Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].[BH3-]C#[N:19].[Na+].O>CO>[NH2:19][CH:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: [BH3-]C#N
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC(N)CC(=O)OC
Yield: 44.8 %

Procedure:
Dimethyl 3-ketoglutarate (13 g) in methanol (50 ml) was treated with ammonium formate (5 g) and NaCNBH3 (2 g). 10 ml of H2O was added and the excess solvent removed under reduced pressure. The semi-solid was dissolved in 5% aqueous HCl (250 ml), and washed with CH2Cl2 (2×50 ml). The aqueous layer was made basic (pH>9) with K2CO3 and the product was extracted using CH2Cl2 (2×75 ml). The organic layers were combined and dried with Na2SO4. The excess solvent was removed to give 2.5 g of the dimethyl (±)3-aminoglutarate. This was dissolved in methanol (50 ml) and treated with 4N HCl/Dioxane (10 ml). The excess solvent was removed under reduced pressure to give a 2.7 g of dimethyl (±)3-aminoglutarate hydrochloride. MS and 1H-NMR were consistent with the desired product.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:22]#[C:23][C@:24]2([O:32][CH3:33])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:33][O:32][C@@:24]1([C:23]#[C:22][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[OH:40])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1
Reactant: CO[C@]1(C#CC(O)(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)CN2CCC1CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@]1(C#CC(O)(c2ccccc2)C2CCNCC2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Neat TFA (130 μL, 1.67 mmol) was added in one portion to a solution of tert-butyl-4-(1-hydroxy-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propynyl}-1-piperidinecarboxylate 170 (190 mg, 0.42 mmol) in CH2Cl2 (5 ml) at 0° C. After 3 hours at the same temperature, the cooling bath was removed and the reaction warmed up at room temperature. After 10 hours, the reaction was diluted with ether and cooled at 0° C. A solution of NaHCO3 was slowly added till pH was made basic. After separation, the organic layer was dried over Na2CO3 and evaporated in vacuum. The white solid was chromatographied on silica gel (elution: CH2Cl2/MeOH/NH4OH 94/6/0.1) and 3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-1-(4-piperidinyl)-2-propyn-1-ol 136 was obtained as a colorless semi-solid oil (mixture of diastereomers, 57 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1[CH3:27]>CS(C)=O>[CH3:27][C:18]1[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=[C:22]([CH3:23])[C:17]=1[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1

Procedure:
A mixture of dimethylsulfoxide (875 ml), p-methoxyphenol (43.3g 0.3 48 mol), powdered potassium carbonate (69.9 g, 0.5 mol) and 4-chloro-3,5-dimethylnitrobenzene (see example 39, 64.6 g; 0.348 mol) is heated at a temperature of 125° for 18 hours. The suspension is cooled to 25° and pumped onto ice water (2620 ml) with stirring. The mixture is stirred for 2 hours, the product is filtered, washed with water (4×300 ml) and air dried. A solution of the product in tert-butylmethyl ether (3L) is dried over magnesium surface and treated with charcoal (6.4g) for 2.5 hours. The drying agent is filtered off and the filtrate concentrated in vacuo at 50°/3mm Hg to give product which is recrystallized from toluene (212ml) and petroleum ether (600 ml) to give 3,5-dimethyl-4-(4'-methoxyphenoxy)nitrobenzene, m.p. 120°-123°.
Reaction SMILES: [C:1]12([C:7]3[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=3)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][CH:1]1[C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cccc(C23CCCC2O3)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1cccc(C2CCCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4 g (17.2 mmol) of ethyl 3-(6-oxabicyclo[3.1.0]hex-1-yl)benzoate (6) and 50 ml of methylene chloride are introduced into a round-bottomed flask. The mixture is cooled to 0° C. and then 2.2 ml (17.2 mmol) of BF3.Et2O are added dropwise. The reaction mixture is stirred at 0° C. for 1 hour and then 25 ml of a saturated aqueous sodium bicarbonate solution are added. The mixture is separated by settling and the aqueous phase extracted with methylene chloride. The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). The title product is obtained in the form of a pale yellow oil (3.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](C)[N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:17].[CH3:18]O>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:18])=[CH:12][N:11]=2)=[N:17][C:6]=1[CH3:7]
Reactant: CO
Reactant: Cc1cccc(C(=O)c2cc(C)c(C)o2)n1
Reactant: N
Product: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Temperature: 160 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (780 mg), methanol (7 ml), and a 28% aqueous ammonia solution (7 ml) were placed in a sealed tube and were stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (529 mg, yield 68%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Cl:18])(=O)C>>[Cl-:18].[CH:7](=[N+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Cl
Product: C(c1ccccc1)=[N+]1CCOCC1
Product: [Cl-]

Procedure:
The reaction of 17.9 ml (0.200 mol) morpholine and 10.1 ml (0.100 mol) benzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 6.0 ml (0.100 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 10.1 g (corresponding to 48% of the yield calculated by theory) 4-benzylidene-morpholin-4-ium chloride.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH:27][CH3:26])=[O:29])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CNC(=O)c1cccc(-c2cnc(NCCN3C(=O)NC(=O)C3(C)C)nc2-c2ccc(Cl)s2)c1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-(methyl-carbamoyl)phenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 499.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:22]=[C:23]=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11].C(N(CC)CC)C.[CH3:32][C:33]1[NH:37][CH:36]=[N:35][C:34]=1[CH2:38][S:39][CH2:40][CH2:41][NH2:42].CO>O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:9]([C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23]([NH:42][CH2:41][CH2:40][S:39][CH2:38][C:34]2[N:35]=[CH:36][NH:37][C:33]=2[CH3:32])=[S:24])[N:17]=1)[C:10]([NH2:12])=[NH:11]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: N=C(N)Nc1nc(CSCCN=C=S)cs1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]cnc1CSCCNC(=S)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-guanidinothiazol-4-ylmethylthio)ethyl isothiocyanate hydrogen maleate (0.778 g), triethylamine (1.0 g), 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazole (0.364 g) and methanol (20 ml) was stirred at room temperature overnight. The mixture was poured into water (60 ml), extracted with ethyl acetate (2×50 ml), the combined extracts washed with water (25 ml), dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in acetone (10 ml) and added to a solution of maleic acid (0.28 g) in acetone (10 ml). The precipitate was filtered off and recrystallized from ethanol (charcoal) to give 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-3-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea maleate as a white solid, m.p. 90°-93° (decomp.).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17]/[C:18](/[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[CH:19]\[C@H:20]1[C@H:22]([C:23](Cl)=[O:24])[C:21]1([CH3:27])[CH3:26].[C-:35]#[N:36].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[C:35]([CH:11]([O:12][C:23]([C@H:22]1[C@H:20](/[CH:19]=[C:18](\[Cl:17])/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[C:21]1([CH3:27])[CH3:26])=[O:24])[C:10]1[CH:13]=[CH:14][C:15]([F:16])=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)#[N:36]
Reactant: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)Cl
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Yield: 70.5 %

Procedure:
1.08 g (0.005 mol) of 3-phenoxy-4-fluoro-benzaldehyde and 1.52 g (0.005 mol) of (±)-trans-3-(Z-2-chloro-2-(4-chlorophenyl)-vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid chloride were together added dropwise to a mixture of 0.4 g of sodium cyanide, 0.6 ml of water, 20 ml of n-hexane and 0.1 g of tetrabutylammonium bromide at 20°-25° C., whilst stirring, and the reaction mixture was then stirred at 20°-25° C. for 4 hours. 100 ml of toluene were subsequently added and the reaction mixture was extracted twice by shaking with 60 ml of water each time. The organic phases were separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 1.8 g (70.6% of theory) of (±)-trans-3-(Z-2-chloro-2-(4-chlorophenyl)-vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid (±)-α-cyano-3-phenoxy-4-fluoro-benzyl ester were obtained as a viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36](O)[CH:35]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:31][O:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:11][CH2:10][CH2:9][C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH:35]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: Cc1ccc(F)c(CCO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(OCCc2cc(C)ccc2F)c1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2-(2-Fluoro-5-methyl-phenyl)-ethanol (508 mg, 3.29 mmol) was dissolved in THF (23 ml). Triphenylphosphine (1.08 g, 4.12 mmol) and 3-hydroxy-4-methoxy-benzoic acid methyl ester (500 mg, 2.75 mmol) were added, the mixture was cooled in an ice bath, and DIAD (832 mg, 4.12 mmol) was added slowly with stirring. The ice bath was removed and stirring was continued overnight at room temperature. The volatiles were evaporated in vacuo, and the residue was purified by RP HPLC (water/ACN gradient) to give 530 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].Br[CH:19](Br)[C:20]([OH:22])=[O:21].OS(O)(=O)=O>C(O)CC.CO.O>[CH3:12][O:22][C:20]([CH:19]1[O:11][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Br:1])[C:9]=2[O:10]1)=[O:21]
Reactant: O=Cc1ccc(O)c(O)c1Br
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(Br)Br
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCCO
Product: COC(=O)C1Oc2ccc(C=O)c(Br)c2O1
Temperature: 25 °C

Procedure:
To a mixture of 2-bromo-3,4-dihydroxy-benzaldehyde (2.17 g, 10.0 mmol) and K2CO3 (5.56 g, 40.2 mmol) in n-propanol (25 mL) was added dibromoacetic acid (2.18, 10.0 mmol) and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature, another portion of dibromoacetic acid (1.75 g, 8.0 mmol) was added. The mixture was stirred at reflux for 46 h. n-Propanol was evaporated and water (30 mL) was added. The resulting aqueous solution was acidified to pH 2 by adding 1 N HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (MgSO4) and evaporated in vacuo to afford crude 4-bromo-5-formyl-benzo[1,3]dioxole-2-carboxylic acid (1.34 g) as a brownish solid. This crude product was dissolved in anhydrous methanol (50 mL) and conc. H2SO4 (5 mL) was added drop by drop. The resulting mixture was refluxed overnight and cooled to room temperature. Water (50 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (ethyl acetate:hexane=5:95) to furnish 4-bromo-5-formyl-benzo[1,3]dioxole-2-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][C:15]#N.ClCCl.S([O-])([O-])(=O)=[O:22].[Na+].[Na+].Cl>C(OCC)(=O)C.CO>[Br:1][CH:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[CH:4]1[CH2:5][CH2:6][C@@H:7]2[C@H:13]([CH3:17])[CH2:14][CH2:15][OH:22]
Reactant: O=S(=O)([O-])[O-]
Reactant: C[C@H](CC#N)[C@H]1CCC2C(=CBr)CCC[C@@]21C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: C[C@H](CCO)[C@H]1CCC2C(=CBr)CCC[C@@]21C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A 84 mg amount of (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butyronitrile was taken in a 25 ml eggplant-shaped flask, then 5 ml of dried dichloromethane was then added to dissolve the same. The solution was cooled by a −70° C. bath, then 660 μl of a 1.5M [(CH3)2CHCH2]2AlH/toluene solution was added dropwise. The solution was stirred at the same temperature for 1 hour, then 0.5 ml of a saturated aqueous solution of sodium sulfate, 0.3 ml of methanol, 0.5 ml of 2N hydrochloric acid, and 15 ml of ethyl acetate were added and the solution stirred for 30 minutes. The reaction solution was filtered by Celite, then was washed by a saturated solution of ammonium chloride and saturated saline, then was dried over anhydrous magnesium sulfate and the desiccant filtered out. The solvent was distilled off under reduced pressure to obtain (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl]butanol in an amount of 85 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)[OH:10])[CH:2]=1.[O:26]=[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41](O)=[O:42])[C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][C:29]([CH3:33])([CH2:30][CH3:31])[C:28](=[O:34])[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=1)[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:42])=[O:26]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)COc1cccc([C@H](O)CCc2cccnc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cccnc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of alcohol 21 (530 mg, 1.54 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 393 mg, 1.54 mmol, followed by 1,3-dicyclohexylcarbodiimide (381 mg, 1.85 mmol), and 4-(dimethylamino)-pyridine (132 mg, 1.08 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-60% EtOAc/hexanes) to give (1R)-3-(3-Pyridyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (860 mg, 96%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 8.46 (m, 2H), 7.50-6.80 (m, 6H), 5.80 (t, J=6.1 Hz, 1H), 5.32 (d, J=5.0 Hz, 1H), 4.54 (s, 2H), 3.38 (d, J=12.8 Hz, 1H), 3.14 (td, J=12.6, 3.0 Hz, 1H) 2.60 (m, 2H), 2.36 (d, J=13.7 Hz, 1H), 2.25 (m, 1H), 2.10 (m, 1H), 1.75 (m, 4H), 1.49 (s, 9H), 1.45 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.0, 168.2, 167.7, 158.6, 150.2, 148.1, 141.3, 136.6, 130.2, 123.8, 120.1, 115.0, 113.6, 107.9, 82.8, 66.1, 51.7, 47.1, 44.6, 39.2, 37.8, 34.4, 33.0, 29.2, 28.4, 26.7, 25.3, 23.9, 23.5, 21.6, 21.4, 9.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
50.1 g. (0.333 m) 4-methoxyacetophenone and 35.4 g (0.333 m) benzaldehyde were combined in a 500 ml Erlenmeyer flask, with the 4-methoxyacetophenone being previously melted. Then 80 ml 5N NaOH solution (appr.) (1.2 × 0.333 m) was added to the mixture. Approximately 40 ml absolute ethanol was added to the stirred mixture in small portions to keep the mixture homogeneous. It was let stir at room temperature overnight, and a solid white cake resulted. The solid was filtered, washed with water, and then recrystallized from methanol/water to give 72.3 g (91%) of 1-(4-methoxyphenyl)-3-phenyl-2-propen-1-one. 10 g (0.0420 m) of this compound and 160 mg Pd on C (10%) were combined with about 200 ml ethyl acetate and placed under 1 atm of hydrogen. Upon stirring, the mixture absorbed 950 ml H2 (calc. 940 ml) and stopped. The reaction mixture was filtered and the clear solution was concentrated to obtain 9.8 g (98%) of 1-(4-methoxyphenyl)-3-phenyl-1-propanone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:46][C:47]1([OH:51])[CH2:50][NH:49][CH2:48]1>CN(C=O)C>[OH:51][C:47]1([CH3:46])[CH2:50][N:49]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:48]1
Reactant: CC1(O)CNC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C)(O)C1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (5.30 g, 24.4 mmol), and TBTU (9.40 g, 29.3 mmol) was mixed in DMF (50 mL). To the mixture was NMM (6.70 mL, 60.99 mmol) added. After 30 min at rt was 3-methylazetidin-3-ol hydrochloride (3.01 g, 24.39 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (200 mL). The organic phase was washed with NaHCO3 (saturated, 2×150 mL) and brine (150 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (7.00 g, quant. yield). The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 0.76-1.07, 1.31-1.56, 1.78-2.04, 2.55-2.73, 3.64-3.98, 4.04-4.42, 6.52-6.84.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.[CH2:22]=[C:23]([CH3:25])[CH3:24].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:16]([C:15]1[CH:18]=[C:19]([F:21])[CH:20]=[C:13]([Br:12])[CH:14]=1)[CH2:22][C:23]2([CH3:25])[CH3:24])=[O:11]
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(F)cc(Br)c1)N2
Temperature: 85 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and 3-bromo-5-fluoro-benzaldehyde (15.9 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (12.3 g, 40.0%) as a light yellow solid: MS (ESI) M+1=394.0.