Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)=[N:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:30]2[CH2:29][CH2:28][N:27]([C:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:16]4[CH:17]=[CH:18][N:13]=[CH:14][N:15]=4)[CH2:20][CH2:21]3)=[O:26])[CH2:32][CH2:31]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCN(C(=O)C3CCN(c4ccncn4)CC3)CC2)cc1
Yield: 42.4 %

Procedure:
A solution of 4-cyanophenylsulphonyl chloride (363 mg) in dichloromethane (10 ml) was added to a stirred mixture of 1-[1-(4-pyrimidinyl)-4-piperidylcarbonyl] piperazine (412.5 mg) and triethylamine (0.28 ml) in dichloromethane (15 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between dichloromethane and water, and the organic phase washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography using 0.5% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-cyanophenylsulphonyl)-4-[1-(4-pyrimidinyl)-4-piperidylcarbonyl] piperazine (280 mg), mp 180-181° C.;
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[CH3:5][C:6]12[CH2:19][C:10]1([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[N:9]1[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:8]1[S:7]2>ClCCl>[CH3:5][CH:6]1[CH:19]=[C:10]([C:11]([O:13][CH2:14][C:15]([Cl:16])([Cl:17])[Cl:18])=[O:12])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:8]2[S:7]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 71.7 %

Procedure:
A solution of aluminum bromide (3.4 g.) in dried dichloromethane (20 ml.) was dropwise added at -10° C. over about 10 minutes to a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (4.6 g.) in dried dichloromethane (30 ml.). After addition, the reaction mixture was stirred for 4.5 hours at room temperature, washed in turn with 2% hydrochloric acid (30 ml.) three times, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. After drying over magnesium sulfate, the solvent was distilled off and the residue was washed with ether and collected by filtration to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (3.3 g.). This compound was recrystallized from ethanol to give crystals, mp 175° to 178° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[CH2:25]([O:27][P:28]([O:32]CC)[O:29][CH2:30][CH3:31])[CH3:26]>C(OCC)(=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P:28](=[O:32])([O:29][CH2:30][CH3:31])[O:27][CH2:25][CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)OCC
Temperature: 135 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
2-(12-bromododecyl)isoindoline-1,3-dione (9.30 g, 23.6 mmol) was combined with triethylphosphite (11.76 g, 70.7 mmol) in a round bottom flask and the mixture heated and stirred at 135° C. for 16 hours. The reaction mixture was then put under hi-vacuum at 90° C. for 4 hours. The product was then obtained as a clear oil after column chromatography in ethyl acetate. (8.96 g, 84% yield). 1H NMR (400.14 MHz, CDCl3) δ 7.80 (dd, J=5.43, 3.04 Hz, 2H), 7.67 (dd, J=5.47, 3.05 Hz, 2H), 4.08-4.02 (m, 4H), 3.63 (t, J=7.33 Hz, 2H), 1.73-1.45 (m, 6H), 1.32-1.11 (m, 22H). 13C {1H} NMR (100.62 MHz, CDCl3) δ 168.4 (2C), 133.7 (2C), 132.1 (2C), 123.0 (2C), 61.30 (d, J=6.5 Hz, 2C), 37.96, 30.51, (d, J=17.0 Hz), 29.41 (2C), 29.35, 29.25, 29.07, 28.98, 28.49, 26.75, 25.55 (d, J=140.1 Hz), 22.29 (d, J=5.0 Hz), 16.39 (d, J=6.1 Hz, 2C). 31P {1H} NMR (161.97 MHz, CDCl3): δ 33.38. MS (ESI, m/z): 452.235 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 452.256039 (452.254800). Analysis calculated (found) %: C 63.84 (63.41), H 8.48 (8.53).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[CH:6][CH:7]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C/C(/O)=C/C(C)=O.C=C.C=C.[Rh]>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)Oc1cccc(Br)c1
Reactant: O=C1C=CCC1
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@@H](c2cccc(Br)c2)C1
Temperature: 25 °C
Yield: 102 %

Procedure:
Under a nitrogen stream, 3-bromophenylboric acid (14.2 g, 71 mmol), (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl((R)-BINAP) (1.06 g, 1.7 mmol), and acetylacetonato bis(ethylene)rhodium(I) (438 mg, 1.7 mmol) were dissolved in a solvent mixture of 1,4-dioxane (150 mL) and water (15 mL), followed by degassing with ultrasonic waves, and then cyclopentenone (2.4 mL, 28 mmol) was added and the mixture was stirred under reflux with heating for 3 hours. The reaction solution was cooled to room temperature, followed by addition of saturated aqueous sodium bicarbonate solution, and then the solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate/hexane:10/90-20/80) to give the title compound (6.83 g).
Reaction SMILES: C(O[C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)=[CH:14][CH:13]=3)=[O:6])(C)C.[C:44]1([Li])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(O)(=O)C>O1CCCC1.C1C=CC=CC=1>[C:24]1([O:23][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH:9]=[N:8][C:7]([C:5](=[O:6])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:19]([CH2:20][O:21][CH3:22])[C:18]3=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(Oc3nccc4ccccc34)ccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(Oc4nccc5ccccc45)cc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
476 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 10 ml of tetrahydrofuran under argon at -60° C. with 0.79 ml of a 0.9 m solution of phenyllithium in benzene. After 1 hour at -60° C., it is stirred for 16 hours at room temperature. The batch is acidified with glacial acetic acid and concentrated by evaporation. The residue is dispersed in ethyl acetate/water and the organic phase is washed, dried, filtered and concentrated by evaporation in succession with respectively saturated sodium bicarbonate and common salt solution. The residue is chromatographed on silica gel with methylene chloride: ethanol=10:1. The corresponding fractions are combined, concentrated by evaporation and recrystallized. 30 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-3-benzoyl-β-carboline of melting point 159°-160° C. (ethyl acetate/hexane) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:32]([C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([O:22][CH3:21])[CH:24]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:8])=[O:5]
Reactant: COc1cc(NNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Product: COc1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Yield: 74.2 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.400 g, 4.57 mmol), tert-butyl 2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate (step-3 of Intermediate-32, 1.30 g, 4.57 mmol) and DCM 30 mL) to afford 2.0 g of the desired product. 1H NMR (300 MHz, DMSO d6): 1.33-1.46 (m, 9H), 3.87 (s, 3H), 4.40 (s, 2H), 7.06 (d, J=8.4 Hz, 1H), 7.32-7.36 (m, 3H), 7.45-7.52 (m, 1H), 7.96 (d, J=8.7 Hz, 1H), 9.92 (s, 1H), 10.07 (br s, 1H), 11.13 (br s, 1H); MS (m/z): 589.69 (M)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(=O)=O.CO.C([Li])CCC.CCCCCC.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:35]=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:35]([OH:36])[C@@H:34]([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: c1ccc2scnc2c1
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of benzothiazole (0.74 g) in tetrahydrofuran (10 ml) is cooled with dry ice/methanol under a nitrogen atmosphere. A 1.6 M n-butyllithium/hexane solution (3.5 ml) is added dropwise thereto, and the mixture is stirred for 30 minutes. A solution of (2S)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanal (1.25 g, Reference compound No. 2-1) in tetrahydrofuran (10 ml) is added to the mixture, and the whole is further stirred for four hours. A saturated aqueous ammonium chloride solution is added to the reaction mixture, the temperature is raised to room temperature, and the whole is stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate, and the extract is washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (0.93 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29](O)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O=P(Cl)(Cl)Cl.C(O)CO.C(=O)=O>N1C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:42]([CH2:41][CH2:40][O:39][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccccc1
Agent: O=C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: OCCO
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (28-02) (200 mg, 456 μmol, Eq: 1.00) and N-(2-(tert-butyldimethylsilyloxy)ethyl)aniline (46) (126 mg, 501 μmol, Eq: 1.1) in pyridine (2.00 ml) was added POCl3 (210 mg, 127 pμl, 1.37 mmol, Eq: 3.00) at −10° C. (ethylene glycol-dry-ice bath), then the reaction mixture was stirred at 0° C. for 2 hr. Ice cooled water was slowly added to the reaction mixture at 0° C., the reaction mixture was extracted with ethyl acetate, the organic layer was washed with aqueous saturated NaHCO3 solution, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient 5 to 30% ethyl acetate-hexane) to obtain 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-phenylpyrimidine-4-carboxamide (47) (colorless oil, 287 mg, 427 μmol, 93.7% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:51][CH2:52][C@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]1[OH:59]>ClCCl.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:4]2[C:9]([C:10]([NH:51][CH2:52][C@H:53]3[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]3[OH:59])=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: NC[C@H]1CCCC[C@@H]1O
Reactant: Cc1cc(N2CCOCC2)nc(C2CC2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCOCC2)nc(C2CC2)c1C(=O)NC[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized according to the methods described in sections a) to d) of example X1) (0.15 g, 0.57 mmol) in dichloromethane (10 ml) are added N-ethyl-diisopropylamine (0.24 ml, 1.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.13 g, 0.69 mmol), and 1-hydroxybenzotriazole hydrate (0.015 g, 0.11 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0° C., before (1S,2R)-2-(aminomethyl)cyclohexanol (0.07 g, 0.57 mmol) is added and stirring is continued for 3 days. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 60% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-N-[[(1R,2S)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X3) (0.17 g, 0.45 mmol, 80%). [M+H]+374.3.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[C:13]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]2[N:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](=[O:31])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1.COS(OC)(=O)=O>O1CCCC1.[Cl-].[NH4+]>[C:13]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:14]=[CH:15][C:16]([CH2:19][C@H:20]2[N:24]([C:25](=[O:30])[C:26]([CH3:28])([CH3:29])[CH3:27])[C:23](=[O:31])[C@H:22]([CH3:1])[CH2:21]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Solvent: CC(C)NC(C)C
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Reaction time: 0.25 h

Procedure:
0.37 ml of n-butyllithium (1.6 M) was added to a solution of 88 μl diisopropylamine in 1 ml tetrahydrofuran at about 0° C. After about 15 min, 200 mg (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1-a, R1=pivaloyl) of example 4 dissolved in 2 ml tetrahydrofuran were added. After about 15 min, 59 μl dimethylsulphate were added. After about 2 hours at about 0° C., the mixture was diluted with ammonium chloride solution, extracted with ethyl acetate and concentrated to dryness (196 mg). According to HNMR analysis, the ratio of diastereoisomers is 83:17 [(3R,5S):(3S,5S)]. The material was purified by chromatography to afford 43 mg (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one=′H-NMR (DMSO): (2-a, R1=pivaloyl) 1.07 (3H, d, 1-CH3); 1.29 (9H, s, C(CH3)3); 1.63 (1H, m, 4-CHH); 2.03 (1H, m, 4-CHH); 2.81 (2H, m, 3-CH, 1-CHH); 2.94 (1H, dd, 1-CHH); 4.45 (1H, m, 5-CH); 7.34 (3H, m, aromatic); 7.44 (2H, m, aromatic); 7.61 (4H, m, aromatic). m/z: 350 (MH+, 100%). Spectroscopic data for (2-b, R1=pivaloyl) as Example 5-2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)cccc1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cccc3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,6-difluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.6 mg (>100%) of the title compound were recovered.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1
Reactant: CC(=O)Nc1nc(C)cs1
Reactant: CC(C)(C)c1cc(Cl)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)(C)C)c2)s1
Temperature: 150 °C

Procedure:
A mixture of 2-acetamido-4-methylthiazole (92 mg), 4-chloro-2-tert.butylpyridine (83 mg), palladium acetate (10.4 mg), tri-tert-butylphosphonium tetrafluoroborate (28.3 mg) and cesium carbonate (319 mg) in DMF under an argon atmosphere is heated for 3 hours at 150° C. The reaction mixture is cooled, filtered through celite, evaporated and purified by normal and then reversed phase chromatography to give the title compound
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([N+:33]([O-:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([N+:33]([O-:35])=[O:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under argon. (rac)-Allyl 4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (15.0 g, 30.8 mmol) and morpholine (1.5 eq., 4.03 g, 46.3 mmol) were initially charged in dry THF (300 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 1.78 g, 1.54 mmol) was added, and the reaction mixture was stirred at RT for 2 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (700 ml). The organic phase was washed with 0.5 N hydrochloric acid (500 ml) and with saturated sodium chloride solution (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate and dried under high vacuum. The title compound was obtained as a solid (12.87 g, 93% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:19]4[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a cooled suspension (0° C.) of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)piperidin-4-ol (described in Example 82a) (6.95 g, 19.6 mmol) in diethyl ether (200 mL) under nitrogen was added lithium aluminum hydride (1.49 g, 39.2 mmol, 8 eq of hydride) in portions. The suspension was stirred at 0° C. for 30 min and warmed to room temperature. After 18 h at room temperature, the excess reagent was carefully quenched with the following in sequence: water (1.5 mL), 2.5 N NaOH (1.5 mL) and additional water (4.5 mL). The suspension was stirred vigorously until the aluminum salts became a granular white solid. The suspension was diluted with ethyl acetate (100 mL), dried with a small amount of anhydrous magnesium sulfate and filtered. The filter cake was rinsed thoroughly with ethyl acetate. The solvent was removed to yield 6.16 g (92%) of the title compound as a white solid. No additional purification was required. TLC analysis (Rf 0.15, 50% ethyl acetate in hexane). NMR (CDCl3, 300 MHz) 7.20 (m, 4H), 6.95 (m, 3H), 4.60 (s, 1H), 4.24 (s, 1H), 3.70 (m, 1H), 3.34 (s, 2H), 2.88 (m, 2H), 2.58 (s, 2H), 2.37 (m, 2H), 1.57 (m, 2H) MS (CI, CH4) m/z 340 (M+1.98), 342 (33), 322 (100), 368 c(M+29,22), 114 (26)
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[OH:7][CH:8]([CH2:16][NH2:17])[CH2:9][CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12].[CH2:18]([O:25][C:26](ON1C(=O)C2C(C3CC2C=C3)C1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(#N)C>[CH2:18]([O:25][C:26]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][CH:8]([OH:7])[CH2:16][NH2:17])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(O)CC[C@H](N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)C2C3C=CC(C3)C2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NCC(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
Sodium bicarbonate (4.2 g, 0.050 mol) and 5-hydroxylysine hydrochloride (2.50 g, 0.0126 mol) were dissolved in water (70 ml) with stirring at room temperature. Acetonitrile (40 ml) was added, followed by N-benzyloxycarbonyloxy-5-norbornen-2,3-dicarboximide (3.94 g, 0.0126 mol) in acetonitrile (30 ml) over 15 minutes. After 2 hours, most of the acetonitrile was removed in vacuo and the remaining solution was treated with hydrochloric acid to reduce the pH to 2.0. The solution was extracted with ethyl acetate (50 ml), the pH was increased to 5.5 with sodium hydroxide, and the product was purified over Dowex 50W-2X. The product was eluted with 3% pyridine in water, concentrated to a small volume and freeze dried to give III (1.24 g, 0.0042 mol, 33%); nmr (0.5 M NaOD in D2O)δ 1.4-2.1 (m, 4H, --CH2CH2 --), 3.1-3.5 (m, 2H, --NCH2CH ), 3.5-3.9 (m, 1H, --NCHRCO), 3.9-4.2 (m, 1H, --CH2CHOHCH2 --), 5.10 (s, 2H, --CH2O), 7.39 (s, 5H, --CH2O); mass spectrum (FAB): 297 (M+1).