Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([C:15]([F:18])([F:17])[F:16])[C:9]([C:19]([O:21]CC)=[O:20])=[CH:8]2)([F:4])[CH3:3].C1COCC1.CCO.O.[OH-].[Na+]>O>[F:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([C:15]([F:16])([F:17])[F:18])[C:9]([C:19]([OH:21])=[O:20])=[CH:8]2)([F:4])[CH3:3]
Reactant: CCOC(=O)C1=Cc2cc(C(C)(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.1 %

Procedure:
A 500 mL round bottom flask was charged with ethyl 6-(1,1-difluoroethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Step 1 (0.385 g, 1.145 mmole), THF: EtOH: H2O (7:2:1 volume ratio, 3 ml), and aqueous NaOH (0.55 mL, 1.374 mmole) and stirred at r.t. for two days. The reaction was concentrated in vacuo yielding a semi-solid. The semi-solid was dissolved in water washed with diethyl ether, and the resulting aqueous phase sparged with nitrogen with warming. The resulting organic solvent-free aqueous phase was acidified with concentrated HCl solution (to pH 1) yielding a gummy solid. This mixture was extracted with ethyl acetate. The combined organics were dried over MgSO4, filtered, diluted with isooctane, and concentrated in vacuo yielding an oil. Upon standing, the oil formed a white crystalline powder (0.159 g, 45%): mp 156-158° C. (w/decomp). LCMS m/z 309 (M+H). HRMS m/z 307.0408 (M−H, C13H8F5O3, Calc'd 307.0388). 1H NMR (acetone-d6/300 MHz) 12.2-11.2 (br s, ˜0.5H (1H exch), 7.97 (s, 1H), 7.72 (s, 1H), 7.61(d d, 1H, J=8.5, 2.2 Hz), 7.13 (d, 1H, J=8.7 Hz), 5.89 (q, 1H, J=7.0 Hz), 1.97 (t, 3H, J=18.3 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12](C(O)=O)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.OC1CC[N:56]([C:59]([O:61][C:62](C)(C)C)=[O:60])CC1>O1CCOCC1.C(OCC)(=O)C>[NH:30]1[CH2:31][CH2:32][CH:62]([O:61][C:59](=[O:60])[NH:56][C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:16](=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=[C:6]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=5)[CH:7]=4)[NH:15][C:14]=3[CH:13]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)O)ccc4c3c2)c1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(NC(=O)OC5CCNCC5)ccc4c3c2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylic acid (36 mg, 0.100 mmol, Example 82B) and 4 A° molecular sieves (36 mg) in 1,4-dioxane (1.5 mL) at 50° C. was added triethylamine (0.034 mL, 0.247 mmol) and diphenylphosphoryl azide (70.0 mg, 0.247 mmol). The mixture was stirred for 1.5 h and at that point tert-butyl 4-hydroxypiperidine-1-carboxylate (201 mg, 0.999 mmol) was added. The reaction mixture was stirred at 80° C. for 5 h. The reaction was cooled, diluted with ethyl acetate, and filtered. The solvent was removed from the filtrate and the Boc-protected product was isolated by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=80:20 and ending with A:B=0:100 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of the solvents. It was treated with a mixture of DCM (6 mL) and TFA (3 mL) at rt for 2 h. The solvent was removed and the crude product was purified by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=90:10 and ending with A:B=30:70 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) The HPLC fractions that contained the product were applied onto a cartridge of PHENOMENEX® Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 29.4 mg of piperidin-4-yl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate as a solid. MS (ESI) m/z 459.2 (M+H). 1H NMR (MeOD) δ ppm 8.40 (1H, s), 8.11 (1H, s), 8.04 (1H, d, J=8.55 Hz), 7.88 (1H, br. s.), 7.30-7.43 (3H, m), 7.15-7.27 (2H, m), 6.86-6.97 (1H, m), 3.89 (3H, s), 3.37 (1H, s), 3.04-3.14 (2H, m), 2.67-2.80 (2H, m), 2.00 (2H, dd, J=9.00, 4.12 Hz), 1.63-1.74 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[O:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)[CH2:20][CH2:21]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CC(N2CCOCC2)CCN1
Product: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Yield: 59.9 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (10 g) and 4-morpholinopiperidine (27 g), the title compound (9.4 g) was obtained. melting point: 84-86° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.[Cl:14][C:15]([Cl:19])([CH3:18])[CH:16]=O.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:20]1([CH:16]([NH:9][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)[C:15]([Cl:19])([Cl:14])[CH3:18])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(Cl)(Cl)C=O
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1ccc(C(F)(F)F)cc1)n1nnc2ccccc21

Procedure:
A suspension of 4-(trifluoromethyl)benzamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: O.C([NH:5][C:6]1[NH:7][C:8](=[O:42])[C:9]([CH2:19][CH2:20][NH:21][C:22]2[CH:41]=[CH:40][C:25]([C:26]([NH:28][C@H:29]([C:36]([O:38]C)=[O:37])[CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:27])=[CH:24][CH:23]=2)=[C:10]([N:12](C(=O)C)C(=O)C)[N:11]=1)(=O)C.C(O)C.SCCO>[OH-].[Na+]>[NH2:5][C:6]1[NH:7][C:8](=[O:42])[C:9]([CH2:19][CH2:20][NH:21][C:22]2[CH:41]=[CH:40][C:25]([C:26]([NH:28][C@H:29]([C:36]([OH:38])=[O:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:27])=[CH:24][CH:23]=2)=[C:10]([NH2:12])[N:11]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(NCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1)C(=O)OC
Agent: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(N)c(CCNc2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)c(=O)[nH]1
Reaction time: 18 h
Yield: 38 %

Procedure:
A crude preparation of dimethyl N-[4-[2-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)ethylamino]benzoyl]-L-glutamate hydrate (prepared on a 3.3 mmol scale but without recrystallization) was dissolved in 1N sodium hydroxide (100 ml) and ethanol (50 ml) containing 2-mercaptoethanol (0.25 ml). The reaction was heated with stirring to 55° for 18 hours and then spin evaporated in vacuo to a small volume. The pH of the ice bath cooled solution was adjusted to pH 4 with hydrochloric acid (12N) to precipiate the product. Recrystallization from methanol/ether gave 0.52 g (38% of theory) of N-[4-[2-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)ethylamino]benzoyl]-L-glutamic acid, mp 180°-185°.
Reaction SMILES: [CH3:1][N:2]([N:9]=O)/C(/N)=N/[N+]([O-])=O.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N+:2](=[CH2:1])=[N-:9].[N+:2](=[CH:1][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])=[N-:9]
Reactant: CN(N=O)/C(N)=N/[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: C=[N+]=[N-]
Product: [N-]=[N+]=CC(=O)c1ccccc1
Reaction time: 20 h

Procedure:
An ethereal solution of diazomethane is prepared from n-methyl-n-nitro-n-nitroso guanidine (15.72 g) for an estimated yield of 64 mmol. To the ethereal solution (400 ml) at 0° is added triethylamine (9.0 ml, 64 mmol), then dropwise benzoyl chloride (7.4 ml, 64 mmol). The reaction is warmed to 22° and stirred for 20 hrs, then filtered through celite and concentrated. The residue is recrystallized from ether/pentane to give the title compound.
Reaction SMILES: N[C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[C:8]([C:16]4[O:17][C:18]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:19][C:20](=[O:22])[CH:21]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-:30].[K+].[K+].[CH3:35][O:36][C:37](=[O:40])[CH2:38]Br>CN(C=O)C>[CH3:35][O:36][C:37](=[O:40])[CH2:38][O:30][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[C:16]3[O:17][C:18]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][C:20](=[O:22])[CH:21]=3)[CH2:13][C:14]=2[CH:15]=1
Reactant: Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 25 °C
Reaction time: 100 h

Procedure:
To a solution of 2-(7-Amino-9H-thioxanthen-4-yl)-6-morpholin-4-yl-pyran-4-one (1.01 g, 2.56 mmol) in anhydrous DMF (25 ml) was added powdered potassium carbonate (716 mg, 5.18 mmol) followed by methylbromoacetate (400 μl, 4.1 mmol). The reaction was stirred at room temperature for 100 hours whereupon it was quenched by dropwise addition of water (75 ml). The mixture was extracted using EtOAc (3×30 ml). The organic extracts were then combined, dried using MgSO4, filtered and concentrated in vacuo to give the title compound as a brown oil that was used without further purification (1.02 g, 85.7%), m/z (LC-MS, ESP), RT=4.05 min, (M++1)=466
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21]>O1CCCC1>[CH:1]1([O:7][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:20]([F:21])([F:23])[F:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(OC2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A solution of cyclohexanol (1.00 g, 10.0 mmol) in anhydrous tetrahydrofuran (6 ml) was added dropwise to a suspension of 60% sodium hydride (0.240 g, 6.00 mmol) in anhydrous tetrahydrofuran (6 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 1-Fluoro-4-nitro-2-(trifluoromethyl)benzene (1.05 g, 5.00 mmol) was added to the reaction mixture under ice cooling, and the mixture was refluxed for 3 hours. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Methanol (10 ml) and 10% platinum on activated carbon (0.100 g) were added to the residue obtained by evaporation of the solvent under reduced pressure, and the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction mixture was filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (0.60 g, 47%) as a colorless liquid.
Reaction SMILES: [CH2:1]([N:4]1C=CC=N1)[C:2]#C.C(NC(C)C)(C)C.[C:16]([C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:42]2[CH:47]=[CH:46][C:45]([C:48]#[C:49][CH2:50][N:51]3[CH2:56]COCC3)=[CH:44][CH:43]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36]([OH:38])=O)=[C:32]([CH3:41])[CH:31]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[O:57]1CCC[CH2:58]1>[Cu]I>[C:16]([C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:42]2[CH:47]=[CH:46][C:45]([C:48]#[C:49][CH2:50][N:51]3[CH:56]=[CH:2][CH:1]=[N:4]3)=[CH:44][CH:43]=2)=[CH:27]/[CH2:28][O:29][C:30]2[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36]([O:57][CH3:58])=[O:38])=[C:32]([CH3:41])[CH:31]=2)=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(C)(C)C)cc2)ccc1OCC(=O)O
Reactant: C1CCOC1
Reactant: C#CCn1cccn1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C

Procedure:
N-Propargylpyrazole (130 mg, 1.23 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]cetate (350 mg, 0.614 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)alladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature over night, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1-3:1) yielding methyl (Z)-[4-[3-(4-tert-butyl-phenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4([C:26](O)=O)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][C:3]=1[CH3:29].[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33]C[CH2:31]1.CN([C:41]([O:45]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4([CH:26]5[CH2:31][N:30]([CH2:35][CH2:36][NH:37][CH:41]=[O:45])[CH2:34][CH2:33]5)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][C:3]=1[CH3:29]
Reactant: NCCN1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc(Nc2nc3cc(OC4(C(=O)O)C=CC=CN4)ccc3n2C)ccc1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc3cc(OC4(C5CCN(CCNC=O)C5)C=CC=CN4)ccc3n2C)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[4-bromo-3-methylpheylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4bromo-3-methylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. MS: MH+=549.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:36]([NH:44][NH2:45])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][NH:44][C:36]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:43])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 in dehydrated methylene chloride (14.1 mL) was cooled to 0° C. under an argon atmosphere, and isobutyl chloroformate (231.1 mg) was gradually added so that the temperature does not exceed 0° C. Then, triethylamine (185 mg) was gradually added so that the temperature does not exceed 0° C. followed by stirring for 30 minutes, thereby a mixed acid anhydride in the reaction system was prepared. To this reaction mixture was gradually added nicotinic acid hydrazide (580 mg). After the addition, the temperature was raised to room temperature, followed by stirring for 1 hour. This reaction mixture was washed with 0.5M hydrochloric acid and saturated brine, and the organic layer was dried over magnesium sulfate, and then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1-0/1, ethyl acetate/methanol=30/1) to afford 439.5 mg of the title compound as a colorless oil (yield 78.8%).
Reaction SMILES: CN1CCCC1=O.[F:8][C:9]1[C:10]([NH:17][CH3:18])=[N:11][C:12](F)=[C:13]([F:15])[CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([NH:26][C:12]1[C:13]([F:15])=[CH:14][C:9]([F:8])=[C:10]([NH:17][CH3:18])[N:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CNc1nc(F)c(F)cc1F
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CNc1nc(NCc2ccccc2)c(F)cc1F
Temperature: 140 °C
Reaction time: 19 h

Procedure:
To 20 ml of N-methylpyrrolidone were added all amount of the above-described 3,5,6-trifluoro-2-(methylamino)-pyridine together with 10 g of benzylamine, and the mixture was stirred at 140° C. for 19 hours and allowed to cool. To the solution was added 50 ml of chloroform and the mixture was washed six times with 200 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a crude oil.
Reaction SMILES: [C:1]([CH2:3][C@H:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[C:5](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:6])#[N:2].[Li+].[BH4-].Cl>C1COCC1.O>[OH:6][CH2:5][C@@H:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[CH2:3][C:1]#[N:2]
Reactant: N#CC[C@@H](C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC[C@@H](CO)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-[(R)-β-Cyano-α-(2-fluorophenyl)-propionyl]-4-(R)-phenyl-2-oxazolidinone (400 g, 1.18 mol) is suspended in THF (4000 mL) and H2O (25 mL). The reaction mixture is cooled in ice bath to 0° C. and a solution of LiBH4 in THF (2M, 887 ml, 1.77 mol, 1.5 eq) is added slowly. The mixture is then stirred at 0° C. for 2 hours, after which 2N HCl (1500 mL) is cautiously added. The resulting solution is then extracted with Et2O (2×1500 mL). The combined organic phases are then washed with saturated NaCl solution (2×1500 mL), dried over MgSO4 and concentrated in vacuo. The solid 4(R)-phenyl-2-oxazolidinone is recovered by filtration and washed with Et2O (2×100 mL). The filtrate is then chromatographed (silica gel, EtOAc/Hexanes, 1:3 ) to give β(R)-(hydroxymethyl)-β-(2-fluorophenyl)-propionitrile as an oil.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CO>[C:1]1([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CC1
Yield: 147.5 %

Procedure:
To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol) in CH3OH (200 mL) was added TsOH (3 g, 0.1 mol) at room temperature. The mixture was refluxed overnight. The solvent was evaporated under reduced pressure to give crude product, which was dissolved into EtOAc. The EtOAc layer was washed with aq. sat. NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 1-phenylcyclopropanecarboxylate (26 g, 96%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5 H), 3.63 (s, 3 H), 1.63-1.60 (m, 2 H), 1.22-1.19 (m, 2 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](=[S:18])=[S:17].[OH-].[K+].[CH2:21](Br)[CH2:22]Br>CS(C)=O.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10](=[C:16]2[S:18][CH2:22][CH2:21][S:17]2)[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C=S
Reactant: BrCCBr
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCN(Cc2ccccc2)C(=O)C1=C1SCCS1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
1-Benzyl-2,4-dioxopiperidine (2.03 g) and carbon disulfide (760 mg) are dissolved in dimethylsulfoxide (20 ml), and thereto is added dropwise a solution of potassium hydroxide (1.1 g) in water (3 ml) at room temperature. The mixture is stirred for 30 minutes and thereto is added dropwise a solution of 1,2-dibromomethane (1.87 g) in dimethylsulfoxide (3 ml). The mixture is stirred at room temperature for 2 hours and further at 60° C. for 1 hour. The reaction mixture is poured onto water and extracted with benzene-ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, benzene:ethyl acetate=8:2) and is recrystallized from ethanol to give 1-benzyl-3-(1,3-dithiolan-2-ylidene)-2,4-dioxopiperidine (1.08 g) as pale yellow needles. m.p. 148°-150° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Br:10][C:11]([OH:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:14][C:11]([Br:10])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(O)Br
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nicotinic acid chloride (2.56 g, 20 mmol) and 30 mg of DMAP were added to a mixture of 2-bromo-2-propanol (2.8 g, 20 mmol), triethylamine (5.6 mL, 20 mmol) in dichloromethane at 0° C. The resulting mixture was stirred at room temperature overnight. The product was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, and concentrated to yield 1-Bromoisopropyl nicotinate, which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([S:7](CP(=O)(OCC)OCC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:34]([C:42]([O:44][CH3:45])=[O:43])(=O)[C:35]1C=CC=CC=1.C(OCC)(=O)C.[CH3:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[C:54]1([CH:2]2[C:1](=[S:7](=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[C:3]2[C:34](=[CH2:35])[C:42]([O:44][CH3:45])=[O:43])[CH:53]=[CH:52][CH:57]=[CH:56][CH:55]=1
Reactant: CCOP(=O)(CS(=O)(=O)c1ccccc1)OCC
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: CCCCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C(=O)OC)C1=CC=CC(=S(=O)=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine diethyl phenylsulphonylmethylphosphonate (T. A. Blumenkopf Synth. Commun. 26, 139-147, (1986)) (117.0 g, 400 mmol) and tetrahydrofuran (500 mL). Cool in an ice-bath. Add lithium bis(trimethylsilyl)amide (480 mL, 1M in tetrahydrofuran, 480 mmol). Stir for 30 minutes after the addition of lithium bis(trimethylsilyl)amide, then add methyl benzoylformate (72.0 g, 439 mmol). Warm to ambient temperature and stir for 2 hours. Partition between water and ethyl acetate. Extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over magnesium sulfate and evaporate in vacuo to give an oil. Triturate with cyclohexane to give a solid. Chromatograph the solid on silica gel eluting sequentially with 10% ethyl acetate/hexane, 15% ethyl acetate/hexane, and 33% ethyl acetate/hexane. Evaporation of the product containing fractions give a solid. Recrystallize form ethyl acetate/hexane to give 2-phenyl-3-sulfonylphenyl-propenoic acid, methyl ester as a solid. Elem. Anal calculated for C16H14O4S: C, 63.56; H, 4.67. Found: C, 63.25; H, 4.70.