Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:50][CH2:49]2)=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:57]([O:56][C:54]([CH:51]1[CH2:50][CH2:49][N:48]([C:45]2[CH:46]=[CH:47][C:42]([NH:41][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]3)=[O:30])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1)=[O:55])[CH3:58]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
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: ClCCl
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)cc2)CC1
Reaction time: 0.5 h
Yield: 291.1 %

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) in dichloromethane (5 ml) were added N,N-DIISOPROPYLETHYLAMINE (33 mg) and ethyl 1-(4-aminophenyl)piperidine-4-carboxylate (63.8 mg, 0.257 mmol, Bionet Research Intermediates) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (29 mg, Chem-Impex) and the reaction mixture was stirred for 30 min; Another portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg) was added and stirring was continued for 30 min before the addition of the last portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg). 1 hr later, the reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give 1-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid ethyl ester as off-white solid (86.9 mg, 97%). MS (ES+) m/z Calcd: [(M+H)+]: 697. found: 697.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:12]([C:15]([N:17]3[CH2:22][C@@H:21]4[CH2:23][C@H:18]3[CH2:19][O:20]4)=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>COCCOC>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[C:3]3[N:4]([C:12]([C:15]([N:17]4[CH2:22][C@@H:21]5[CH2:23][C@H:18]4[CH2:19][O:20]5)=[O:16])=[CH:13][N:14]=3)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=2)[CH:27]=[N:26]1
Reactant: O=C(c1cnc2c(Br)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(C(F)(F)F)cn3c(C(=O)N4C[C@@H]5C[C@H]4CO5)cnc23)cn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A mixture of (8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone (50.0 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.0 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (10.5 mg) and cesium carbonate (125 mg) in DME (2.5 mL) was stirred with microwave irradiation at 120° C. for 30 min. To the reaction mixture was added 0.1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.6 mg).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[C:31]([C:33]([OH:35])=O)[CH:32]=[C:27]2[C:26]([CH3:36])=[N:25]1.[NH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>CN(C)C=O>[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[C:31]([C:33]([NH:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:35])[CH:32]=[C:27]2[C:26]([CH3:36])=[N:25]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1nn(C)c2ncc(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Cc1nn(C)c2ncc(C(=O)NCCNC(=O)OC(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Hydroxybenzotriazole (3.55 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.45 g) were added to a solution of 1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (4.00 g) in N,N-dimethylformamide (40 ml) with ice cooling. The mixture was stirred for 30 minutes at room temperature, and then t-butyl (2-aminoethyl)carbamate (3.65 ml) was added thereto and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic phase was washed with 10% citric acid solution, 4% sodium bicarbonate solution and a saturated saline solution. The product was dried under sodium sulfate anhydrous and concentrated under reduced pressure to give t-butyl {2-[(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl)amino]ethyl}carbamate (4.02 g, Y.:57%) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:31])[CH2:22][C:23]([C:25]1[S:26][CH:27]=[CH:28][C:29]=1[Cl:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:29]1[CH:28]=[CH:27][S:26][C:25]=1[C:23]1[CH2:22][C:21](=[O:31])[NH:20][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccccn3)cc2N1

Procedure:
Prepared from {2-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamic acid tert.-butyl ester (Example K12) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown powder (51 mg).
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1>[ClH:19].[ClH:19].[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([N:16]3[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]3)[CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(-c2csc(Cc3ccccc3)n2)ccn1
Solvent: C1CCNCC1
Product: Cl
Product: c1ccc(Cc2nc(-c3ccnc(N4CCCCC4)c3)cs2)cc1
Yield: 73.5 %

Procedure:
A solution of 2-benzyl-4-(2-chloro-4-pyridyl)thiazole (1.00 g, 0.0035 mol) in piperidine (15 mL) was heated to reflux for 16 hours. The reaction mixture was concentrated, taken up in ether (50 mL), filtered through celite, and the filtrate washed with water (2×). The ether layer was dried and concentrated. The residue was taken up in ethanol (20 mL) and treated with an excess of dry hydrochloric acid. Careful dilution with ether afforded 2-benzyl-4-[2-(1-piperidyl)-4-pyridyl]thiazole dihydrochloride (525 mg, 49%). mp. 145° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)(=O)[CH3:2].C([O-])([O-])=O.[K+].[K+].ClCC[CH2:35][N:36]1[CH2:41][CH2:40][N:39]2[C:42]([C:45]([F:48])([F:47])[F:46])=[N:43][N:44]=[C:38]2[CH2:37]1>CN(C=O)C.O>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:1][CH2:2][CH2:35][N:36]4[CH2:41][CH2:40][N:39]5[C:42]([C:45]([F:48])([F:46])[F:47])=[N:43][N:44]=[C:38]5[CH2:37]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OC(C)=O
Reactant: FC(F)(F)c1nnc2n1CCN(CCCCl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCn2c(nnc2C(F)(F)F)C1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (0.62 g) and K2CO3 (0.35 g) in 10 mL of DMF was added 7-(3-chloropropyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.68 g) at rt. The reaction mixture was heated at 80° C. for 6 h, diluted with water and extracted with CH2Cl2. The combined organic phases were dried over anhydrous Na2SO4 for 1 h, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a white solid (0.43 g, 40.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 552.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.80 (m, 2H), 2.46 (t, J=4.2 Hz, 2H), 2.78 (t, J=3.6 Hz, 2H), 3.58 (s, 2H), 4.03 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 4.15 (t, J=3.6 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57 (m, 1H), 7.91 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[CH:15][N:14](S(C4C=CC=CC=4)(=O)=O)[C:11]3=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CC4CCCCC4)cc23)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2c[nH]c3ncc(CC4CCCCC4)cc23)cn1
Temperature: 105 °C

Procedure:
A mixture of 97 (25 mg, 0.0575 mmol) and 10% aq. NaOH (0.32 mL) in EtOH (2 mL) was refluxed (oil bath temperature 105° C.) for 30 min., cooled to r.t. and partitioned between water:AcOEt. The aqueous layer was extracted with AcOEt. The extract was dried (MgSO4), concentrated and separated by means of PTLC using AcOEt as eluent to afford desired inhibitor 98 (2.23 mg, 11% over 2 steps) as a solid. 1H NMR (400 MHz; CDCl3) δ 0.86-0.97 (m, 2H), 1.05-1.26 (m, 4H), 1.53-1.73 (m, 5H), 2.54 (d, J=7.1 Hz, 2H), 3.93 (s, 3H), 7.29 (d, J=2.3 Hz, 1H), 7.55 (s, 1H), 7.69 (d, J=0.5 Hz, 1H), 7.74 (d, J=1.9 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 9.31 (bs, 1NH); MS (CI) m/z 295 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=[O:13])[CH3:12].C(N(CC)C(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Sc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)CSc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-Bromothiophenol (2.89 g, 15.29 mmol) and chloroacetone (1.278 mL, 16.06 mmol) were mixed in THF (80 mL) and cooled to 0° C. N,N-Diisopropylethylamine (6.65 mL, 38.23 mmol) was added and the reaction was stirred at 0° C. for five minutes then allowed to warm to room temperature and stirred overnight. The reaction was then extracted with EtOAc and H2O and the organic portion was concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10](F)(F)F)=C)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[N:26][OH:27])=[CH:21][C:20]=1[CH2:28][C:29]([F:32])([F:31])[F:30]>ClCCl.[O-]Cl.[Na+]>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:10][CH:8]([C:6]3[CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=[C:2]([Cl:1])[CH:7]=3)[O:27][N:26]=2)=[CH:21][C:20]=1[CH2:28][C:29]([F:30])([F:31])[F:32]
Reactant: ON=Cc1ccc(Br)c(CC(F)(F)F)c1
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: FC(F)(F)Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)C2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (680 mg, 2.48 mmol, 1.00 equiv), a solution of N-[[4-bromo-3-(2,2,2-trifluoroethyl)phenyl]methylidene]hydroxylamine (700 mg, 2.48 mmol, 1.10 equiv) in dichloromethane (20 mL), NaClO (10 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:10). This resulted in 600 mg (50%) of 3-[4-bromo-3-(2,2,2-trifluoroethyl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole as yellow oil.
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:41])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27](=[O:39])[C:26]2=[O:40])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:41])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27](=[O:39])[C:26]2=[O:40])=[CH:18][CH:19]=1)(=[NH:11])[NH2:13]
Reactant: CC(C)(C)OC(=O)CN1CCN(CCCC(=O)Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)c1ccc(NC(=O)CCCN2CCN(CC(=O)O)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.1 %

Procedure:
To a solution of 0.28 g of tert-butyl (4-[4-(4-benzyloxycarbonylamidinophenylamino)-4-oxobutyl]-2,3-dioxopiperazin-1-yl]acetate in 2.8 ml of methylene chloride was added 1.4 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 12 hours and then distilled under reduced pressure to remove the solvent. To the resulting residue were added 0.08 g of 5% palladium-carbon and 5.6 ml of N,N-dimethylformamide, followed by hydrogenation at ordinary temperature and atmospheric pressure for 3 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. To the resulting concentrate were added 5 ml of water and 0.042 g of sodium hydrogencarbonate to obtain a homogeneous solution. This solution was purified by a reversed phase column chromatography (eluent: a 10% aqueous acetonitrile solution) to obtain 0.08 g of [4-[4-(4-amidinophenylamino)-4-oxobutyl]-2,3-dioxopiperazin-1-yl]acetic acid as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH3:33])[C:8](=[O:32])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Br)[CH2:24][CH2:23]2)=[N:11][CH:10]=1.C(=O)(O)[O-:44].[Na+]>CN1CCCC1=O>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH3:33])[C:8](=[O:32])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][OH:44])[CH2:24][CH2:23]2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(N2CCN(C(=O)CBr)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccccc1-c1cc(N2CCN(C(=O)CO)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 64 %

Procedure:
A mixture of 0.12 g (0.18 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-(4-bromoacetyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide, 1.2 ml 1-methyl-2-pyrrolidone and 0.2 ml half-saturated aqueous sodium bicarbonate solution was stirred at 100° C. over night. After cooling to room temperature and dilution with water the mixture was extracted with five portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate, concentrated and dried in vacuo (0.5 mbar) at 70°. Flash column chromatography afforded 71 mg (64%) of the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21](C=O)C.[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36](I)[CH:37]=2)[C:32]([OH:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])[C:31]1=[O:49])[CH3:26].C1(C)C=CC=CC=1>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2]>[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36]([C:20]#[N:21])[CH:37]=2)[C:32]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])([OH:48])[C:31]1=[O:49])[CH3:26]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(I)cc21
Agent: [C-]#N
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To Pd2(dba)3CHCl3 (5.69 mg, 5 mol %) and triphenyIphosphine (5.76 mg, 20 mol %) under a nitrogen atmosphere was added anhydrous DMF (0.5 mL). The mixture was stirred at room temperature for 30 minutes to give orange/yellow mixture. To this was then added 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-chloro-6-iodooxindole (57.0 mg, 1.1×10−4 mol) followed by Zn(CN)2 (17.2 mg, 0.8 eq., 60%). The resulting suspension was heated to 60° C. (bath temperature) and stirred at that temperature for 3 hours. The mixture was allowed to cool and diluted with EtOAc:toluene (10 mL, 1:1). The mixture was washed with H2O (2×10 mL) and dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo to give the crude title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[OH:38]>>[OH:38][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][C:23]=1[O:22][CH3:21]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)c(OC)c3)ccn2c1=O
Yield: 78.3 %

Procedure:
Methyl 8-(4-hydroxy-3-methoxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (102.7 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (101 mg, 78%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21](Cl)[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[CH:21][N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1ncc(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
A mixture of 1.00 g of 10% palladium/carbon and 1.00 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol was stirred at 25° for five minutes. Hydrogen gas was bubbled into the solution, and the mixture was stirred under H2 (g) (1 atm.) at 25° for 3.5 hours. The mixture was filtered, and the resulting solution concentrated in vacuo. Column chromatography (elution: 0-5% methanol/chloroform) furnished 0.33 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl imidazole. NMR (200 MHz, DMSO-d6) δ8.20 (s, 1H); 7.98 (d, 2H); 7.65 (t, 1H); 7.41 (A2M2, 4H); 6.80 (s, 1H); 5.30 (s, 2H); 5.12 (t, 1H); 4.37 (d, 2H); 3.90 (s, 3H); 2.52 (t, 2H); 1.51 (quint., 2H); 1.27 (sext., 2H); 0.80 (t, 3H).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:5][CH:6]=[O:7]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:3][C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:5][C:6]([OH:1])=[O:7]
Reactant: [OH-]
Reactant: CC(C)(C)C(Cl)=CC=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(Cl)=CC(=O)O
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of sodium hydroxide (1.09 g, 27.3 mmol) in water (10 mL) was added to a solution of silver nitrate (2.32 g, 13.65 mmol) in water (15 mL) at ice cold temperature for 15 min. 3-Chloro-4,4-dimethylpent-2-enal (1.0 g, 6.825 mmol) was added dropwise at the same temperature for 15 min. The reaction mixture was allowed to rt and stirred for 1 h. The reaction mixture was poured into ice cooled water and filtered through hyflowgel to remove black particles. The hyflowgel bed was washed with hot water and cooled. The solution was acidified with dil. HCl and the solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product a white color solid (1.0 g, 91%), mp 146-148° C. 1H NMR (400 MHz, CDCl3): δ 8.02 (1H, br s), 6.11 (1H, s), 1.24 (9H, s); LC-MS (negative ion mode): m/z 161, 163 (M−H)−.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:28]([Cu])#[N:29]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(F)cc3)cc2c1O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(F)cc3)cc2c1O

Procedure:
Synthesized from 1-bromo-6-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to Example 3a.; MS-(−)-ion: M−1=379.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].C1(P(Cl)([Cl:35])=O)C=CC=CC=1>O>[Cl:35][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=1
Reactant: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: O
Product: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 150 °C

Procedure:
To 1.0 g of 3,4-diethoxycarbonyl-5-nitro-6-phenyl-2-pyridone was added 1.3 ml (3.37 eq.) of phenylphosphonic dichloride, and the mixture was heated at 150° C. for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 1:2), to give an oily product. Yield: 950 mg (90.5%).