Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:3][CH2:2]2.[F:24][C:25]([F:36])([F:35])[C:26]([O:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:27]>>[F:24][C:25]([F:36])([F:35])[C:26]([OH:28])=[O:27].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:29](=[O:34])[C:30]([F:31])([F:32])[F:33])=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:3][CH2:2]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Product: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2ccc(NC(=O)C(F)(F)F)cc2)o1)N1CCN2CCC1CC2

Procedure:
The title compound was prepared according to Method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone and trifluoroacetic anhydride. Mp. 219° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C)[CH:10]=2)[NH:5][C:4](=O)[N:3]=1.F[C:15](F)(F)C1C=C(C=CC=1)N>C(O)C>[CH3:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2[nH]c(=O)nc(Cl)c2c1
Solvent: CCO
Product: Cc1cccc2c(Cl)ncnc12

Procedure:
0.45 g of 4-chloro 6-methyl quinazolone and 0.405 g, of m-trifluoromethylaniline in 20 ml ethanol were refluxed 1 hour. Treatment with aqueous Na2CO3 and extraction with CH2Cl2 gave 0.2 g of P15 as a white solid, mp-215° C., as the free base. NMR CDCl3 δ 8.78 (1H, S), 8.06 (2H, m), 7.86 (1H, d, J=7.6 Hz), 7.65 (2H, m), 7.54 (1H, t, J=8.0 Hz), 7.42 (1H, m), 2.58 (3H, S).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1.[I-].[K+]>CN(C=O)C>[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][N:47]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (6.0 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.4 g), diisopropylethylamine (5.1 ml), 1-(3-chlorophenyl)piperazine (4.9 g) and potassium iodide (0.3 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 18 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine twice, and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel) afforded 3.4 g of 5-[3-(4-(3-chlorophenyl)-1-piperazinyl)propyl]-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil. The hydrochloride was prepared in methanol with ethereal HCl. The precipitate was filtered and washed with anhydrous ether, m.p. 104°-106° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[N:5]=1)(=O)[NH2:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[N:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(N)=O)CC1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a stirring solution of tert-butyl 4-(3-carbamoyl-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (example 16) (9 mg, 0.019 mmol) in THF (1 mL) at room temperature under argon was added TEA (5.65 mg, 0.056 mmol), and was followed by addition of TFAA (11.73 mg, 0.056 mmol). The resulting reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(3-cyano-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (6 mg, white solid, 69.2%). 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H) 1.74-1.94 (m, 2H) 1.92-2.12 (m, 2H) 3.32-3.55 (m, 2H) 3.58-3.81 (m, 2H) 4.42-4.72 (m, 1H) 6.26 (s, 1H) 7.45 (dd, J=8.79, 2.20 Hz, 1H) 7.55 (d, 1H) 7.72 (d, J=2.20 Hz, 1H). MS (ESI) 409 (M+H-tBu).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].[OH:17][CH2:18][CH2:19][CH2:20][NH2:21].C(Cl)(=O)C(Cl)=O.CNC(C1C2C(=CC(OC)=CC=2)N(C)C=1C)=O>>[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15]
Reactant: NCCCO
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Agent: CNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NCCCO)c(C)n(C)c2c1

Procedure:
This material was prepared by the reaction of 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c with 3-hydroxy-propyl amine and oxalyl chloride in a manner as previously described for 16d. 1H NMR (300 MHz, CD3OD) δ 7.52 (1H, d, J=8.6 Hz), 6.73 (1H, d, J=2.1 Hz), 6.68 (1H, dd, J=2.1, 8.6 Hz), 3.69 (2H, t, J=6.1 Hz), 3.79 (3H, s), 3.63 (3H, s), 3.51 (2H, m), 2.57 (3H, s), 1.85 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 291. found 291.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])=[CH:26][CH:25]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: COc1ccc(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Yield: 20.6 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 64 μL (0.55 mmol) of 4-methoxyaniline. After purification by chromatography on silica (eluent dichloromethane/methanol/acetonitrile 95/3/2) then trituration in diethyl ether, 21 mg (10%) of 8-(4-methoxy-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>O>[Si:2]([OH:8])([OH:4])([OH:1])[OH:3].[S:7]([O-:11])([OH:10])(=[O:9])=[O:8].[Na+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])O
Product: O[Si](O)(O)O
Reaction time: 1.5 h

Procedure:
About 100 parts by weight of granular sodium metasilicate containing less than 6 mols of water per mol of sodium metasilicate is slowly added to 100 parts by weight of concentrated sulfuric acid while agitating and keeping the temperature below 100° C. The chemical reaction is complete in 1 to 2 hours, thereby producing a white granular silicic acid compound and sodium hydrogen sulfate. The mixture is washed with water, filtered to remove the sodium hydrogen sulfate and recover the white granular silicic acid compound. The silicic acid compound is air dried at 25° to 75° C by blowing air thru the granules.
Reaction SMILES: N[C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].S(=O)(=O)(O)[OH:17].N([O-])=O.[Na+]>>[OH:17][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(N)cccc1C(=O)CCC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1c(O)cccc1C(=O)CCC(=O)O

Procedure:
3-(3-amino-2-methylbenzoyl)propionic acid was diazotised in a solution of sulphuric acid with sodium nitrite, and the diazonium salt solution was added dropwise to boiling aqueous sulphuric acid to give 3-(3-hydroxy-2-methylbenzoyl)proprionic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC.[OH-].[Na+]>O.C(OCC)C>[CH3:17][N:16]1[C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[B:18]([OH:23])[OH:19])=[CH:13][CH:14]=[N:15]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
An 250-mL round-bottom flask was charged with 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole (2.956 g, 9.69 mmol), diethyl ether (74.5 ml), and triisopropyl borate (2.70 ml, 11.63 mmol). The flask was cooled to −78° C. for 10 minutes, after which butyllithium (2.5M in hexanes) (4.65 ml, 11.63 mmol) was added dropwise. The mixture was stirred for 30 min, then warmed to room temperature. A 2N aq. NaOH solution (100 mL), and the resulting biphasic mixture was stirred vigorously for 1 h. The mixture was diluted with water, and the layers separated. The ethereal layer was extracted with water (2×) and the water layers were combined, and washed with diethyl ether. The ether layers were back-extracted once more, and all aqueous layers combined and acidified to about pH 2 with 6N aq HCl to give a clear solution. The aqueous layer was extracted with ethyl acetate (2×), and the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was concentrated from DCM to give (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (2.36 g, 8.74 mmol, 90% yield) as a yellow solid. m/z (ESI) 271.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]=[C:9]1[CH2:12][CH2:11][CH2:10]1>CCOCC.[Zn]>[Cl:1][C:2]1([Cl:7])[C:9]2([CH2:12][CH2:11][CH2:10]2)[CH2:8][C:3]1=[O:4]
Reactant: C=C1CCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CC2(CCC2)C1(Cl)Cl
Temperature: 20 °C

Procedure:
6.25 g of powdered zinc and then 11 ml of trichloroacetic acid chloride in solution in 170 ml of ether are added to 5 g of methylenecyclobutane in solution in ether. The solution is subjected to sonication for 3 hours while maintaining the temperature at 20° C., and then the black solution is filtered through Whatman filter. The filtrate is washed, dried, filtered and concentrated to yield the expected product in the form of a brown oil.
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: CCOC(C)=O
Solvent: CN(C)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, 4S)-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: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([C:16]#[N:17])(O[Si](C)(C)C)[C:6]=2[CH:18]=1.P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([C:16]#[N:17])[C:6]=2[CH:18]=1
Reactant: C[Si](C)(C)OC1(C#N)CCOc2ccc(F)cc21
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1=CCOc2ccc(F)cc21
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of 32 g (0.12 mole) of the crude 6-fluoro-2,3-dihydro-4-cyano-4-[(trimethylsilyl)oxy-]4H-benzopyran in 170 ml of dry pyridine was added 60 ml (0.6 mole) of phosphorous oxychloride. The reaction was heated to reflux for 5 hours then cooled to room temperature. The resulting solution was added dropwise to a solution of 300 cc of concentrated HCl in 1 L of water. This aqueous layer was extracted with EtOAc and the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 16.1 g of product m.p. 114°-115° C. NMR (CDCl3) ppm (delta) 5.00 (d, 2H, J=4 Hz), 6.6-7.3 (m, 4H).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[Cl:13][CH2:14][C:15]1[C:16]([CH3:21])=[N:17][O:18][C:19]=1[CH3:20]>>[ClH:13].[CH3:21][C:16]1[C:15]([CH2:14][O:1][NH2:2])=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CON
Product: Cl

Procedure:
Prepared by a similar procedure as described for preparation 13. Starting materials: N-hydroxyphthalimide and 4-(chloromethyl)-3,5-dimethylisoxazole (Aldrich). 13C-NMR (DMSO-d6) δ 169.7, 159.6, 108.2, 64.4, 10.8, 9.5.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([O:8][OH:9])([CH:6]=[CH2:7])[CH3:5].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O>[C:10]([O:9][O:8][C:4]([CH3:5])([CH:6]=[CH2:7])[CH3:3])(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CC(C)(C)OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CC(C)(C)OOC(=O)C(C)(C)C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred mixture cooled at 10° C. of 10 g of demineralized water, 17.3 g of a 45% by weight-potassium hydroxide solution in water (0.139 moles) and 12.9 g of 2-methyl-3-buten-2-yl hydroperoxide (0.120 moles) there were added over a period of 25 minutes 14.5 g of pivaloyl chloride (0.120 moles); the temperature of the reaction mixture was kept at 10°-12° C. Stirring was continued for 1 hour, after which the organic layer was isolated. It was washed successively with an aqueous solution of 10% by weight-KOH (15 min, 10° C.), an aqueous bisulphite/acetate buffer (20 min., 10° C.) and a dilute solution of sodium bicarbonate in water (2x). Finally, the organic layer was dried with MgSO4 and the product was isolated by filtration. There were obtained 17.3 g of colourless oil containing 97.7% of peroxy ester, which corresponds to a yield of 75.6%. The identity of the product was confirmed by IR and NMR spectroscopy (1H and 13C).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:19]([CH2:18][NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)#[N:20]
Reactant: N#CCBr
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: N#CCNCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 2.11 g (10 mmol) 3,3-diphenylpropylamine (Aldrich), (0.54 g, 4.54 mmol) bromoacetonitrile (Aldrich), and 2.5 g potassium carbonate in 5 ml acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed with water, the solvent evaporated, and the residue chromatographed on silica gel column with 30% ethyl acetate in hexanes to give 1.24 g (yield 50%) N-cyanomethyl-3,3-diphenylpropylamine as an oil which solidified on standing. 1H NMR (CDCl3, 300 MHz) 7.45-7.10 (m, 10 H), 4.05 (t, 1 H), 3.50 (s, 2 H), 2.67 (t, 2 H), 2.23 (dt, 2H); 13C NMR (CDCl3, 75 MHz) 144.25, 128.53, 127.68, 126.33, 117.72, 48.58, 47.13, 37.19, 35.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH:21]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:23][CH2:22]1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:24]([CH:21]2[CH2:22][CH2:23]2)([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: O=C(c1ccccc1)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(CC(O)(c2ccccc2)C2CC2)ccn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
(4-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (200 mg, 0.96 mmol) is dissolved in dry THF (10 mL) and it is cooled down to −78° C. After 1.6 M n-BuLi (3.0 mL, 4.8 mmol) is added at −78° C., the cooling bath is removed and the mixture is stirred at room temperature for 15 min. Then the reaction mixture is cooled down to −78° C. again and cyclopropyl-phenyl-methanone (0.68 mL, 4.8 mmol) is added. After the mixture is stirred for 30 min at −78° C., saturated NH4Cl aqueous solution (35 mL) is added and the reaction is warmed up to room temperature. EtOAc (70 mL) is added along with water (70 mL). The mixture is stirred for another 10 min and the aqueous layer is separated, extracted with EtOAc (2×35 ml). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 280 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Br[N:16]1C(=O)CC[C:17]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:41]([O:45][C:46]([O:48]C(OC(C)(C)C)=O)=O)([CH3:44])([CH3:43])[CH3:42]>C(#N)C.C(N(CC)CC)C.C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10][N:16]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:48])[CH3:17])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CN(C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To 1.0 g of the crude product of 5-methyl-2-nitrobenzoic acid methyl ester synthesized in the foregoing step 1, there were added 1.4 g of N-bromosuccinimide, 0.5 g of benzoyl peroxide and 30 mL of benzene, the resulting mixture was refluxed with stirring for 4 hours and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 30 mL of acetonitrile, this solution was added to 36 mL of a 2M methylamine solution in THF and the mixture was further stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, then ethyl acetate was added, followed by the washing thereof four times with a 1M hydrochloric acid solution. The resulting ethyl acetate phase was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution and the solvent was distilled off under reduced pressure. The crude product thus prepared was dissolved in 30 mL of acetonitrile, 1.1 g of di-tert-butyl-dicarbonate and 1.1 mL of triethylamine were added to the solution and the resulting mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, ethyl acetate was added thereto, the insoluble matter was then removed through filtration and the filtrate thus obtained was concentrated under reduced pressure. The resulting crude product was purified by the silica gel chromatography (hexane:ethyl acetate=90:10→80:20) to thus give 0.71 g of the title compound. MS (ESI+): m/z 325 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:22][CH:21]=[CH2:20])=[O:8]
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(N)ccc1[N+](=O)[O-]
Yield: 70.9 %

Procedure:
5-Amino-2-nitrobenzoic acid (4 g, 22 mM) was dissolved in DMF (40 ml) and anhydrous potassium carbonate (3.64 g, 26.4 mM) added while stirring. Allyl bromide (3.86 g, 26.4 mM) was added and the mixture stirred at ambient temperature overnight. The solvent was removed by evaporation and the residue taken up in acetonitrile. The organic layer was washed with water, dried (MgSO4) evaporated and purified by silica chromatography with acetonitrile/petroleum ether (40/60) to give allyl 5-amino-2-nitrobenzoate as a yellow solid (3.46 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([OH:14])=O)[CH2:7]1.[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:12]([CH:8]1[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])[CH2:7]1)=[O:14])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (31.7 g) in chloroform (300 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (20.0 g), WSC.HCl (23.8 g) and 4-dimethylaminopyridine (6.90 g) under ice-cooling, the mixture was stirred for 15 minutes, warmed to room temperature and stirred for 18 hours. This reaction mixture was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/9) to give the titled compound (low-polarity component 26.4 g, high-polarity component 13.3 g).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(F)cc1F

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (5.99 mL, 34.9 mmol), pyridine (3.76 mL, 46.5 mmol) and 2,4-difluoroaniline (2.34 mL, 23.2 mmol). The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2,4-difluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=258.1 (M+1).