Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:38])C>CCCCCC>[CH2:1]([O:8][C:9]1[N:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cccnc1OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=Cc1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
To a mixture of 2-(benzyloxy)nicotinonitrile (47.50 g) and anhydrous toluene (100 mL) was dropwise added a solution (1 M, 500 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1.5 hrs. A saturated aqueous ammonium chloride solution was dropwise added to the mixture and the mixture was stirred at room temperature for 30 min. Ethyl acetate was added to the mixture, and the mixture was further stirred at room temperature for 30 min. Insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(benzyloxy)nicotinaldehyde as an oil (19.71 g, 41%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>CO.O>[OH:20][CH:18]([CH3:19])[CH2:17][NH:16][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CC(O)CN
Solvent: CO
Solvent: O
Product: CC(O)CNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 28.1 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.20 mole) and 1-amino-2-propanol (4.51 g, 0.060 mole) was heated in an oil bath at 125° C. for 1 hour. After standing at ambient temperature for 18 hours, the viscous oil was dissolved in 20 ml of methanol and diluted with water causing a white solid to precipitate. The solid was collected, washed with water, and dried under ambient conditions to give 4.57 g (84%) of the product which was recrystallized from toluene to give 3.65 g solids; m.p. 116°-118° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[CH2:10]([NH2:12])C.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][NH:12][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCN
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)CCCCl
Yield: 73.7 %

Procedure:
3-Chloropropylsulfonyl chloride 1 (16.8 g, 94.9 mmol), ethylamine hydrochloride (13.5 g, 200 mmol), and potassium carbonate (27.6 g, 200 mmol) were sequentially added to ethyl acetate (500 ml). After the addition of N-benzyltrimethylammonium chloride (about 200 mg) to the mixture, the resultant mixture was stirred for 2 hours at room temperature and dried over anhydrous sodium sulfate. The mixture was filtered through a small amount of silica2 gel and the filtrate was concentrated in vacuo to give 12 g (74%) of crude N-methyl-3-chloropropylsulfonamide (intermediate 3b) as a pale yellow oil.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][Zn+].Br[C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+]>C1COCC1>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: [Zn+]CCC1OCCO1
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1Br
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2)sc1CCC1OCCO1
Yield: 52.2 %

Procedure:
A THF solution of (2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (35 mL. 17.3 mmol) was added to a degassed solution of ethyl 5-bromo-2-phenylthiazole-4-carboxylate (3.6 g, 11.5 mmol) and tetrakistriphenylphosphine palladium (666 mg, 0.58 mmol) in THF (20 mL). The reaction mixture was heated at reflux for 16 h then poured into sat aq NaHCO3. The mixture was extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with pentane/EtOAc (0-100% gradient) to give ethyl 5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenylthiazole-4-carboxylate (2.0 g, 52% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:24]=1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][CH3:20])[CH:24]=5)[CH2:30]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNCc1cccc(C2CCNC2)c1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CNCc1cccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)c1
Yield: 91 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.93 g, 3.5 mmol) and N-methyl-3-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (1.38 g, 91%) as a white solid, mp 239°-240° C.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C@H:10]([NH2:12])[CH3:11])[CH:6]=[N:5]1.C(C1C=NN(C[C:23]([O:25][CH3:26])=[O:24])C=1C)(=O)C>>[ClH:1].[ClH:1].[NH2:12][CH:10]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:23]([O:25][CH3:26])=[O:24])[C:8]=1[CH3:9])[CH3:11]
Reactant: Cc1c([C@@H](C)N)cnn1C
Reactant: COC(=O)Cn1ncc(C(C)=O)c1C
Agent: Cl
Product: COC(=O)Cn1ncc(C(C)N)c1C
Yield: 6.6 %

Procedure:
The title compound was prepared in 6.6% yield by the process as described for (R)-1-(1,5-dimethyl-1H-pyrazol-4-yl)ethanamine dihydrochloride (Amine 2) using methyl 2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)acetate (Step A8A) as a starting material. 1H NMR (300 MHz, DMSO-d5) δ 1.48 (3H, d, J=6.0 Hz), 2.22 (3H, s), 3.69 (3H, s), 4.29-4.33 (1H, m), 5.05 (2H, s), 7.59 (1H, s), 8.26 (3H, brs).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[NH:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1)N>>[CH3:31][C:27]1[CH:26]=[C:25]([N:23]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(C#N)c3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=355.2 (M+H)+
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:40])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of 1.00 g (3.57) of 4-tert-butyldimethylsilyloxy-3-propylbenzyl alcohol and 1.12 g (4.00 mmol) of triphenylphosphine in 10 mL methylene chloride was added 1.42 g (4.00 mmol) of carbon tetrabromide in portions as the reaction mixture was magnetically stirred at 0°-5° C. After the addition was complete, the ice-water bath was removed and the reaction was stirred for an additional 30 minutes and allowed to warm to room temperature. The methylene chloride was removed in vacuo, and the residue was applied to a silica gel flash chromatography column and eluted with 5% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 1.10 g (90%) of the title compound.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])(C)(C)C>C(O)C>[ClH:1].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCCNS(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)NCCCCN
Temperature: 100 °C

Procedure:
A solution of hydrochloric acid in ethanol was added to a solution of tert-butyl[4-(methanesulfonylamino)butyl]carbamate (18.9 g, 71.1 mmol) in ethanol (100 mL), and the reaction was heated at 100° C. for two hours. The solvent was removed under reduced pressure. A mixture of dichloromethane:hexanes was added to the resulting oil and removed under reduced pressure; this process was repeated several times. The residue was dried for three days under vacuum to provide 14.3 g of N-(4-aminobutyl)methanesulfonamide hydrochloride as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:6]2[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=2)=[O:20])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCCCC(=O)c2cc(C)c(O)c(C)c2)cc(C)c1O
Temperature: 0 °C
Yield: 17.6 %

Procedure:
To 300 ml of methylene chloride was dissolved 10 g/82 mmol of 2,6-dimethylphenol, and the solution was cooled to 0° C. in sodium chloride-ice bath. After adding 49 g/368 mmol of anhydrous aluminum chloride, methylene chloride solution of 7.3 g/40 mmol of adipic dichloride was added dropwise to the mixture with thorough stirring while maintaining the temperature to not more than 5° C. The reaction mixture was added to 50 ml of ice containing conc. hydrochloric acid to decompose excessive anhydrous aluminum chloride, and the mixture was extracted twice with methylene chloride. The organic layer was washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystalized from toluene to obtain 2.5 g of 1,6-bis(3',5'-dimethyl-4'-hydroxyphenyl)hexane-1,6-dione. MS: 354 (M+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:30]=[C:22]3[CH2:23][N:24]([CH:27]4[CH2:29][CH2:28]4)[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[OH-].[Li+]>>[CH:27]1([N:24]2[CH2:25][CH2:26][N:21]3[N:20]=[C:19]([NH:18][C:16]4[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=[C:12]([C:11]5[CH:10]=[CH:9][N:8]=[C:7]([N:33]6[CH2:45][CH2:44][N:36]7[C:37]8[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=8[CH:43]=[C:35]7[C:34]6=[O:46])[C:6]=5[CH2:5][OH:4])[CH:17]=4)[CH:30]=[C:22]3[CH2:23]2)[CH2:29][CH2:28]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3CC3)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc3n(n2)CCN(C2CC2)C3)c1=O
Yield: 17.5 %

Procedure:
Following the procedures as described in Example 113, 128d (331 mg, 0.53 mmol) was hydrolyzed with lithium hydroxide afforded 128 as a white solid (54 mg, 20%). LCMS: [M+H]+ 581. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=5.0, 1H), 7.93 (d, J=2.0, 1H), 7.72 (d, J=2.0, 1H), 7.40 (s, 1H), 7.34 (d, J=5.0, 1H), 6.90 (s, 1H), 5.70 (s, 1H), 5.03-5.02 (m, 1H), 4.64-4.62 (m, 1H), 4.52 (s, 1H), 4.32 (s, 1H), 4.16-4.03 (m, 4H), 3.89-3.87 (m, 1H), 3.80 (s, 2H), 3.70 (s, 3H), 3.12-3.10 (m, 2H), 2.61-2.57 (m, 4H), 1.90 (d, J=5.5, 3H), 1.79 (s, 2H), 0.56 (d, J=6.0, 2H), 0.53 (s, 2H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[CH3:18][N:19]=[C:20]=[S:21].O>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]([NH:19][CH3:18])=[S:21])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2cc(-c3ccc(N)cc3)nc2c1
Reactant: CN=C=S
Solvent: CS(C)=O
Solvent: O
Product: CNC(=S)Nc1ccc(-c2cn3ccc(C)cc3n2)cc1
Yield: 81.9 %

Procedure:
A solution of 7-methyl-2-(4-aminophenyl)imidazo-[1,2-a]pyridine (14.9 g) and methyl isothiocyanate (6.4 g) in dimethyl sulfoxide (400 ml) was stirred at 50° C. for 10 hours. The reaction mixture was poured into water (1 l) and the resultant precipitate was collected by filtration, washed with water and ethyl acetate successively and dried over phosphorus pentoxide to give 7-methyl-2-[4-(3-methylthioureido)-phenyl]imidazo[1,2-a]pyridine (16.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[Li][CH3:35]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])([OH:13])[CH3:35])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1
Reactant: [Li]C
Reactant: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanone (0.225 g, 0.474 mmol, Intermediate 11: step b) was added THF (15 mL). The solution was cooled to −78° C. and MeLi (1.6 M in Et2O, 0.36 mL, 0.58 mmol) was introduced which resulted in an immediate light orange homogeneous mixture. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (4×30 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (10% CH3CN-DCM increasing to 25% CH3CN and then to 5% MeOH) provided the title compound as a pale yellow amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J=1.9 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.61 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.35 (s, 2H), 4.07 (s, 3H), 2.57 (s, 1H), 2.39 (s, 3H), 1.99 (s, 3H), 1.92 (s, 3H); MS (ESI): mass calcd. for C25H22ClF3N2O3, 490.1, m/z found 491.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(2,4-dimethyloxazol-5-yl)ethanol was purified by chiral chromatography (Chiralpak AD-H, solvent: 95% heptane/5% ethanol), to give 2 enantiomers. The first eluting enantiomer was Example 10b and the second eluting enantiomer was Example 10c.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@H:11]2[CH3:16])=[O:9])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][C@H:11]3[CH3:16])=[O:9])=[CH:6][N:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (15 mL), (R)-(6-aminopyridin-3-yl) (3-methylmorpholino)methanone 248a (332 mg, 1.5 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (480 mg, 1.8 mmol), and cesium carbonate (978 mg, 3.0 mmol). After bubbling nitrogen through the suspension for 3 minutes, Xantphos (87 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.075 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 2.5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (2:1 to 1:2) to afford 249a (430 mg, 70%) as a yellow solid. MS-ESI: [M+H]+ 407.3
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16](C)([O-])C.[K+].ICC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
1-tert-Butoxycarbonyl-3-oxopiperazine (7.5 g) was dissolved in dry DMF (250 ml) and potassium tert-butoxide (8.4 g) was added. The mixture was stirred at ambient temperature for 30 minutes, then iodoethane (3.3 ml) added, and stirring continued at the same temperature for 24 hours. A further equal portion of iodoethane was added and stirring continued for 24 hours. Solvent was evaporated, and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, evaporated, and purified by chromatography on silica, using as eluant a gradient increasing in polarity from 0 to 25% isopropanol in iso-hexane. Relevant fractions were combined and evaporated to give 1-tert-butoxycarbonyl-4-ethyl-3-oxopiperazine (6.0 g).
Reaction SMILES: O.C[O:3][C:4](=[O:27])[CH2:5][C@@H:6]([OH:26])[C@H:7]([N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.O.[OH-].[Li+].Cl>C1(C)C=CC=CC=1>[C:22]([O:21][C:19]([N:17]([CH3:18])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[C@H:6]([OH:26])[CH2:5][C:4]([OH:27])=[O:3])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C[C@@H](O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(Cl)c(Cl)c1)[C@H](O)CC(=O)O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Water (3 ml) is added to the stirred reaction mixture containing (3R,4R)-4-(tert-butoxy-carbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-hydroxy-pentanoic acid methyl ester (5) at 18-22° C., then lithium hydroxide monohydrate (0.755 g, 18 mmol) is added. Stirring at 18-22° C. is continued for approx. 2 hours. Hydrochloric acid (approx. 12.6 ml of 2N, 25.2 mmol)) is added over a period of approx. 30 minutes, until pH 1.7-2.2 is obtained. Toluene (12 ml) is added to the stirred mixture and stirring at 18-22° C. is continued for approx. 10 minutes. Stirring is stopped and the layers are allowed to separate. The lower, aqueous layer is separated and the upper, organic layer is extracted with water (12 ml). Stirring is stopped and the lower, aqueous layer is separated. The organic layer is filtrated over a filter charged with anhydrous sodium sulfate (3 g) in order to remove remains of water and 1,3-dicyclohexyl urea, the latter originating from step 1. The filter cake is rinsed with toluene (2 ml), then N,N-dimethylformamide (12 ml) is added to the filtrate. The resulting solution is concentrated by distilling toluene at a mantle temperature of approx. 50° C. under reduced pressure, until the volume of the residue is approx. 14 ml. This resulting solution, containing (3R,4R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-hydroxy-pentanoic acid (6) is used as such in the following step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.[Br:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>CC#N.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[Br:31])[CH:8]=[N:9][CH:10]=1
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: BrCc1ccccc1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cncn1Cc1ccccc1Br
Temperature: 25 °C

Procedure:
To a solution of 3-(1-trityl-1H-imidazol-4-yl)propanoic acid methyl ester (5.0 g, 12.6 mmol) in CH3CN (80 mL) is added a solution of 2-bromobenzylbromide (2.84 g, 11.4 mmol) in CH3CN (20 mL). The resulting clear solution is stirred at ambient temperature over the weekend. The mixture is concentrated and the remaining oil is taken up in 85 mL methanol and heated up at 70° C. for 2 h. Then the mixture is concentrated to give a yellow oil, which is taken up in EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated to yield a viscous oil. The crude reaction mixture is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to give the desired compound. MS (ESI) m/z 323 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[N:3]=1.C([Mg]Cl)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1([CH:30]=[O:31])[CH2:27][CH2:28][CH3:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1([CH:30]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[N:3]=1)[OH:31])[CH2:27][CH2:28][CH3:29])=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: Clc1ccc(Br)nc1Cl
Reactant: CCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC1(C(O)c2ccc(Cl)c(Cl)n2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a stirred solution of 2-bromo-5,6-dichloro-pyridine (0.500 g, 2.20 mmol) in THF (6 mL) at 0° C. and under nitrogen was added isopropylmagnesium chloride (1.21 mL of a 2 M solution in THF, 2.42 mmol) dropwise. After 2 hours, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.317 g, 1.32 mmol) in THF (1 mL) was added to the reaction mixture dropwise. After 30 minutes, the reaction mixture was warmed to ambient temperature and stirred for one hour, then quenched by the addition of saturated aqueous NH4Cl (10 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. Purification of the residue by chromatography (silica, 0 to 40% EtOAc in hexanes) gave 2-[(5,6-dichloro-pyridin-2-yl)-hydroxy-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.289 g, 0.745 mmol, 56%) as a yellow oil and as an inseparable mixture of diastereomers.