Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C1(N=C=O)C=CC=CC=1.[CH3:44][Sn:45]([CH3:55])([CH3:54])[C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:50][C:49]1[CH:52]=[CH:53][C:46]([Sn:45]([CH3:44])([CH3:55])[CH3:54])=[CH:47][CH:48]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Sn](C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C=Nc1ccccc1
Product: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCNCc1ccc([Sn](C)(C)C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 40 %

Procedure:
The following compounds of the general structure 8 were prepared in overall yields ranging from 20-60% by the route depicted in Scheme B. The key synthetic intermediate (4) was reacted with the appropriate phenylisocyanate at room temperature to afford the desired protected intermediates (5) in good yields. The t-butyl ester protecting groups were removed in the presence of 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator purified by HPLC or recrystallization to afford the desired products (6) in 40-90% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[FH:14].F.F.C(N(CC)CC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([OH:11])[C@H:10]([F:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](F)C1

Procedure:
Stir a mixture of 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100 mg, 0.54 mmol) and triethylamine trihydrofluoride (88 μL, 0.54 mmol) at 100° C. for 30 min in a microwave (CEM Discover, 300W). Add saturated aqueous sodium hydrogen carbonate and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give trans-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester which may be used without further purification. 1H NMR (300 MHz, CDCl3) δ 4.85 (1H, d, J=50.86 Hz), 4.29 (1H, dd, J=8.01, 2.92 Hz), 3.38-3.65 (4H, m), 1.39 (9H, s).
Reaction SMILES: N[C:2]1N(CC)[N:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=CC(S(C(F)(F)F)(=O)=O)=C[C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[C:12]([OH:14])(=[O:13])[C:11]1[C:4](=[CH:3][CH:2]=[CH:18][CH:10]=1)[NH2:5]
Reactant: O=C(O)c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: CCn1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-amino-1-ethylpyrazole (0.56 g, 5 mmol), 2-chloro-5-(trifluoromethylsulfonyl)benzoic acid (1.4 g, 4.9 mmol), K2CO3 (0.69 g, 5 mmol), Cu(OAc)2 (0.1 g) and DMF (10mL) was refluxed for 4 hours and then was cooled to room temperature and was allowed to stand for about 3 days. Water was added to the reaction mixture and then the solution was acidified with acetic acid to a pH of about 5. The mixture was extracted with CH2Cl2 and then the CH2Cl2 layer was evaporated to afford N-(1-ethylpyrazol-5-yl)-5- trifluoromethylsulfonyl)anthranilic acid.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH2:3][OH:4].[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>CCN(CC)CC>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)[C@H](N)CO
Solvent: CCN(CC)CC
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Yield: 91 %

Procedure:
Accordingly, the intermediate (S)-2-amino-3-ethyl pentan-1-ol (9) is condensed with 5-chlorothiophene-2-sulfonyl chloride in the presence of Et3N to obtain (S)—N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol, in 91% yield and 98% ee (determined by chiral HPLC).
Reaction SMILES: [OH-].[K+].[C:3]([SH:7])([CH3:6])([CH3:5])[CH3:4].CS(C)=O.Cl[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]>O.C(OCC)(=O)C>[CH3:4][C:3]([CH3:6])([S:7][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])[CH3:5]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)(C)S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)Sc1ccccc1C=O
Temperature: 120 °C

Procedure:
Powdered potassium hydroxide (21.9 g, 390 mmol) and 56 ml (497 mmol) of terbutyl mercaptan were mixed 55.5 ml of dimethylsulfoxide in a 250 ml three-neck flask. To this stirred mixture was added dropwise over a ten minute period 50 g (356 mmol) of 2-chloro-benzaldehyde. During addition of the 2-chlorobenzaldehyde, the reaction mixture warmed to 120° C. After addition was complete, the mixture was allowed to react at about 110° C. for 1.5 hours. At the end of this time, the mixture was cooled to room temperature and taken up on 600 ml of ethyl acetate and 1 liter of water. The organic layer was separated, dried and evaporated to yield 2-(1,1-dimethylethylthio)benzaldehyde, b.p. 80°-82° C. at 0.05 mm Hg, which was used without further purification in the next step of the process.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[NH:48][NH2:49]>CN(C=O)C>[C:52]([O:51][C:47]([NH:48][NH:49][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=1[F:10])=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
N,N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) and O-(7-azabenzotriazol-1-yl)-N,N, N′, N′-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixture stirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, washed well with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M+H]+=300.
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 12.3 g of (3R, 4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone in 150 ml of DMF is added a solution of 1.6 g of potassium cyanide in 24 ml of water under ice-cooling and the mixture is stirred at room temperature (approx. 25° C.) for 30 minutes. To the reaction mixture are added ice water and ethyl acetate, and the ethyl acetate layer is taken, washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column [eluant: ethyl acetate-n-hexane (1:1)] to give 6.7 g of (3S, 4RS)-4-cyano-3-tritylamino-2-azetidinone (4R:4S=1:1).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=O)[CH2:6]1)=O.[Li].[H-].[Al+3].[H-].[H-]>>[CH2:10]([N:8]1[CH2:7][CH2:6][CH:5]([CH2:3][NH:2][CH3:1])[CH2:9]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li]
Product: CNCC1CCN(Cc2ccccc2)C1

Procedure:
40 g of the compound obtained in stage A is reduced by means of 13.1 g of lithium and aluminum hydride.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[CH:5][C:6]2[N:11](C(=O)C)[N:10]=[CH:9][C:7]=2[N:8]=1>O1CCCC1>[Cl:2][C:3]1[N:4]=[CH:5][C:6]2[NH:11][N:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CC(=O)n1ncc2nc(Cl)ncc21
Agent: Cl
Solvent: C1CCOC1
Product: Clc1ncc2[nH]ncc2n1
Yield: 47.8 %

Procedure:
Hydrochloric acid (70 mL, 8%) was added dropwise to a solution of 1-[5-chloro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethan-1-one (7 g, 33.83 mmol, 1.00 equiv, 95%) in tetrahydrofuran (70 mL) at 50° C. The resulting solution was refluxed for 30 min and then extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.5 g (45%) of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12]O>>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-methylnicotinic acid (20 g, 146 mmol) in MeOH (300 ml) was treated with HCl gas until the solvent was saturated. The reaction was capped and stirred for 1.5 h at RT. The mixture was treated again with HCl gas until the solvent was saturated and was capped and stirred overnight at 22° C. The solution was concentrated to yield A-2. Data for A-2: LRMS m/z (M+H): 152.75.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]C(Cl)(Cl)Cl)=[CH:4][N:3]=1>CN(C=O)C.O.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][C:4]=2[N:3]=1
Reactant: Clc1ncc(-c2ccccc2SC(Cl)(Cl)Cl)c(Cl)n1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc2c(n1)sc1ccccc12
Temperature: 110 °C
Yield: 38.4 %

Procedure:
A solution of 2,4-dichloro-5-(2-((trichloromethyl)thio)phenyl)pyrimidine (0.618 g, 1.650 mmol) and copper(I) iodide (0.031 g, 0.165 mmol) in DMF (24.63 ml) was degassed with nitrogen and heated at 110° C. overnight. The reaction solution was cooled to room temperature, diluted with water and filtered. The resulting brown solids were washed with water and a small volume of EtOH. The aqueous layer was extracted twice with EtOAc, combined with the solids, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluted with 10-20% EtOAc/heptanes (v/v), affording 0.14 g (38% yield) of the 2-chlorobenzo[4,5]thieno[2,3-d]pyrimidine as white solids.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH2:3]1>O>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH:3]=1
Reactant: CC1CC=C(C(=O)O)CC1
Solvent: O
Product: CC1=CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Reaction: ##STR17## into 1 liter reaction flask equipped with stirrer thermometer reflux condenser and heating mantle is placed 100 ml anhydrous methyl, 1.25 moles (100 grams) of 50% aqueous NOAH solution, 100 ml water and 154 grams (1 mole) of the methyl ester of 4-methyl-cyclohexene-1-carboxylic acid. The reaction mass is stirred for a period of 5 hours at room temperature and then extracted with 1 volume of diethyl ether. The aqueous layer is set aside with 10% hydrochloric acid and extracted with diethyl ether. The diethyl ether extracts are washed with saturated sodium chloride solution and the ether is evaporated yielding 100.5 grams of solid melting at 95° C. This material is the carboxylic acid having the structure: ##STR18## as confirmed by NMR and IR analysis.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C1(C)C=CC=CC=1>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(CO)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
5-Methoxycarbonyl-2-methyl-pyridine (3.0 g, 19.8 mmole) was dissolved in toluene (60 ml) and cooled to -78° C. To this solution, a 39.7 ml of a solution of 1M diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred for 1 hour at -78° C., allowed to warm to room temperature and stirred for an additional 18 hours. Methanol (8 ml) was then added dropwise at room temperature to the reaction mixture. The mixture was stirred until a thick gel was formed. 1N HCl (10 ml) was added to dissolve the gel. The resulting phases were separated, the organic phase was extracted in ethyl acetate and dried over MgSO4. The solvents were removed yielding crude 5-hydroxymethyl-2-methylpyridine (540 mg) as an oil, which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: ClCCCOc1ccc(I)cc1
Product: Ic1ccc(OCCCN2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
1-[(3-chloropropyl)oxy]-4-iodobenzene (10 g, 33.7 mmol) and piperidine (2.87 g, 67.4 mmol) were mixed, and stirred at 85° C. for 4 hours. After cooled to room temperature, this was concentrated, and the residue was dissolved in ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline, and the organic layer was dried with sodium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=50/50 to chloroform/methanol=10/1) to obtain the entitled compound (8.39 g, 72%) as a brown solid.
Reaction SMILES: [C:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)#[N:2].N>C(O)C.O.[Ni]>[NH2:2][CH2:1][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CC1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(CN)CC1
Reaction time: 24 h
Yield: 67.1 %

Procedure:
To a solution of ethyl 1-cyanocyclopropanecarboxylate (1 g, 7.18 mmol) in ethanol-water-conc. ammonia solution (7 ml-350 μl-1 ml) was added raney nickel (ca. 350 μl) and the mixture was sittred for 24 hr at 50° C. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to obtain the title compound (690 mg, 67%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([C:10]1[CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:13]([C:17]#[N:18])[NH:14][C:15]=1[CH3:16])([OH:9])=[O:8].[CH:32](O)([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:17]([C:13]1[NH:14][C:15]([CH3:16])=[C:10]([C:7]([O:9][CH:32]([CH3:34])[CH3:33])=[O:8])[CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:12]=1[C:19]([O:21][CH3:22])=[O:20])#[N:18]
Reactant: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Phosphorus pentachloride (2.46 g) was added to a suspension of (+)-methyl 5-carboxy-2-cyano-6-methyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (3.12 g) in methylene chloride (30 ml) under ice-cooling, and the mixture was stirred for 30 minutes. Then, a solution of isopropyl alcohol (1.4 g) in methylene chloride (10 ml) was added dropwise thereto over a period of 10 minutes. After being stirred for 20 minutes, 5% aqueous sodium carbonate (30 ml ) was added to the reaction solution and then stirred at ambient temperature for an hour. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (75 g) using a mixture of benzene and ethyl acetate (10:1) as an eluent. The eluate was evaporated in vacuo and the residue was crystallized from diisopropyl ether to give (+)-5-isopropyl 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3.34 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:13][OH:14])[CH:9]=[CH:10][C:11]=1[I:12])[CH2:2][CH2:3][CH3:4]>[O-2].[O-2].[Mn+4]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[I:12])[CH:13]=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)ccc1I
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCOc1cc(C=O)ccc1I

Procedure:
The oxidation of (3-butoxy-4-iodophenyl)methanol (IX) using manganese dioxide makes it possible to obtain 3-butoxy-4-iodobenzaldehyde (X).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:17][NH2:18]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:17][NH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reaction time: 72 h
Yield: 93.5 %

Procedure:
1-tert-Butoxycarbonylpiperid-4-one (6.18 g, 31 mmol) was dissolved in a 2.0 M solution of methylamine in methanol (56 mL, 112 mmol). This solution was added to 10% palladium on carbon (wet, 1.3 g) and the mixture placed under an atmosphere of hydrogen for 72 h. The reaction mixture was then purged with nitrogen and filtered through a pad of Celite, which was then washed with methanol. The resulting hazy filtrate was filtered through a 0.2 μm filter and then concentrated in vacuo to afford the title intermediate (6.16 g, 29 mmol, 93.5% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[CH:23][CH:24]=1)#[CH:18]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:18]#[C:17][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:22]=[CH:23][CH:24]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C#Cc2nc(Cl)ncc2F)c1)C(F)(F)F
Yield: 77.6 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloro-5-fluoropyrimidine (1.56 g, 9.4 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (62 mg, 0.09 mmol), copper(I) iodide (10 mg, 0.05 mmol), and triethylamine (0.164 g, 0.23 mmol). After heating the reaction at 60° C. for 30 min, N-(3-ethynylphenyl)-2,2,2-trifluoroacetamide (1.0, 4.69 mmol) was added dropwise as a solution in THF (25 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (2-10% EtOAc in hexanes) to afford the desired product (1.25 g, 78%) as an off-white solid. ESIMS (M+H)+=344.
Reaction SMILES: Br[C:2]1[C:3]([O:14][C@H:15]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]2)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[CH:31]([B-](F)(F)F)=[CH2:32].[K+].CCOC(C)=O.O>CCO.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH:31]=[CH2:32])[C:3]([O:14][C@H:15]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]3)=[N:4]2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3cc2Br)CN1C(=O)OC(C)(C)C
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=Cc1cc2ccc(OC)cc2nc1O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4R)-4-[(3-bromo-7-methoxyquinolin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate (2.0 g, 4.2 mmol) in EtOH (30 mL), TEA (0.87 mL, 6.23 mmol) was added. Potassium vinyltrifluoroborate (0.84 g, 6.23 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.17 g, 0.21 mmol) were then added, and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was worked up with EtOAc and H2O, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified on silica (gradient elution, 0-40% EtOAc/hexanes) to yield the title compound as an oil. LRMS (M+H-tBu)+=373.3.
Reaction SMILES: C([N:8]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH2:9][CH:10]([OH:26])[CH2:11][O:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH:16]1[C:17]2[NH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[C:13]([O:12][CH2:11][CH:10]([OH:26])[CH2:9][NH:8][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:14][CH:15]=1
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 50 °C
Reaction time: 7 h

Procedure:
10 g of 1-{Benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amino}-3-(9H-carbazol-4-yloxy)-propan-2-ol (20 mmol) were dissolved in 80 ml methanol. 1 g of Pd—C (10%) were added and the suspension was warmed to 50° C. The mixture was hydrogenated at normal pressure for about 7 hours. The Pd-catalyst was filtered under suction and washed with 25 ml of hot methanol. 80 ml of methanol were distilled off and the residue was cooled to 0° C. and hold at this temperature for 6 h. The product was filtered and washed twice with 3 ml cold methanol. The substance was dried at 60° C. for 12 h.