Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[O:10][C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])OC1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].O>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH2:8][CH2:7][CH2:6][C:4](=[O:10])[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNc1ccccc1
Reactant: CC1(CCCCl)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CCCN(C)c1ccccc1
Reaction time: 8 h

Procedure:
To 49.4 g (0.30 mol) 5-chloro-2-pentanone ethylene ketal and 64.2 g (0.60 mol) N-methylaniline in 100 ml toluene, add 27.7 g (0.33 mol) NaHCO3 and 2.0 g KI. Reflux with a water separator overnight. Allow to cool, filter, and concentrate. Distill at 50°/0.1 mm to remove N-methylaniline. Stir the residual liquid with 175 ml 1.0 N HCl for 2 hrs. Neutralize with NaHCO3 and extract with ether. Dry, concentrate, and distill to collect a fraction of b.p. 103°-110° /0.1 mm.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[CH:18]=[N:17][C:16]=2[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[CH:18]=[N:17][C:16]=2[C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[CH:11][CH:10]=1
Reactant: O=C(Nc1cnc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)nc2)n1)C1CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2ccc(O)nc2)n1)C1CC1
Reaction time: 18 h
Yield: 27.1 %

Procedure:
To a stirred solution of N-[6-(6-benzyloxypyridin-3-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide (0.22 g, 0.51 mmol) in ethanol (11 mL) was added palladium on activated carbon (10%) (0.033 g) and the mixture was hydrogenated under atmospheric pressure. After 18 h, the mixture was filtered, washed with ethanol and evaporated under vacuum to provide the titled compound as a brown solid (0.046 g, 27%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([CH:10]1[CH2:12][CH:11]1[C:13](Cl)=[O:14])=[O:9])[CH3:6].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(Cl)Cl>[CH2:22]([C:16]1[CH:17]=[CH:18][C:19]([C:13]([CH:11]2[CH2:12][CH:10]2[C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:14])=[CH:20][CH:21]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCOC(=O)C1CC1C(=O)Cl
Reactant: CCCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)C2CC2C(=O)OCC)cc1
Temperature: 0 °C
Yield: 60.3 %

Procedure:
Aluminum chloride (6.93 g) is added in one portion to a solution of 2-ethoxycarbonyl-cyclopropane carboxylic acid chloride (4.17 g) and 1-phenyloctane (4.49 g) in methylene chloride (100 ml). After the initial exothermic reaction subsides, the mixture is heated under reflux for 16 hours. The mixture is cooled and poured into ice water (500 ml) containing conc. hydrochloric acid (50 ml). The product is extracted with ether (3×200 ml). The extract is dried over MgSO4 and then evaporated under reduced pressure. The residue is chromatographed on silica gel (hexane/ether) to provide ethyl 2-(4-n-octylbenzoyl)cyclopropane carboxylate as an oil (4.7 g). This ester is heated under reflux in aqueous 2N NaOH (36 ml) for 24 hours. The reaction mixture is diluted with water (100 ml), acidified and extracted with ether (3×50 ml). The extract is dried (MgSO4) and evaporated. The residue is crystallized from petroleum ether (40°-60°) to provide 2-(4-n-octylbenzoyl) cyclopropane carboxylic acid (1.88 g), m.p. 45°-47° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[N:23]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].N#N>O1CCOCC1.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.O.C(Cl)Cl.O>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[CH:26]=[C:25]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=3)[CH:24]=[N:23]2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(N)nc3)cn2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Into a well stirred suspension of 2-amino-5-bromopyridine (14.6 g, 84.8 mmol), 4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butylester (40.0 g, 106 mmol) and Cs2CO3 (55.1 g, 170 mmol) in dioxane (700 mL)/water (140 mL) was bubbled N2 gas for 15 min at ambient temperature. Pd(PPh3)4 (4.8 g, 4.2 mmol) was then added to the solution followed by N2 gas bubbling for another 10 min. The reaction mixture was then heated at 100° C. for 3 h. The cooled reaction mixture was concentrated under reduced pressure to yield an off-white residue. It was stirred with water/DCM (100 mL each) for 5 min, and the organic layer was separated. The aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a light yellowish residue. It was triturated with 1:1 EtOAc:Hexane (100 mL) with ice cooling for 10 min. Off-white crystals separated out which were filtered and dried in vacuo to give the title compound as white solid. 1H NMR (300 MHz, CDCl3): δ=1.49 (s, 9H), 1.89-2.03 (m, 2H), 2.12-2.22 (m, 2H), 2.91 (m, 2H), 4.23-4.28 (m, 3H), 4.48 (s, broad, 2H), 6.53 (d, J=8.4 Hz, 1H), 7.24-7.33 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.90 (d, 1H, J=2.1 Hz), 8.25 (d, 1H, J=2.1 Hz).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[B]=O.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.B(OC(C)C)(OC(C)C)OC(C)C.C(N)CCC.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CC(=O)CC(C)=O
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCCCN
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)C=Cc1ccc2[nH]ccc2c1
Temperature: 70 °C
Yield: 49.1 %

Procedure:
In a 300 mL pear-shaped evaporating flask equipped with a cooling tube were placed 15.5 mL of ethyl acetate, 15.9 mL (155 mmol) of 2,4-pentanedione, and 3.24 g (46.5 mmol) of boron oxide. To the mixture under stirring at 70° C., 4.50 g (31.0 mmol) of 1H-indole-5-carboxaldehyde and a solution of 7.2 mL (31 mmol) of triisopropyl borate in ethyl acetate (31 mL) were added dropwise. The mixture was stirred at 70° C. for 30 minutes and a solution of 3.68 mL (37.2 mmol) of n-butylamine in ethyl acetate (9.3 mL) was added dropwise. After being stirred at 85° C. for 1 hour, the mixture was cooled down to 50° C., and 3 N hydrochloric acid (22 mL) was added thereto. The mixture was stirred at the same temperature for 10 minutes and neutralized with a saturated sodium bicarbonate solution. The resulting solution was diluted with ethyl acetate, washed twice with saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 70/30) and crystallization (ethyl acetate/hexane) to give 3.46 g (49% yield) of the title compound as a yellow powder with the following properties.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[NH2:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:13]([O:12][C:10]([C:9]1[S:15][C:3]([C:4]([OH:6])=[O:5])=[CH:2][N:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(C(=O)O)s1
Yield: 47.8 %

Procedure:
Bromopyruvic acid (22.7 g, 135.33 mmol) was added to a solution of ethyl 2-amino-2-thioxoacetate (Intermediate W, 18 g, 135.3 mmol) in dioxane (200 mL) and refluxed for 5 h. After completion the reaction mixture was poured into water (200 mL), the residue was basified with sat NaHCO3 and extracted with EtOAc (2×250 mL). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (2×250 mL) The combined extracts were washed with water (250 mL), brine (250 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (13 g crude). The crude was carried to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]([F:22])([F:21])[C:10](=O)[CH2:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>C(O)(=O)C>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[C:10]([C:9]([F:22])([F:8])[F:21])[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]2[N:4]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccnc1
Solvent: CC(=O)O
Product: Cc1nc2nc(C(F)(F)F)cc(-c3cccnc3)n2n1
Yield: 47.5 %

Procedure:
A reaction mixture of 0.986 g of 3-amino-5-methyl-1,2,4-triazole and 2.178 g of 4,4,4-trifluoro-1-(3-pyridyl)-1,3-butanedione in 25 ml of glacial acetic acid was refluxed for 4 hours. The mixture was then evaporated to dryness in vacuo and gave a crystalline residue. This residue was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane and the procedure of Example 1 was continued to give 1.33 g of the desired product as colorless crystals, mp 195°-197° C.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>CCO>[C:1]([C:3](=[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=1)[S:10][CH3:11])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CSC(Nc1ccc(Cl)c(Cl)c1)=C(C#N)C(N)=O

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 172 mg (1.0 eq.) 3,4-dichloroaniline. Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain 2-cyano-3-((3,4-dichlorophenyl)amino)-3-(methylthio)acrylamide as a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]>CN1CCCC1=O>[N:13]1([C:11](=[O:12])[CH2:10][O:5][C:4](/[CH:3]=[CH:2]/[C:1]([OH:8])=[O:7])=[O:6])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CN1CCCC1=O
Product: O=C(O)/C=C/C(=O)OCC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
Following general procedure A, fumaric acid (1.00 g, 8.60 mmol) was reacted with chloro acetyl morpholine (1.4 g, 8.6 mmol) and Ag2O (4.2 g, 9.47 mmol) at ca. 100° C. in N-methylpyrrolidinone. The reaction mixture was cooled to room temperature, filtered over Celite®, and the filter cake was washed with ethylacetate (EtOAc). The combined organic filtrates were subjected to acidic aqueous work-up and the crude material was purified by mass-guided preparative HPLC to give 0.50 g (24% yield) of the title compound (47) as a white solid. 1H NMR (CD3CN, 400 MHz): δ 6.85-6.80 (m, 2H), 4.85 (s, 2H), 3.64-3.60 (m, 4H), 3.57-3.54 (t, J=4.8 Hz, 2H), 3.42-3.39 (t, J=5.2 Hz, 2H). MS (ESI): m/z 244.06 (M+H)+, 242.07 (M−H)−.
Reaction SMILES: [C:1]1([Mg]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:17])[CH2:16][CH2:15][CH2:14]1.Cl>C(OCC)C>[OH:17][C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCC1
Reactant: Br[Mg]c1cccc2ccccc12
Agent: Cl
Solvent: CCOCC
Product: OC1(c2ccc3ccccc3c2)CCC1

Procedure:
To a mixture of 23.1 g. of naphthyl magnesium bromide and 250 ml. of diethyl ether, 7 g. of cyclobutanone are slowly added. After the addition, the mixture is refluxed for 1 hour, cooled, acidified with aqueous hydrochloric acid and filtered. The product is isolated by methylene chloride extraction to furnish 2-(1'-hydroxycyclobutyl)-naphthalene. The product is hydrogenated in 200 ml. of ethanol with a molar equivalent of hydrogen in the presence of 50 g. of Raney nickel; the reaction mixture is filtered after the hydrogenolysis and evaporated to furnish 2-cyclobutylnaphthalene.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6]1([CH2:13][N+]([O-])=O)[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7]1)C.[CH3:18]O>[Ni]>[CH3:12][C:8]1([CH3:11])[CH2:9][CH2:10][C:6]2([CH2:5][C:4](=[O:17])[CH2:18][CH2:13]2)[CH2:7]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC(C)(C)C1
Reactant: CO
Agent: [Ni]
Product: CC1(C)CCC2(CCC(=O)C2)C1
Reaction time: 24 h
Yield: 94 %

Procedure:
The ester 3 (380 mg, 1.6 mmol) and Raney Nickel (1 g) were suspended in methanol (75 mL) and shaken under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration, the filtrate concentrated to give the lactam 4 (246 mg, 94%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: CCOC(=O)CCCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of Compound 6 (5.0 g, 15.39 mmol) and 4-fluoro-2-methyl-1H-indol-5-ol (3.56 g, 21.55 mmol) in acetonitrile (50 mL) was added cesium carbonate (15.05 g, 46.18 mmol). The reaction mixture was stirred at 50° C. for 2 h. TLC showed that no starting material remained. The inorganic material was removed by filtration and the filtrate was concentrated to give a brown solid. The solid was dissolved in ethyl acetate (100 mL) and washed with water (100 mL×2). The organic phase was concentrated and the residue was purified by silica column (gradient of hexane:ethyl acetate 5:1 to 1:2) to give Compound 7 (5.90 g) as a purple solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1.C(OCC)(=O)C>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:13]([F:14])([F:16])[F:15])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 4.0 g (16.1 mmol) 4-nitro-3-trifluoromethyl-benzoic acid methyl ester in 50 mL methanol 0.4 g 10% palladium on charcoal was added and the suspension stirred for 2 h at room temperature under an atmosphere of hydrogen (1.7 bar). After the addition of 100 mL ethyl acetate the catalyst was filtered off, the filtrate evaporated and dried under high vacuum to give the title compound as a white solid (98%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11])#[N:13]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)O)cc1F
Temperature: 90 °C

Procedure:
4-Bromo-3-fluorobenzoic acid (7.5 g, 0.034 mol), Zn(CN)2 (4.0 g, 0.034 mol) and Pd(PPh3)4 (3.95 g, 0.0034 mol) were added together with 60 mL of DMF (degassed). The mixture was heated at 90° C. under N2 for 3 h. It was cooled to room temperature and filtered to remove insoluble inorganic salts (discarded). The filtrate was diluted with water and extracted with EtOAc. The EtOAc mixture was washed with water, brine, dried over MgSO4, and concentrated to yield 4.5 g of the desired product with 90% purity. This material was taken into the next step without further purification. 1H-NMR (500 MHz, d4-MeOH) δ 7.82 (m, 1H), 7.90 (m, 3H), 7.56 (d, J=10.0 Hz, 1H), 7.68 (s, 1H), 7.96 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:13](=[O:15])[NH:43][CH2:44][CH2:45][CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])[CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(CCNC(=O)C(NC(=O)OCc1ccccc1)C(O)C(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoic acid (368 mg, 1.31 mmol) in anhydrous tetrahydrofuran (5 ml) was added hydroxybenzotriazole (177 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 1.31 mmol). The resulting solution was stirred at room temperature under nitrogen for 30 minutes. A solution of 1-amino-3,3-diethoxypropane (183 mg, 1.25 mmol) in tetrahydrofuran (2 ml) and N,N-diisopropylethylamine (0.228 ml, 169 mg, 1.31 mmol) were added and stirred at room temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate (75 ml) and water (40 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×75 ml). The combined extracts were washed with 2% cold hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to provide [1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 79%) as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:10][CH2:9]1)(C)(C)C.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[CH:24]=[CH:23][CH:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[C:20]=5[CH:19]=[CH:18][C:17]4=[O:30])[CH2:10][CH2:9]3)=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To 0.2 mL of an ethyl acetate solution containing 9.0 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature for 42 hours. The solvent was removed under reduced pressure to give 8.4 mg of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,2-dihydro-2-oxoquinoline-5-carboxylate hydrochloride as a white solid.
Reaction SMILES: [C:1]1([C@H:7]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:23]([CH3:25])=[CH2:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH:9]([C@H:8]1[O:11][C:23]([CH3:25])([CH3:24])[N:12]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH2:10]
Reactant: C=C[C@@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C[C@H]1OC(C)(C)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 38 %

Procedure:
32 mg (0.12 mmol) of (1S,2R)-1-phenyl-1-benzoylamino-2-hydroxy-3-butene, in suspension in 0.64 cm3 of anhydrous toluene, are put, under an argon atmosphere, in a 10 cm3 single-necked, round-bottomed flask equipped with a magnetic stirrer system and a reflux condenser. 226 μl (173 mg, 2.4 mmol) of 2-methoxypropene, 6.0 mg (0.024 mmol) of pyridinium p-toluenesulphonate and 8 grains of 4 Å molecular sieve are then added. The resulting reaction mixture is allowed to react at a temperature in the region of 15° C. for 2.5 hours and is then heated at 100° C. for 2 hours. After cooling to a temperature in the region of 15° C., the reaction mixture is diluted in 40 cm3 of dichloromethane. The organic phase is washed once with 5 cm3 of a saturated sodium bicarbonate solution, 3 times with 5 cm3 of water and once with a saturated aqueous sodium chloride solution and is then dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting a first time with an ethyl ether/dichloromethane (2/98 by volume) mixture and then a second time with an ethyl acetate/hexane (10/90 by volume) mixture. There are thus obtained, with a yield of 38%, 14 mg (0.0456 mmol) of (4S,5R)-5-vinyl-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][OH:17])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:19].[C:27]([O:31][C:32](ONC(C1C=CC=CC=1)C#N)=[O:33])([CH3:30])([CH3:29])[CH3:28].O.CCOC(C)=O>C(N(CC)CC)C>[C:32](=[O:33])([O:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[C:2]([Cl:1])[CH:7]=1)[O:31][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)ONC(C#N)c1ccccc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCO)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCOC(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Compound 102 (200 mg) was dissolved in dry triethylamine (3.0 mL) and {[(tert-butoxycarbonyl)oxy]amino}(phenyl)acetonitrile (148 mg) was added. The solution was stirred at 70° C. for 5 h. The reaction mixture was cooled to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using petroleum ether/diethyl ether 8:1 as the eluent to afford the title compound.