Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=2)[CH:6]=1
Reactant: Cc1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc(C(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc(C(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (35 mg, 72.4 μmol) in dichloromethane (1.1 mL) was added trifluoroacetic acid (165 mg, 112 μL, 1.45 mmol) and the mixture stirred at room temperature for 20 h. The mixture was concentrated in vacuo and then the residue diluted with dichloromethane and a few drops of 25% aqueous NH4OH added until the mixture was measured at pH˜8. The mixture was then washed with water, the organic phase collected, concentrated in vacuo, and finally purified by chromatography (silica, 3 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxamide (15 mg, 39.1 μmol, 54%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.64 (s, 1H), 6.79 (d, J=4.3 Hz, 1H), 6.73 (s, 1H), 6.60 (s, 1H), 3.90 (s, 1H), 2.98 (m, 1H), 2.27 (s, 3H), 1.52-1.76 (m, 6H), 1.38 (m, 2H), 1.27 (d, J=7.0 Hz, 6H); MS (EI/CI) m/z: 384.1 [M+H].
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:36]1[CH:40]=[CH:39][CH:38]=[N:37]1>>[C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:36]4[CH:40]=[CH:39][CH:38]=[N:37]4)=[CH:19][C:18]=3[C:24]([F:26])([F:27])[F:25])(=[O:16])=[O:15])[CH2:11][CH:10]2[C:28]([N:30]2[CH2:33][C:32]([F:34])([F:35])[CH2:31]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: N#CC1(NC(=O)C2CC(S(=O)(=O)c3ccc(-n4cccn4)cc3C(F)(F)F)CC2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and pyrazole. White foam. MS (EI): 572.14 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O[C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.BrCCCCBr>CN(C)C=O>[NH:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][CH:17]=2)[CH:12]=[CH:13][C:14]1=[O:18]
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCCCBr
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2[nH]1
Temperature: 60 °C

Procedure:
To a stirred suspension of anhydrous potassium carbonate (K2CO3) (10.50 g, 0.075 mol) in 100 mL of anhydrous N,N-dimethylformamide (DMF) was added 7-hydroxyquinolinone 1 (10.00 g, 0.06 mol) followed by 1,4-dibromobutane 2 (25.91 g, 0.12 mol). The resulting mixture was heated at 60° C. for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC) technique. After cooling to room temperature, the reaction mixture was filtered through a sintered funnel and the precipitate was washed with ethyl acetate (25 mL×2). The combined filtrate was concentrated on a rotavapor. The residue was diluted with 250 mL of ethyl acetate, washed with water (100 mL×2), dried over anhydrous magnesium sulfate and evaporated the solvent. The residue was triturated with hexane and then filtered the precipitate to give the pure title compound 3. White solid, 12.88 g (72%). 1H NMR (400 MHz, CDCl3): δ 1.92-1.97 (m, 2H); 2.05-2.10 (m, 2H); 2.64 (t, J=9.2 Hz, 2H); 2.92 (t, J=9.2 Hz, 2H); 3.50 (t, J=7.6 Hz, 2H); 3.98 (t, J=7.6 Hz, 2H); 6.37 (d, J=3.2 Hz, 1H); 6.50-6.54 (m, 1H); 7.04 (d, J=11.2 Hz, 1H), 8.61 (broad s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C1C=CC=CC=1.N1C=CC=CC=1>O>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reaction time: 24 h
Yield: 916 %

Procedure:
4-n-Butylbenzoyl chloride (39, 2 g, 0.2 m) was added dropwise to a solution of 4-hydroxybenzaldehyde (24.4 g), (0.2 m) anhydrous benzene (320 ml) and dry pyridine (30 ml) with stirring. After completion of addition stirring was continued for 24 hours at room temperature. The resulting reaction mixture was poured into cold water. The organic layer was separated and washed with diluted hydrochloric acid solution, diluted potassium hydroxide solution and water, then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield p-(4'-n-butylbenzoyloxy)benzaldehyde (26.3 g, 46%) mp 49.7° C.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:14]=1)=[O:12]>CO.O1CCCC1.ClCCl.ClCCl>[ClH:10].[NH:4]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:14]=1)=[O:12])[C:3]([NH2:5])=[NH:2]
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: N=C(N)NC(=O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
0.974 g (10.2 mmol) of guanidine hydrochloride is added to a solution of 0.55 g (10.2 mmol) of sodium methoxide in 10 cm3 of methanol at a temperature in the region of 22° C. under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 2 hours, the solvent is evaporated off under reduced pressure (2.7 kPa). The residue, placed under an argon atmosphere, is taken up in 20 cm3 of a tetrahydrofuran/dichloromethane (1/1 by volume) mixture and then 0.7 g (2.04 mmol) of 3-chlorocarbonyl-1-(isoquinol-3-yl)-1H-indole hydrochloride, dissolved in 5 cm3 of the same tetrahydrofuran/dichloromethane mixture, is added thereto. After 15 hours at a temperature in the region of 22° C. and then heating at a temperature in the region of 60° C. with stirring for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in dichloromethane. The insoluble material is then filtered off and discarded, and the filtrate is concentrated under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 by volume)]. After concentrating the fractions under reduced pressure, 0.263 g of 3-guanidinocarbonyl-1-(isoquinol-3-yl)-1H-indole hydrochloride is obtained in the form of a white solid which decomposes at 235° C. Mass spectrum (EI): m/e 329 (M+·), m/e 271. IR spectrum (KBr): 3392, 1692, 1629, 1593, 1538, 1514, 1462, 1227, 1202 and 747 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][S:15]([CH:18]3[CH2:20][CH2:19]3)(=[O:17])=[O:16])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=2)[CH2:3]1.[C:34](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([N:14]([CH3:34])[S:15]([CH:18]3[CH2:20][CH2:19]3)(=[O:17])=[O:16])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:22]=2)[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2)S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
To a mixture of cyclopropanesulfonic acid [4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (100 mg, 0.21 mmol), and potassium carbonate (89.4 mg, 0.64 mmol) in N,N-dimethylformamide (4 mL) was added idomethane (0.02 mL, 0.32 mmol). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was extracted with ethyl acetate (2×50 mL), washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methyl-amide (20 mg, 19%) as a white solid: MS (ESI) M+1=484.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:4]3[N:5]([C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=2[Cl:30])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)ccn2c1=O
Temperature: 200 °C
Yield: 32 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (20 mg, 0.05 mmol), 2,4-dichlorophenylboronic acid (38 mg, 0.20 mmol), and tetrakis(triphenylphosphine)palladium (3 mg, 0.002 mmol) in dioxane (0.4 mL) at 20° C. was added K2CO3 (30 mg, 0.2 mmol) in water (0.13 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (7 mg, 0.016 mmol) as a yellow oil. MS: [M+H]+=446.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O>>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1ccc(OCCCN2CCCCC2)cc1
Yield: 56.3 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-piperidin-1-yl-propoxy)-phenylamine (550 mg, 1.3 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (380 mg, 2.00 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (464 mg, 58%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[C:47]([CH2:52][CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[CH3:59])[CH:46]=[CH:45]2>COCCOC.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:59][C@@H:55]1[CH2:56][CH2:57][CH2:58][N:54]1[CH2:53][CH2:52][C:47]1[CH:46]=[CH:45][C:44]2[C:49](=[CH:50][CH:51]=[C:42]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[CH:43]=2)[N:48]=1
Reactant: OB(O)c1cccnc1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3cccnc3)ccc2n1
Temperature: 80 °C

Procedure:
Tetrakis(triphenylphosphine) palladium (0) (28.8 mg, 0.025 mmol), 2-(dicyclohexylphosphino)biphenyl (35.0 mg, 0.10 mmol), 3-pyridinylboronic acid (0.375 mmol), and sodium carbonate (40.0 mg, 0.375 mmol) were combined in 1,2-dimethoxyethane (4 mL) and water (1.5 mL). The mixture was then treated with the product from Example 42D (80 mg, 0.25 mmol) and heated at 80° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with HCl in IPA:ethyl acetate to give the trihydrochloride salt. mp 205-207° C.; MS (ESI) 318 (M+H)+; 1H NMR (DMSO-d6) δ 9.48 (1H, br, s), 9.05 (1H, d), 8.96 (1H, d), 9.00 (1H, d), 8.86 (1H, br, s), 8.60 (1H, d), 8.59 (1H, d), 8.32 (1H, dd), 8.23 (1H, d), 4.08 (1H, br, m), 3.90 (2H, br, m), 3.65 (2H, br, m), 3.46 (1H, q), 2.40 (1H, m), 2.19 (2H, m), 1.84 (1H, m), 1.58 (3H, d).
Reaction SMILES: [SH:1][CH2:2][C@@:3]12[C@@H:22]3[C@H:11]([C@H:12]4[C@:19]([CH3:23])([CH2:20][CH2:21]3)[C@@H:15]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:24])[CH2:5][CH2:4]2.[F:25][C:26]([F:37])([F:36])[C:27]([O:29]C(=O)C(F)(F)F)=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[F:25][C:26]([F:37])([F:36])[C:27]([OH:29])=[O:28].[SH:1][CH2:2][C@@:3]12[C@@H:22]3[C@H:11]([C@H:12]4[C@:19]([CH3:23])([CH2:20][CH2:21]3)[C@@H:15]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:24])[CH2:5][CH2:4]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CS)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of 3.47 g of 19-mercaptopregn-4-ene-3,20-dione and 4-dimethylaminopyridine in 50 ml of dichloromethane is chilled to 0° C. and treated with 4.2 ml of trifluoroacetic anhydride and 8.4 ml of triethylamine. The ice-bath is removed and the solution allowed to stir for 1 hour. The solution is concentrated. The residue is taken up in ether and washed once with 1N hydrochloric acid, twice with water and once with sodium bicarbonate solution and brine. The resulting solution is dried and concentrated. Recrystallization of the resulting residue from ethyl acetate/hexane provides 19-mercaptopregn-4-ene-3,20-dione trifluoroacetate as white crystals.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.[N+:35]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)([O-:37])=[O:36]>O1CCCC1.CCCCCC.O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]=[CH:42][C:41]2[CH:44]=[CH:45][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(CC=Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a suspension of [2-(4-methylphenyl)ethyl]triphenyl-phosphonium bromide (55.4 g) in anhydrous tetrahydrofuran (840 ml) kept at -50° C., a 1.5 N solution of n-butyl lithium in hexane (80 ml) was added, and the resultant mixture was stirred for a while. A solution of p-nitrobenzaldehyde (15.1 g) in anhydrous tetrahydrofuran (100 ml) was added thereto. The resulting mixture was allowed to stand at room temperature overnight, diluted with water and extracted with ethyl acetate. The extract was concentrated under reduced pressure and chromatographed on a column with silica gel, followed by eluting with a mixture of hexane and ethyl acetate to give 4-[3-(4-methylphenyl)-1-propenyl]nitrobenzene (21 g). nD24 1.5321.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)S(O[C:49]1[N:50]=[CH:51][C:52]2[C:57]([CH:58]=1)=[CH:56][CH:55]=[CH:54][C:53]=2[O:59][CH3:60])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:69][C:70]1[N:71]=[C:72]([O:78][C@H:79]([CH3:84])[CH2:80][N:81]([CH3:83])[CH3:82])[C:73]([C:76]#[N:77])=[N:74][CH:75]=1>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:83][N:81]([CH3:82])[CH2:80][C@H:79]([O:78][C:72]1[C:73]([C:76]#[N:77])=[N:74][CH:75]=[C:70]([NH:69][C:49]2[N:50]=[CH:51][C:52]3[C:57]([CH:58]=2)=[CH:56][CH:55]=[CH:54][C:53]=3[O:59][CH3:60])[N:71]=1)[CH3:84]
Reactant: C[C@H](CN(C)C)Oc1nc(N)cnc1C#N
Reactant: COc1cccc2cc(OS(=O)(=O)C(F)(F)F)ncc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc2cc(Nc3cnc(C#N)c(O[C@H](C)CN(C)C)n3)ncc12
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 0.2 %

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium (0) (7.9 mg, 0.009 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.017 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 8-Methoxyisoquinolin-3-yl trifluoromethanesulfonate (26.6 mg, 0.087 mmol), cesium carbonate (28 mg, 0.087 mmol) and (R)-5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (19 mg, 0.087 mmol) were added and the mixture degassed for a further 5 minutes. The mixture was heated at 130° C. for 30 minutes in a microwave reactor and then partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%). The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) and brine, then dried (Na2SO4) and passed sequentially through 2 PS-Thiol cartridges and concentrated to dryness. Preparative HPLC afforded the title compound (0.62 mg, 0.00016 mmol, 2%). 1H NMR (d6-DMSO, 400 MHz) δ 9.34 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.69-7.65 (m, 1H), 7.37 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=7.6 Hz), 5.53-5.47 (m, 1H), 4.02 (s, 3H), 2.68-2.63 (m, 1H), 2.57-2.53 (m, 1H), 2.21 (s, 6H), 1.46 (d, 3H, J=6.3 Hz). LC-MS (2) Rt=3.18 min; m/z (ESI+) 379 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[N:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:11]([C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)[N:16]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:14]=2)=[O:12])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(C(=O)O)cc(Oc3ccc(C#N)cc3)n2)cc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)nc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 89.6 %

Procedure:
2,6-bis(4-Cyano phenoxy)-isonicotinic acid (0.220 g, 0.61 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.142 g, 0.71 mmol) were coupled using the procedure of Example 5(c) to afford 0.295 g of the required product. Percentage purity (LCMS): 59.4%, (M+1)=439.2+1 (with BOC). 1H NMR (DMSO-d6): δ 1.40 (9H, s), 1.81 (4H, m), 2.86 (4H, m), 3.82 (1H, m), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.64 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1])[CH3:33]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A suspension of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (200 mg), potassium carbonate (161 mg) and ethyl iodide (181 mg) in DMF (5 mL) was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was recrystallized from hexane/ethyl acetate to give the title compound (167 mg).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[C:13]1([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[CH:12][C:3]([OH:2])=[CH:4]3)=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc2ccc(-c3ccccc3)cc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc2ccc(-c3ccccc3)cc2c1

Procedure:
The title compound was prepared by reacting 2-methoxy-7-phenylnaphthalene (0.53 g, 2.26 mmol) with pyridinium HCl (10 g) at 190° C. according to method B to yield 0.36 g (72%) of a white solid: mp 142–143° C.; 1H NMR (DMSO-d6): δ 7.10 (1H, dd, J=2.75 Hz, J=8.70 Hz), 7.23 (1H, d, J=2.29 Hz), 7.37–7.40 (1H, m), 7.48–7.51 (2H, m), 7.58 (1H, dd, J=1.83 Hz, 8.70 Hz), 7.78–7.90 (3H, m), 7.86 (1H, d, J=8.24 Hz), 7.99 (1H, d, J=0.92 Hz) 9.81 (1H, s); MS (ESI) m/z 219 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([Br:12])=[CH:10][CH:11]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Br:12][C:9]1[N:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:13])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(Br)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
750 mg (3.1 mmol) of 3-(6-bromo-pyridin-3-yl)-acrylic acid methyl ester was dissolved in 30 ml of dioxane and 4.65 ml of a 2 N aqueous sodium hydroxide solution was added. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was poured into water and acidified with concentrated hydrochloric acid, whereupon the product precipitated. The product was isolated by filtration and dried under reduced pressure. Yield: 673 mg.