 30 minutes, filtered and washed with EtOAc. Filtrate and washings were combined and washed with cold water and dried over anhydrous Na2SO4. After filtration and evaporation under vacuum a pink solid was obtained. Purification by column chromatography on silica gel (Hexane-EtOAc, 1:1, v/v) provided the product (4.8 g, 55%).
Reaction SMILES: II.[NH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16](=[O:19])[N:17]([CH3:18])[C:10]=23)=[CH:6][CH:5]=1.[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[CH3:18][N:17]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:20]=[CH:21][C:4]([NH:3][C:32]([NH:31][C:29]3[N:28]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[N:27]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:30]=3)=[O:33])=[CH:5][CH:6]=2)[NH:15][C:16]1=[O:19]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(F)cc2)n1
Reactant: Cn1c(=O)[nH]c2nccc(Oc3ccc(N)cc3)c21
Agent: II
Product: Cn1c(=O)[nH]c2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(F)cc4)cc3)c21
Yield: 34.9 %

Procedure:
Method I2 was used with 7-(4-aminophenoxy)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (25 mg, 0.1 mmol) and phenyl 3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl-carbamate (42 mg, 0.12 mmol) to afford the title compound (18 mg, 35%). 1H-NMR (δ, ppm, DMSO-d6): 1.29 (s, 9H, t-Bu), 3.46 (s, 3H, CH3N), 6.37 (s, 1H, HPyz,4), 6.41 (d, 1H, HPy,6), 7.13 (d, 2H, Harom,Ph,3+5), 7.38 (t, 2H, Harom,4-F-Ph,3+5), 7.48 (d, 2H, Harom,Ph,2+6), 7.57 (dd, 2H, Harom,4-F-Ph,2+6), 7.80 (d, 1H, HPy,6), 8.38 (s, 1H, NHurea), 9.08 (s, 1H, NHurea), 11.61 (bs, 1H, NHPy3). LC-MS (m/z): 516 (M+H, 100). Acc. mass (C27H26N7O3F): calculated 516.2159, found 516.2086.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.[OH-].[K+].C(O)(=O)C(O)=O>CO>[O:37]1[C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9][CH:8]1/[CH:7]=[CH:6]/[CH2:5][CH2:4][C:3]([OH:38])=[O:2]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(/C=C/CCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(/C=C/CCC(=O)O)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 480 mg of (4E,13E)-(6RS,9α,11α,15S)-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prosta-4,13-dienoic acid methyl ester (prepared as described in Example 7) in 3 ml of methanol was added 5 ml of a 5% aqueous solution of potassium hydroxide at 45° to 50° C., and the mixture was stirred for one hour at the same temperature. The reaction mixture was then acidified to pH 5 to 6 with an aqueous solution of oxalic acid and extracted with ethyl acetate. The extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethanol (20:1) as eluent to give 460 mg of the title compound having the following physical characteristics: