Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.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>[Cl:1][C:2]1[C:12]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(C#C[Si](C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
To a slurry of the compound of Example 239 (0.763 g, 2.0 mmol), bis(triphenylphosphine)palladium dichloride (28 mg, 0.04 mmol) and cuprous iodide (15 mg, 0.08 mmol) in anhydrous triethylamine (10 mL) was added trimethylsilylacetylene (0.236 g, 2.4 mmol). The brown slurry was stirred at RT for 3.5 h, concentrated, slurried in ether and filtered through silica gel (ether). The crude product was further purified by flash chromatography (ethyl acetate/hexanes) followed by recrystallization from hexanes to afford the title compound as white crystals (0.618 g, 88%). m.p. 131-132° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].C(#[N:17])C.[ClH:18].C(O)C>>[ClH:18].[NH2:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4]
Reactant: CC#N
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: NCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (22 g), NaN(CHO)2 (9.5 g) and acetonitrile (50 mL) was stirred at room temperature for 3 hr and at 70° C. overnight, and the insoluble material was removed by filtration. The filtrate was concentrated to give an oil. The oil was dissolved in hydrogen chloride-ethanol, and the mixture was stirred at room temperature for 48 hr. The resulting precipitate was collected by filtration, and washed with ether to give the title compound (2.7 g) as a solid. The filtrate was concentrated, and the residue was dissolved in water. The aqueous layer was washed with ether, and the solvent was evaporated under reduced pressure to give the title compound (7.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH2:21][CH2:22][OH:23])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O-])(=[O:40])=[O:39])=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:20][CH2:21][CH2:22][O:23][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=3)(=[O:40])=[O:39])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)(c2ccc(Br)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ambient solution of Example 54C (0.450 g, 1.17 mmol), triethylamine (0.178 mL, 1.28 mmol), and 4-dimethylaminopyridine (0.005 g, 0.041 mmol) in dichloromethane (3 mL) was added p-toluenesulfonate chloride (0.224 g, 1.17 mmol). The reaction was stirred at room temperature for 8 h and was then partitioned between water (10 mL) and diethyl ether (10 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% ethyl acetate in hexane to 25% ethyl acetate in hexane) to give the title product. MS (ESI) m/z 541 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:12]([NH:20][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1ccccn1
Solvent: CCO
Product: O=C(NCCc1ccccc1)c1ccccn1

Procedure:
A mixture of 20 ml of ethyl pyridine-2-carboxylate and 27 ml of phenethylamine was stirred at 180° C. for 5 h., with the ethanol formed being distilled off over a 30 cm Vigreux column. Distillation of the residue yielded 30.9 g of pyridine-2-carboxylic acid phenethyl-amide as a yellowish oil, b.p. 150°-155° C./0.8 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][C:16]=3[F:25])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:14]=[C:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=3)[CH2:13][CH2:12]2)=[C:16]([F:25])[CH:17]=1)([OH:23])=[O:22]
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
9.0 g of 1-(4-chlorobenzoyl)-4-[2-fluoro-4-methoxycarbonylbenzylidene]piperidine in 150 ml of methanol are treated with a solution of 4.0 g of 84% caustic potash in 100 ml of water and the mixture is stirred overnight at ambient temperature. The methanol is evaporated off, the residue is mixed water with cooling and the mixture is acidified with dilute hydrochloric acid. The precipitate is suction-filtered, washed with water and dried in vacuo. 8.6 g (95% of theory) of 4-(4-carboxy-2-fluorobenzylidene)-1-(4-chlorobenzoyl)piperidine of melting point 170°-173° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]2[C:14](=[CH:15][C:16]=1Cl)[N:13]=[C:12](C)[CH:11]=[CH:10]2)(=[O:5])=[O:4].Cl[C:29]1C=CC(C2C(O)=C(C)C=C3C=2C=CC=N3)=CC=1>>[F:27][C:2]([F:1])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:29])[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:4])=[O:5]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1O
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F

Procedure:
Compound 3F was prepared following the procedure used to prepare compound 1F of Example 1, except that 5-(4-chloro-phenyl)-7-methylquinolin-6-ol (3E) was used instead of compound 1E. LCMS-ESI+ (m/z): 402.0, 404.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CCOCC>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1)(=[O:22])=[O:21]
Reactant: OCCCCCCCC1=CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCCCCCCCC1=CC1
Temperature: 0 °C

Procedure:
A solution of 3.8 mmol of 1-(7-hydroxyheptyl)-cyclopropene in 50 ml of ether was cooled in an ice bath. Triethylamine (1 ml) and 0.48 g of methanesulfonyl chloride (4.2 mmol) were added and the reaction mixture was stirred for 2½ hours at 0° C. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 1-(7-methanesulfonyloxyheptyl)-cyclopropene which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[F:13][C:14]1[C:19]([CH:20]=O)=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[F:13][C:14]1[C:19]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: O=Cc1cccnc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2cccs2)=NC1=Cc1cccnc1F
Temperature: 90 °C
Yield: 64.4 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 2-fluoropyridin-3-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 53 mg of the above-captioned compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccnc(Cl)c2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (33%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]=2)=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([CH3:23])=[CH:6][NH:7]2>CCO.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([CH3:23])=[CH:6][NH:7]2
Reactant: CCOC(=O)C1CC=C(c2ccc(N)c3c(=O)c(C)c[nH]c23)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c(=O)c(C)c[nH]c32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 4-(5-amino-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohex-3-ene-1-carboxylate (Compound 304C, 0.270 g, 0.83 mmol) and palladium 10% wt on activated carbon (88.0 mg, 0.083 mmol) in EtOH (2.17 mL) was evacuated and purged with hydrogen (3×) and subsequently stirred under one atmosphere of hydrogen at rt for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an orange oil. The product was purified by mass directed purification which resolved the cis and trans isomers. Compound 304A, the trans isomer eluted first: 1H NMR (400 MHz, MeOD) δ ppm 1.27 (t, J=7.07 Hz, 3 H) 1.53-1.73 (m, 4 H) 1.79 (d, J=4.29 Hz, 2 H) 2.02 (d, J=0.76 Hz, 3 H) 2.26 (d, J=13.14 Hz, 2 H) 2.70-2.82 (m, 2 H) 4.17 (q, J=7.07 Hz, 2 H) 6.38 (d, J=8.34 Hz, 1 H) 7.12 (d, J=8.34 Hz, 1 H) 7.63 (s, 1 H). MS (ES+): m/z 329.16/329.36 (100/70) [MH+]. HPLC: tR=1.28 min (Micromass TOF: polar—3 min). Compound 304B, the cis isomer eluted after: 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 1.54 (br. s., 1 H) 1.70 (d, J=12.63 Hz, 1 H) 1.87 (br. s., 1 H) 2.02 (d, J=0.51 Hz, 1 H) 2.07 (br. s., 1 H) 2.35-2.45 (m, 1 H) 2.69-2.81 (m, 1 H) 4.12 (q, J=7.07 Hz, 1 H) 6.39 (d, J=8.34 Hz, 1 H) 7.20 (d, J=8.34 Hz, 1 H) 7.64 (d, J=0.76 Hz, 1 H). MS (ES+): m/z 329.14/329.35 (100/70) [MH+]. HPLC: tR=1.30 min (Micromass TOF: polar—3 min).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:20][C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 97.2 %

Procedure:
A mixture of 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (VII) (5.70 g, 20.2 mmol), 4-amino-6-chloropyrimidine (I) (2.10 g, 16.2 mmol) and 4-(N,N-dimethylamino)-pyridine (2.90 g, 23.7 mmol) in dichloromethane (50 ml) was heated to reflux temperature for 18 hours. The progress of the reaction was monitored by TLC, then dichloromethane was completely distilled off. Aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with ethyl acetate (3×100 ml). The organic layers were separated, dried over sodium sulfate and concentrated to obtain 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (5.9 g, 79%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1.[B:18]1(B2OC(C)(C)C(C)(C)O2)[O:22]C(C)(C)C(C)(C)[O:19]1.C([O-])(=O)C.[K+]>CN(C=O)C>[C:14]([O:13][C:11]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([B:18]([OH:22])[OH:19])[CH:3]=[C:4]2[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)cnc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(B(O)O)cnc21
Temperature: 100 °C

Procedure:
To a mixture of tert-butyl 5-bromo-2,3-dihydropyrrolo[2,3-b]pyridine-1-carboxylate (B-12-2) (725 mg, 2.42 mMoles) and bis(pinacolato) diboron (894 mg, 3.52 mMoles) in 20 ml DMF were added potassium acetate (691 mg, 7.04 mMoles) and [1,1-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II) dichloromethane (1:1) complex (34.3 mg, 0.0469 mMoles). The mixture was heated in 100° C. microwave reactor for 60 min. LCMS indicated reaction was complete. RXN was filtered and the filtrate was concentrated to dryness under high vacuum. The residual was partitioned between EtOAc and saturated aqueous NaCl. The aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a 25 g silica gel cartridge with 1˜4% MeOH in DCM as solvent. The crude product and was used as is in the next step.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25](C)=[CH:24][CH:23]=2)(=O)=O)=[N:17][N:16]=[N:15]1)(OC(C)(C)C)=O.C1C=CC(S)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]1([S:19][C:18]2[N:14]([CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[N:15]=[N:16][N:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)c2nnnn2C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: c1ccc(Sc2nnnn2C[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 135.4 %

Procedure:
The mixture of 2 (6.0 g, 14.7 mmol), phenylthiol (6.5 g, 58.8 mmol) and K2CO3 (4.5 g, 41.1 mmol) in CH3CN (74 ml) was stirred for 2 days at room temperature. The reaction mixture was filtered through a pad of Celite and then concentrated in vacuo. The crude was purified by silica gel column with (Hexane:EtOAc=1:1) as an eluant to give 3 (5.2 g, 97%) as an colorless oil. [α]D −29.2 (c 1.34, CHCl3). 1H NMR (400 MHz, CD3OD, −20° C., rotamers 1:1): δ 1.30 & 1.42 (s, 9H), 1.73 & 2.01 (m, 4H) 3.40 & 3.45 (m, 13.2 Hz, 2H), 4.23 & 4.25 (m, 1H), 4.38 & 4.58 (m, 2H), 7.42 & 7.46 (m, 3H) 7.56 & 7.60 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 21.2, 23.6, 28.5, 46.5, 49.7, 50.4, 56.7, 60.5, 80.7, 128.1, 129.9, 133.1, 153.5, 154.9; IR (film): 2975, 1693, 1391, 1167, 688 cm−1; MS:(ESI) [M+1]+ 361.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: Cc1cccc(C)c1B(O)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 47.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.034 g (47%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](Cl)=[O:45]>ClCCl>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:10][N:11]=1)[C:44](=[O:45])[C:43]1[CH:47]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=1[CH3:48]
Reactant: CN(C)CCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)N(CCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 0.75 g of 10-[[6-[2-(dimethylamino)ethylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane is added (slowly) 0.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solution washed well with water. The organic layer is dried (MgSO4) and the solvent removed under vacuum. The residue is purified by column chromatography on silica gel with 30% methanol in chloroform as eluent to give 0.80 g of yellow solid; mass spectrum (CI), 511 (M+1).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[O:16])=[CH:8][CH:7]=1.[ClH:17]>O.Cl[Cu]>[Cl:17][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: Cl
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
NaNO2 (0.7 g; 10 mmol) dissolved in water (10 mL) was added with stirring to an ice-cold solution of 7-amino-1-tetralone (1.4 g; 8.8 mmol; from step (i) above) in conc HCl (aq.) over a period of 5 minutes. The resultant cold solution was then added slowly to an ice-cold solution of CuCl (1.5 g, 15 mmol) in conc. HCl (aq.), whereafter the resultant solution was stirred at RT for 2 hours and at 60° C. for 30 minutes. The slurry was cooled with ice, and the resultant precipitate was suction filtered, washed with water, and air dried. Yield 1.50 g (94%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=2)[CH2:24][CH2:23]1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:31][CH2:30][C:28]2[N:29]=[C:25]([CH:22]3[CH2:24][CH2:23]3)[S:26][CH:27]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: NCc1csc(C2CC2)n1
Product: O=C(NCc1csc(C2CC2)n1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9, 54 mg, 0.35 mmol) as starting materials; off white solid (66 mg, 45.4%). MS (ESI): 440 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=457.0, tR (minutes, Method G)=3.02. [α]D20=+4.17 (c=3.04 mg/mL,CHCl3) And the corresponding enantiomer
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=O)[CH3:10].N1C=CC=CC=1>O>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=[N:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH3:10]
Reactant: NN1CCCC1=O
Reactant: CCOC(=O)CC(=O)c1cccc(C)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CC(=NN1CCCC1=O)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-[6-methyl-(pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1).