Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([CH3:25])[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:24])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:23])[CH2:16]2)[C@:19]2([CH3:22])[C@H:4]([CH2:3][C@@:2]([OH:1])([CH3:25])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Solvent: O
Product: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C1

Procedure:
A stirred solution of 3α-hydroxy-3β-methyl-5α-pregnane-11,20-dione (17) (5.0 g., 15.0 mmole) in methanol (300 ml.) was treated with a solution of bromine (1.0 ml.) in methanol (30 ml.) at 0° and at such a rate that the yellow colour of the solution disappeared before further addition of the bromine solution took place. The mixture was then poured into water; the precipitated title compound (2.8 g.) was collected by filtration and dried over P2O5 in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:18])[CH3:17]
Reactant: Cc1ccc(NCc2ccccc2)cc1
Reactant: CC(C)P(=O)(Cl)Cl
Product: Cc1ccc(N2Cc3ccccc3P2(=O)C(C)C)cc1
Yield: 32 %

Procedure:
The procedure of Example 1 was employed utilizing N-(4-methylphenyl)-N-benzylamine and isopropyl phosphonic dichloride to yield 1-isopropyl-2-(4-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (5.4 g, 32% yield) as white crystals having a melting point of 135°-137° C. and the following analysis:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C:6](=[O:29])[C@@H:7]3[C@@H:22]2[CH2:21][C@H:20]([OH:27])[C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.O[C@@H]1CC[C@@]2(C)[C@H](C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(O)=O)C1>>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C@H:6]([OH:29])[C@@H:7]3[C@@H:22]2[CH2:21][C@H:20]([OH:27])[C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
The procedure of Example 1 is followed except that an equivalent amount of 3α, 12α-dihydroxy-7-keto-5β-cholanoic acid is substituted for the 3α, 7α-dihydroxy-5β-cholanoic acid to yield 3α, 7β, 12α-trihydroxy-5β-cholanoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][C@@H:18]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:35]([O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:27]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:19]3[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:53])[CH:3]=1.[CH2:54]([O:61][C:62]([N:64]([CH2:69][CH2:70][C:71]([NH2:73])=[O:72])[CH2:65][CH2:66][CH2:67]Br)=[O:63])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:54]([O:61][C:62]([N:64]([CH2:65][CH2:66][CH2:67][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][C@@H:18]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:35]([O:36][C:37](=[O:42])[C:38]([CH3:39])([CH3:41])[CH3:40])[C@H:27]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C@H:19]3[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:53])[CH:3]=1)[CH2:69][CH2:70][C:71](=[O:72])[NH2:73])=[O:63])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: Cc1cc(O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: NC(=O)CCN(CCCBr)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(OCCCN(CCC(N)=O)C(=O)OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.4 g), 3-[N-benzyloxycarbonyl-N-(3-bromopropyl)amino]propionamide (0.28 g) and tetra(n-butyl)ammonium bromide (87 mg) in dichloromethane (4 mL) was added 5 mol/L aqueous sodium hydroxide solution (0.32 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/3-1/6) to give the title compound (0.42 g).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: Fc1cc(Cl)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of potassium tert-butoxide (1.6 g) in anhydrous tetrahydrofuran (75 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.5 g). After stirring at 0° C. for 45 minutes a solution of 1-bromomethyl-4-chloro-2-fluorobenzene (2.6 g) in tetrahydrofuran (25 mL) was added and the resulting mixture stirred at room temperature for 17 hours. The mixture was diluted with water and the tetrahydrofuran removed under reduced pressure. The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:19 to 1:9 by volume) to afford title compound, 1.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:28])=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cn[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
In benzene (10 ml) was dissolved 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (1.54 g), and to the solution was added m-chloroperbenzoic acid (1.72 g). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (300 ml), saturated sodium hydrogen carbonate solution (300 ml) and sodium nitrite (500 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one-1-oxide (478 mg) as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.ClCCl>[CH2:24]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[N:3]=[CH:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(-c2ncc(-c3c[nH]cn3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc(Cn2cnc(-c3cnc(-c4ccccc4)nc3)c2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 36.5 %

Procedure:
To a solution consisting of 5-(1H-imidazol-4-yl)-2-phenylpyrimidine (Step B, 0.050 g, 0.193 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.133 g, 0.965 mmol) at room temperature under dry conditions. After heating the reaction mixture in an 80° C. oil bath for one hour, benzyl bromide (Aldrich, 0.039 g, 0.231 mmol) was added to the mixture. The solution was left stirring in an 80° C. oil bath for 24 hours. Upon cooling, the reaction was diluted with dichloromethane (100 mL) and washed with saturated aqueous ammonium chloride (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica. Elution through an 8-g Silicycle® flash silica cartridge with gradient of 100% dichloromethane to 5% methanol in dichloromethane afforded the title compound as a white solid (22 mg, 36%). Rf 0.56 with 95:5 v/v dichloromethane-methanol; melting point 195° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.25 (s, 2H), 8.44-8.42 (m, 2H), 8.03 (s, 2H), 7.56-7.54 (m, 3H), 7.45-7.36 (m, 5H), 5.38 (s, 2H); MS (ESI+) m/z 313.1 (M+1); H-PGDS FPBA IC50: 4 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(O)=[O:22].OO.S([O-])([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:22]
Reactant: O=CO
Reactant: CSc1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CS(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (683.2 mg, 2.18 mmol), formic acid (2.47 mL, 65.5 mmol), and water (0.41 mL) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (1.11 mL, 10.9 mmol). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was treated with a saturated aqueous sodium sulfite solution. The resulting solution was poured into water (50 mL) and was then extracted into methylene chloride (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2(R)-(3-chloro-4-methanesulfinyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (724 mg, 100%) as a white foam: EI-HRMS m/e calcd for C15H17ClO4S (M+Na)+ 351.0428, found 351.0433.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([N:13]2[N:17]=[N:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:14]2)[CH2:10][CH:9]1[C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]#[N:41])[CH2:30][CH2:29]1)=[O:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:15]1[N:16]=[N:17][N:13]([C@@H:11]2[CH2:12][NH:8][C@H:9]([C:26]([N:28]3[CH2:29][CH2:30][N:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]#[N:41])[CH2:32][CH2:33]3)=[O:27])[CH2:10]2)[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2nnc(-c3ccc(F)cc3F)n2)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reaction time: 5 h
Yield: 87.9 %

Procedure:
2-[4-(2-Cyano-phenyl)-piperazine-1-carbonyl]-4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.184 g, 0.33 mmol) was added to CF3COOH (0.22 g, 1.95 mmol), and the reaction mixture was stirred for 5 h. After removal of CF3COOH, the residue was dissolved in DCM, washed with sat. NaHCO3, brine, dried and concentrated to give title product as yellow oil (0.136 g, 0.29 mmol). MS m/e=465.2 [M+H]+.
Reaction SMILES: O[NH:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[NH:23]O)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[NH:4].[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C.[Pd]>[C:26]([OH:29])(=[O:28])[CH3:27].[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:7]3[O:6][C:5]([C:3]([NH2:4])=[NH:2])=[CH:9][CH:8]=3)=[CH:11][CH:12]=2)=[CH:21][CH:20]=1)(=[NH:23])[NH2:25]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(NO)c1ccc(-c2ccc(-c3ccc(C(=N)NO)o3)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)o3)cc2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 3 (1 mmol) in glacial acetic acid (10 mL) was slowly added acetic anhydride (0.35 mL). After stirring for overnight TLC indicated complete acylation of the starting material, then was added 10% palladium on carbon (80 mg). The mixture was placed on Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered through hyflo and the filter pad washed with water. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 5 in 71% yield, mp 236-238° C. 1H NMR (D2O/DMSO-d6); δ 1.78 (s, 2×CH3), 7.31 (d, J=3.6 Hz, 1H), 7.61 (d, J=3.6 Hz, 1H), 7.85-8.11 (m, 8H). EIMS m/e (rel. int.); 304 (M+, 20), 287 (100), 270 (50), 216 (30), 190 (10). High resolution Calc. for C18H16N4O ms 304.13241. Observed 304.13201. Anal. Calc. for C16H14N4O2-2.0AcOH-1.75H2O-0.25EtOH: C %, 57.81; H %, 6.25; N %, 11.98; Found. C %, 58.18; H %, 5.90; N %, 11.56.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]N)=[CH:16][CH:15]=1.CS(C)=O.CCN(CC)CC>O.II>[F:1][C:2]1[C:8]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4]
Reactant: NCc1ccc(Br)cc1
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Agent: II
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1c([N+](=O)[O-])ccc(Cc2ccc(Br)cc2)c1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A round bottom flask was charged with 2,3-difluoro-6-nitroaniline (0.50 g, 2.87 mmol, 1.00 equiv.) and 4-bromobenzylamine (0.959 g, 5.15 mmol, 1.80 equiv.). Dimethyl sulfoxide (2.5 mL) was then added flowed by Et3N (0.968 mL, 6.88 mmol, 2.40 equiv.) and I2 (catalytic, 10 mg). The reaction mixture was heated to 120° C. and stirred for 3 h. The reaction mixture was then cooled to ambient temperature, diluted with water (75 mL) and extracted with Ethyl acetate (2×60 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude material, which was purified by silica gel column chromatography (10% ethyl acetate/hexane) to afford compound 3 as the desired product (0.869 g, 89%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[C:18](\[O:23][CH3:24])/[C:19]([O:21][CH3:22])=[O:20])[CH:14]=[CH:13][C:12]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([O:34]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:26]=1)[CH2:7][CH2:8][CH3:9].O.C(OCC)(=O)C>CN(C)C=O>[CH2:6]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[C:18](\[O:23][CH3:24])/[C:19]([O:21][CH3:22])=[O:20])[CH:14]=[CH:13][C:12]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:44])[C:32]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:34])[CH:26]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1-c1cccc(N(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
0.075 mL (0.75 mmol) of n-butylamine is added to a solution of 0.4 g (0.6 mmol) of methyl (Z)-3-{2-butoxy-3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}-2-methoxyacrylate in 5 mL of dimethylformamide. The reaction mixture is rapidly placed in an oil bath preheated to 80° C. and then stirred at 80° C. for 3 hours. After cooling, the reaction is stopped by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.2 g (67%) of methyl (Z)-3-[2-butoxy-3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]2([OH:85])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]2)=[C:73]([CH3:86])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]4([OH:85])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]4)=[C:73]([CH3:86])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])[CH:10]=1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 39 mg, 0.171 mmol), palladium acetate (2.5 mg, 0.011 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.0 mg, 0.022 mmol), potassium phosphate (73 mg, 0.342 mmol) and water (0.2 mL) were added to a solution of 4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-pyran-4-ol (Example 131-(3); 57.4 mg, 0.114 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for three hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (29.1 mg, 48%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[N+]=[N-].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCOP(=O)(CCOCCN=[N+]=[N-])OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCOCCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 2-(2-azidoethoxy)ethylphosphonate (1 eq) was dissolved in EtOH (0.1 M). Pd(OH)2 (0.05 eq) was added to the reaction. Hydrogen gas was introduced via a balloon; and the reaction was stirred for 2 hours at room temperature. The mixture was filtered through Celite and washed with MeOH. The solvent was removed en vaccuo and the crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM with 2% NH3 in methanol to give the product as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][C:16]1[N:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])=[CH:24][CH:23]=2)[C:18](=[O:21])[NH:19][N:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:19]1[C:18](=[O:21])[N:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])=[CH:26][CH:27]=2)[C:16]([CH3:15])=[N:20]1)[CH3:13]
Reactant: Cc1n[nH]c(=O)n1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: Cc1nn([C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)c(=O)n1-c1ccc(OC(F)(F)C(F)F)cc1
Yield: 48.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.50 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.58 g of 5-methyl-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.46 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-5-methyl-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=3)=[CH:11][C:12](=[O:14])[CH:13]=2)[CH:3]=1.OCCN1CCNCC1>ClC1C=CC=CC=1>[N:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:8]1[NH:9][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:11][C:12](=[O:14])[CH:13]=1
Reactant: O=c1cc(-c2cc(Cl)ccn2)[nH]c(-c2cc(Cl)ccn2)c1
Agent: OCCN1CCNCC1
Solvent: Clc1ccccc1
Product: O=c1cc(-c2ccccn2)[nH]c(-c2ccccn2)c1

Procedure:
A mixture of 3.18 9 (10 mmol) 4,4″-dichlor-1′H-[2,2′;6′,2″]terpyridin-4′-on, 5.21 g (40 mmol) 1-(2-hydroxyethyl)-piperazin, and 30 mg Zn(II)-chloride in 300 ml chlorobenzol is refluxed for 18 hours. Afterwards the solution is concentrated by a rotary evaporator. The raw product is recrystallized from 40 ml water respectively 30 ml methanol. The whitish 4,4″-Bis-[4-(2-hydroxy-ethyl)-piperazin-1-yl)]-1′H-[2,2′;6′,2″]terpyridin-4′-on is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](/[C:37]3[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=3)\[CH3:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (84 mg, 0.359 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol) and K3PO4 (183 mg, 0.862 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 55 mg. 1HNMR (DMSO-d6, Oxalate salt) δ (ppm): 7.82 (m, 1H), 7.62 (s, 1H), 7.55 (m, 2H), 7.20 (m, 2H), 7.12 (d, 1H), 3.38 (m, 4H), 3.10 (m, 4H), 2.90 (s, 3H), 1.80 (s, 3H).