Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]=[C:6]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][C:7]1[C:8](=[O:12])[C:9]2[C:5]([C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: COc1ccc2c(c1)C(c1ccccc1)=CC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
5-Methoxy-3-phenyl-1H-inden-1-one (2.8 g, 11.85 mmol) obtained in Step 3 was placed into a flask and dissolved in CCl4 (20 mL). To the resulting solution, NBS (2.53 g, 14.22 mmol, 1.2 eq) and AIBN (280 mg, 10%/w) were added. The resulting mixture was allowed to reflux for 2 h. After cooling to room temperature, the reaction mixture was quenched with sat. Na2S2O3 (20 mL) extracted with CH2Cl2(20 mL×3). The organic layers were washed H2O and brine, dried over MgSO4 and concentrated in vacuo to give the desired product (2.45 g, 66%).
Reaction SMILES: CC1C=CC=C(C)C=1C.C[OH:11].[C:12]([N:15]1[CH2:19][CH2:18][CH:17]=[CH:16]1)(=[O:14])[CH3:13].[O:20]1[CH2:24]CC[CH2:21]1>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>[CH3:21][O:20][C:24](=[O:11])[C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)N1C=CCC1
Reactant: CO
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cccc(C)c1C
Product: COC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 100 °C
Reaction time: 44.25 h
Yield: 47.9 %

Procedure:
A 70 mL stainless steel high pressure reactor having a Pyrex glass liner and a magnetic stir bar was charged with 5 mL of tetrahydrofuran, 0.5 mmol of 1,2,3-trimethylbenzene internal standard, 0.6 mmol of CH3OH, 35.1 mg of (PPh3)2PdCl2, and 55.5 mg of N-acetyl-2-pyrroline. The reactor ws pressurized to 1000 psi with CO at room temperature, and the reaction mixture was stirred for 44.25 hours at 100° C. Thereafter, the reactor was cooled to room temperature and vented to atmospheric pressure. The product mixture was analyzed by gas chromatography and mass spectroscopy, and the analysis indicated complete conversion of N-acetyl-2-pyrroline and a 47.9% yield of N-acetylproline methyl ester.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]([Cu])#[N:12].C(N)CN>CC(N(C)C)=O>[NH2:8][C:5]1[C:4]([CH3:9])=[C:3]([CH3:10])[C:2]([C:11]#[N:12])=[CH:7][N:6]=1
Reactant: Cc1c(Br)cnc(N)c1C
Reactant: N#C[Cu]
Solvent: NCCN
Solvent: CC(=O)N(C)C
Product: Cc1c(C#N)cnc(N)c1C
Temperature: 170 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 5-bromo-3,4-dimethyl-pyridin-2-ylamine (500 mg, 2.49 mmol), CuCN (445 mg, 4.97 mmol) and DMA (3.5 mL) was stirred under nitrogen for 20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a 20% aqueous solution of ethane-1,2-diamine. The layers were separated and the aqueous layer was extracted 3× with EtOAc. The combined organics were washed with water, followed by brine and dried over MgSO4. Concentration in vacuo afforded compound 850A (362 mg, 99%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[OH:10][NH:11][C:12](=N)[CH:13]([CH3:15])[CH3:14].Cl>C(OCC)(=O)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[CH:13]([C:12]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:10][N:11]=1)([CH3:15])[CH3:14]
Reactant: N#CN1CCC(O)CC1
Reactant: CC(C)C(=N)NO
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carbonitrile (1 g, 7.93 mmol) and N-hydroxyisobutyrimidamide (0.972 g, 9.51 mmol) in ethyl acetate (40 mL) was added zinc chloride (1 M in Et2O, 9.5 mL, 9.5 mmol) dropwise at rt under argon. Precipitate formed immediately, and the reaction mixture was stirred at rt for 30 min. The solid was collected via filtering, rinsed several times with ether. The solid was dissolved in concentrated HCl (4 mL, 132 mmol), diluted with ethanol (8 mL), and refluxed for 1 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated to approximately half of the volume, and diluted with water (15 mL). The solution was basified with solid Na2CO3, followed by extraction with CH2Cl2 (3×30 mL). The combined organic layers were washed with saturated NaHCO3 (60 mL) and brine. It was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (hexanes-EtOAc gradient 0-50% EtOAc) to afford 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (0.59 g, 2.79 mmol, 35% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (d, J=7.07 Hz, 6H) 1.55 (d, 1H) 1.60-1.70 (m, J=12.98, 8.61, 8.61, 4.17 Hz, 2H) 1.93-2.02 (m, 2H) 2.89 (spt, J=6.95 Hz, 1H) 3.38 (ddd, J=13.20, 9.03, 3.79 Hz, 2H) 3.88-4.04 (m, 3H). LCMS (m/z)=212 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccccn1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccccn1
Yield: 89.3 %

Procedure:
tert-Butyl (E)-3-(2-pyridyl)-2-propenoate (1.1 g, 5.4 mmol) was dissolved in ethanol (12 ml), and a solution of ammonium formate (2.0 g, 32.0 mmol) in water (3 ml) was added thereto. The reaction mixture was refluxed for 1.5 hrs, combined with ethyl acetate and water and filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (1.0 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[OH:17][CH2:18][C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:17][CH2:18][C:19]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-(bromomethyl)-4′-fluorobiphenyl (398 mg, 1.16 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (280 mg, 0.96 mmol) were combined in dimethylformamide (5 mL) and cooled to 0° C. The reaction was treated with sodium hydride (46 mg, 1.92 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 470 mg (73%). 1H-NMR (CDCl3, 500 MHz) δ 7.51 (s, 1H), 7.28-7.42 (m, 6H), 7.19-7.23 (m, 2H), 7.06-7.14 (m, 3H), 4.34 (s, 2H), 3.69-3.74 (m, 2H), 3.40 (s, 2H), 2.98-3.06 (m, 2H), 2.14-2.19 (m, 2H), 1.81-1.90 (m, 2H), 1.41 (s, 9H). Mass spec.: 556.37 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[CH:33]=[C:32]([NH:34][NH2:35])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].O1CCCC1>>[Cl:25][C:26]1[CH:33]=[C:32]([N:34]2[CH:6]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:35]2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: COC(=O)c1ccc2c(c1)OCC(=Cc1ccc(F)cc1)C2=O
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2c2ccc(F)cc2)cc1Cl
Yield: 18 %

Procedure:
The title compound was prepared from methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate; Preparation 30 (155 mg, 0.50 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 (153 mg, 0.75 mmol) according to Method B and Method C. The crude product was purified by reverse-phase HPLC (acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (41 mg, 0.09 mmol, 18% yield). The title compound was largely present as (±)-(3SR,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. ES-MS m/z 448 (M+H).
Reaction SMILES: [CH3:1][O-:2].[Na+].ClC(C([C:10]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:14]=[CH:13][CH:12]=[CH:11]1)=O)(Cl)Cl.[CH3:22][OH:23]>O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[NH:14][C:13]([C:1]([O:23][CH3:22])=[O:2])=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: C[O-]
Reactant: O=C(C(Cl)(Cl)Cl)C1(c2ccc(Cl)cc2)C=CC=N1
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)[nH]1
Reaction time: 2 h

Procedure:
A solution of sodium methoxide (12.73 mL of 4.38M solution in methanol, 0.0556 mol) in methanol is cooled with an ice bath, treated with 5-(p-chlorophenyl)pyrrol-5-yl trichloromethyl ketone (6.0 g, 0.0186 mol), stirred for two hours, diluted with water and filtered to obtain a solid. The solid is washed with water and dried overnight in a vacuum dessicator to give the title product as a tan solid (4.23 g, mp 177°-179° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:32][C:33]([S:47]([CH2:50][C@@H:51]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52](O)=[O:53])(=[O:49])=[O:48])([C:35](=[O:46])[N:36]([CH3:45])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:34].Cl.Cl.[CH3:64][O:65][C:66](=[O:75])[CH:67]([CH2:69][C:70]1[N:71]=[CH:72][S:73][CH:74]=1)[NH2:68]>C(#N)C>[CH3:64][O:65][C:66](=[O:75])[CH:67]([CH2:69][C:70]1[N:71]=[CH:72][S:73][CH:74]=1)[NH:68][C:52](=[O:53])[C@@H:51]([CH2:50][S:47]([C:33]([CH3:32])([C:35](=[O:46])[N:36]([CH3:45])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:34])(=[O:49])=[O:48])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: COC(=O)C(N)Cc1cscn1
Reactant: CN(CCc1ccccn1)C(=O)C(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)N(C)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
0.28 ml (2.1 mmol) of triethylamine and 265 mg (0.7 mmol) of HBTU were added to a solution of 328 mg (0.7 mmol) of (S)-α-[[[1-methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamic acid and 181 mg (0.7 mmol) 3-(thiazol-4-yl)-D,L-alanine methyl ester dihydrochloride in 7 ml of acetonitrile and the mixture was stirred at room temperature overnight. Evaporation of the solution under reduced pressure and chromatography of the residue on silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia as the eluent yielded 309 mg of N-[(S)-α-[[[1-methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamoyl]-3-(thiazol-4-yl)-D,L-alanine methyl ester as a colourless foam, MS: 601 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-nitrobenzotrifluoride (2 g) and 1-methylpiperazine (2 mL) were dissolved in methanol (5 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic solutions were evaporated to give 2-(4-methylpiperazino)-5-nitrobenzotrifluoride.
Reaction SMILES: [CH3:1][C@@:2]1([NH2:20])[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=3)[CH2:8]2)[CH2:4][CH2:3]1.[C:21]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([F:33])[CH2:30][C@H:29]1[C:34]([OH:36])=[O:35])=[O:27])([CH3:24])([CH3:23])[CH3:22].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[F:33][C@H:31]1[CH2:32][NH:28][C@H:29]([C:34]([NH:20][C@:2]2([CH3:1])[C@@H:9]3[C@@H:5]([CH2:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=4)[CH2:8]3)[CH2:4][CH2:3]2)=[O:35])[CH2:30]1.[F:33][C@H:31]1[CH2:32][N:28]([C:26]([O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:27])[C@H:29]([C:34](=[O:36])[NH:20][C@:2]2([CH3:1])[C@@H:9]3[C@@H:5]([CH2:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=4)[CH2:8]3)[CH2:4][CH2:3]2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: C[C@]1(N)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@@]1(C)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: C[C@]1(NC(=O)[C@@H]2C[C@@H](F)CN2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reaction time: 0.08 h

Procedure:
The title compound is prepared by treating a solution of (3aR,4S,6aS)-4-methyl-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 27 (0.075 g, 0.263 mmol) in 1 mL dichloromethane with (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (0.067 g, 0.289 mmol) followed by of 1-hydroxybenzotriazole hydrate (0.044 g, 0.289 mmol). The reaction was stirred for 5 minutes, and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.051 mL, 0.289 mmol) was added to the reaction mixture followed by stirring at ambient temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate, and the crude material was chromatographed using a 12 g silica gel cartridge eluted with 3%-100% ethyl acetate/hexanes over 30 minutes to give (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-4-methyl-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate which was treated with 4 N HCl in 1,4-dioxane (1 mL, 4.00 mmol). An oil slowly gummed out of solution. The reaction was stirred at room temperature for 18 hours, and the solvent was removed under a stream of nitrogen. The crude material was purified using a 12 g silica gel cartridge eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.03 (bs, 1H), 7.52 (m, 1H), 7.00 (d, J=7.2, 1H), 6.55 (d, J=8.5, 1H), 5.22 (dt, J=54.3, 3.5, 1H), 4.22-4.14 (m, 1H), 3.75-3.45 (m, 4H), 3.41-3.27 (m, 2H), 3.22-3.12 (m, 1H), 3.02-2.74 (m, 2H), 2.58 (dddd, J=23.7, 15.0, 8.5, 2.3, 1H), 2.32-2.11 (m, 2H), 1.99 (dq, J=13.3, 8.7, 1H), 1.78 (dt, J=13.2, 8.7, 1H), 1.48 (s, 3H), 1.46-1.13 (m, 1H); MS (ESI+) m/z 401 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[C@H:30]2[C@@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:31]=3[C:28]([CH2:29]2)=[CH:27][NH:26]4)[CH2:19][C:18](=O)[CH2:17]1>[Pd]>[CH3:15][N:16]1[C@H:30]2[C@@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:31]=3[C:28]([CH2:29]2)=[CH:27][NH:26]4)[CH2:19][CH:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][CH:10]=2)[CH2:17]1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: Nc1ccc(Oc2ccccc2)nc1
Agent: [Pd]
Product: CN1CC(Nc2ccc(Oc3ccccc3)nc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-phenoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2F)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([O:32]CC)=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=2)[CH:7]=1)[CH3:2].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[OH-].[Li+].CS(O)(=O)=O>C1COCC1.O>[CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2[N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([OH:32])=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[N:40]=2)[CH:7]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn([C@H](CO)C(C)(C)C)c3nc2F)cn1
Agent: CS(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@H](CO)C(C)(C)C)c3nc2N2CCN(C)CC2)cn1
Temperature: 50 °C
Reaction time: 10 h
Yield: 22 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-7-fluoro-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate Intermediate 76 (200 mg, 0.31 mmol, 1 equiv.) in THF (1.2 mL) was added 1-methylpiperazine (0.041 mL, 0.37 mmol, 1.2 equiv.). This reaction was stirred at 50° C. for 10 h. 2 M lithium hydroxide (0.307 mL) was added. The reaction was stirred at 50° C. for 2 h, cooled to room temperature, and diluted with water. 10% wt. sol. of methanesulfonic acid was added until pH 5-6 was reached. The precipitate was discarded. The solution was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the aqueous layer was concentrated. The compound was purified (HPLC) and concentrated to provide (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a solid (52.8 mg, 22%). Calcd for C32H37F3N8O5S [M+H]+: 703.2. H1NMR (d6-DMSO) δ 15.18 (s, 1H), 9.51 (s, 1H), 8.8 (d, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 8.2 (s, 1H), 7.6 (m, 1H), 5.71-5.68 (m, 1H), 5.09-5.02 (m, 1H), 4.09-4.0 (m, 2H), 3.29-3.27 (m, 2H), 3.21-3.19 (m, 2H), 3.15-3.04 (m, 2H), 2.18-2.14 (m, 2H), 2.05 (s, 3H), 1.95-1.91 (m, 2H), 1.12 (t, 3H), 0.95 (s, 9H).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([N:20]=[C:21]=[O:22])=[CH:14][C:13]=2[O:12]1>C1C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:21]([NH:20][C:15]3[CH:16]=[CH:17][C:18]4[O:19][CH2:11][O:12][C:13]=4[CH:14]=3)=[O:22])=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(Nc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxyaniline (0.35 g) and 3,4-methylenedioxyphenyl isocyanate (0.4 g) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0076B (0.697 g, 950/%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[CH3:25][CH:26]([CH3:33])[C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30]>O1CCCC1>[C:27]([C:28]1[CH:21]([C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[NH:12][C:10](=[O:11])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:29]=1[CH3:30])(=[O:32])[CH:26]([CH3:33])[CH3:25]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(=O)C(C)C
Solvent: C1CCOC1
Product: CC1=C(C(=O)C(C)C)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of N-[3-(trifluoromethyl)phenyl]urea (6.37 g, 31.2 mmol), 4-cyanobenzaldehyde (4.09 g, 31.2 mmol) and 5-methylhexane-2,4-dione (4.0 g, 31.2 mmol) in tetrahydrofuran (150 ml) is added ethyl polyphosphate (12 g). The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[CH:2]=[CH2:3].O=[C:18]([CH3:31])[CH2:19][O:20][C:21]1[CH:29]=[C:25]([C:26]([NH2:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][CH:18]([CH3:31])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:26](=[O:27])[NH2:28])[CH:29]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1OCC(O)CN
Reactant: CC(=O)COc1ccc(O)c(C(N)=O)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: C=CCOc1ccccc1OCC(O)CNC(C)COc1ccc(O)c(C(N)=O)c1
Reaction time: 8 h

Procedure:
A mixture of 11.2 g of 1-(2-allyloxyphenoxy)-3-aminopropan-2-ol and 10.5 g of 5-(2-oxopropoxy)salicylamide is boiled using a water separator in 200 ml of toluene with the addition of a few drops of acetic acid. After the splitting off of water has ceased (after about 2-3 hours), the solution is concentrated by evaporation, the dark red residue is dissolved in 300 ml of ethanol and a total of 5.7 g of sodium borohydride is added in portions whilst stirring. The temperature increases during this operation to 36°. The reaction mixture is stirred for a further 2 hours at 20°-30°, and left to stand overnight. Whilst cooling with ice, it is then brought to pH 3-4 with approximately 6N hydrochloric acid, filtered and concentrated by evaporation. The residue is divided between 100 ml of water and 100 ml of ethyl acetate, the aqueous phase is separated off, rendered alkaline with concentrated ammonia and extracted with 200 ml of ethyl acetate. Working up of the organic phase yields crude oily 1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]propan-2-ol as an enantiomer mixture. By slow crystallisation from isopropanol the two pure enantiomer pairs having melting points of 123°-125° and 98°-102° respectively are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1)[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1)[CH3:50]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: CCOc1ncccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ncccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
DIEA (0.013 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-Ethoxy-pyridin-3-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 403 (MH+).