Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26](OCC)=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[CH2:26][OH:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(CO)Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Yield: 55.4 %

Procedure:
The compound was synthesised in an analogous method to Example 1 using ethyl 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl)-2-ethoxypropanoate (0.994 g, 2.172 mmol) and sodium borohydride (0.164 g, 4.34 mmol). The reaction was quenched after 21 hours and the product was extracted with ethyl acetate. The organic phase was washed with sodium sulfite and brine, dried (sodium sulfate), filtered and solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using heptane:ethyl acetate (gradient 2:1 tol:2) as eluants to give 0.5 g (yield 55%) of the desired product.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:19])[C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][O:8]C(=O)C>CO.O>[CH:12](=[C:6]([CH2:7][OH:8])[C:5]([OH:19])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(=Cc1ccccc1)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=Cc1ccccc1)CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product (143.9 g) in Reference Example 2, namely 2-benzylidene-3-acetoxypropionate methyl ester, is dissolved in methanol (400 ml), followed by addition of an aqueous solution of sodium hydroxide (96.0 g; 2.40 mol; purity of 97%) in water (800 ml). The resulting mixture is stirred at ambient temperature for 90 minutes. The reaction solution is concentrated under reduced pressure to distill off methanol, followed by addition of water (100 ml) and 36% hydrochloric acid (250 ml) for adjusting the resulting mixture to neutrality and subsequent extraction into ethyl acetate (600 ml). The resulting organic phase is washed with saturated saline (300 ml). After filtering off insoluble matters, the resulting solution is concentrated under reduced pressure. To the resulting residue is added toluene (250 ml×4), and the mixture is concentrated under reduced pressure to remove acetic acid to give a crude product of the title compound (107.8 g).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:20][Mg]Br>C1COCC1>[CH3:16][C:17]1[CH:25]=[C:24]([CH:23]=[C:19]([CH3:20])[CH:18]=1)[CH:26]=[C:5]1[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[CH2:8][CH2:9][C:10]2[S:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=C1c2ccccc2CCc2sccc21
Reactant: Cc1cc(C)cc(C[Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C=C2c3ccccc3CCc3sccc32)c1
Yield: 57 %

Procedure:
Following the procedures essentially as described in Example 238 and using 9,10-dihydro-1-thia-benzo[f]azulene-4-one (47.0 mg (0.22 mmol) and solution of 3,5-dimethylbenzyl magnesium bromide(0.650 mmol) in THF, provides, after dehydration, 39.6 mg (57%) of the title compound as a 1.6:1 mixture of E- and Z-isomers. MS (EI): 316 (M+); 1H NMR (CDCl3) δ 2.13 (s, 18/5 H), 2.24 (s, 12/5 H), 2.40-3.80 (m, 4 H), 6.54 (d, J=5.6 Hz, 2/5 H), 6.53-6.55 (m, 7/5 H), 6.74 (s, 3/5 H), 6.83-6.84 (m, 2/5 H), 6.86 (s, 3/5 H), 6.93 (s, 3/5 H), 7.01-7.02 (m, 1 H), 7.08 (app d, J=5.6 Hz, 2/5 H), 7.14 (app d, J=5.6 Hz, 2/5 H), 7.19-7.25 (m, 4 H), 7.30 (d, J=8.0 Hz, 3/5 H), 7.37-7.39 (m, 2/5 H).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>C(OCC)C>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1nccs1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a mixture of 40.6 ml n-butyl lithium (1.6M in hexane) and 18 ml diethylether is added dropwise at −70° C. a solution of 5.03 g thiazole dissolved in 59 ml diethylether. After 30 min 6.41 g trimethylsilylchloride dissolved in 59 ml diethylether is added at −70° C. The reaction mixture is stirred at −70° C. for 1 h and allowed to warm up to room temperature. The mixture is washed with saturated NaHCO3 solution, dried over Na2SO4 and the solvent is evaporated. The residue is distilled, to yield the desired product.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH:10]([CH3:32])[CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:10]([CH3:32])[CH2:9][C:1]#[N:2])=[C:25]([F:31])[CH:26]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C(C)COS(C)(=O)=O)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C(C)CC#N)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
16.2 mg (0.25 mmol) of potassium cyanide were added to 70 mg (0.12 mmol) of the compound from Example 55A in 3 ml of DMSO. The mixture was stirred at 80° C. for 4 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 33.4 mg (69% of theory) of the title compound were obtained as a mixture of diastereomers.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:17]=1[NH2:18].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][C:12]([NH:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[I:15])=[O:14])=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)CC1=CCC2(CC1)OCCO2
Reactant: COc1cccc(I)c1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(I)c1NC(=O)CC1=CCC2(CC1)OCCO2
Yield: 89.6 %

Procedure:
A solution of (1,4-dioxaspiro[4.5]dec-7-en-8-yl) acetic acid (567 mg; 2.86 mmol; 1 eq) (7) and 2-iodo-6-methoxyaniline (1 g; 2.86 mmol; 1 eq) in anhydrous dichloromethane (30 mL) is admixed with 2-chloro-1-methylpyridinium iodide (1.46 g; 5.73 mmol; 2 eq) and triethylamine (3.98 mL; 28.65 mmol; 10 eq). The reaction mixture is heated at reflux for 20 hours. After cooling and acidification with 1N HCl solution to pH=5-6, the mixture is extracted with dichloromethane. The organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 4/6) gives 1.10 g of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxy-phenyl)acetamide (16) in the form of a yellow foam (yield: 90%).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[P:8]([Cl:11])(Cl)Cl>C(#N)C>[CH:1]([N:4]([P:8]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[Cl:11])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: ClP(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Temperature: 25 °C
Yield: 74 %

Procedure:
A 5-liter, 3-neck, round-bottom flask was equipped with a Fredrich's condenser, a ground glass stirrer bearing, a silicon rubber septum, and placed under dry argon. Two liters (1,600 grams, 15.9 mmols, 7.0 eq) of anhydrous diisopropyl amine was added to the flask. The diisopropyl amine was diluted by the addition of two liters of anhydrous acetonitrile. The solution was mixed with a mechanical stirrer attached to a glass stir rod and Teflon blade. An ice/water bath was placed under the 5-liter flask, and the amine solution allowed to cool for 30 min. Phosphorus trichloride (313 grams, 2.3 mmols, 1.0 eq) was dissolved in 1 liter of anhydrous acetonitrile in a separate dry 1-liter flask. The mechanical stirrer was set to vigorous stirring and the phosphorus trichloride solution added slowly to the stirring flask by cannula. Once the addition was complete, the ice/water bath was removed, and the reaction was allowed to warm to room temperature. The reaction was stirred overnight and the extent of the reaction determined by 31P NMR of en aliquot of the reaction mixture using an external lock. Complete conversion of the starting material, phosphorus trichloride (δ 201 ppm), into the product at δ 134 ppm, demonstrated completion of the desired reaction. The reaction mixture was filtered to remove the bulk of the diisopropylamine hydrochloride, which had precipitated. The precipitate was washed with anhydrous ether and the filtrates evaporated into a 2-liter round-bottom flask. The resulting evaporated product was a semi-crystalline solid, which was suspended in 1 liter of anhydrous hexanes. The flask was heated on a mantel, to allow the hexanes to boil. The hot liquid was filtered through a Schlenk filter-funnel to remove residual amine hydrochloride. This resulting clear yellow liquid was evaporated to one half the original volume and placed in a freezer to allow the product to recrystallize. The recrystallized product was isolated by filtration and dried in a vacuum desiccator, yielding 447 grams (74% yield).
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]=1[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=O)[CH2:25][CH3:26])[CH2:18][CH2:17]1.CCOC(C)=O.Cl>C1COCC1>[CH2:24]([NH:23][CH2:22][CH:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:2]2[S:3][C:4]3[CH2:10][CH2:9][O:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:5]=3[N:1]=2)[CH2:17][CH2:18]1)[CH2:25][CH3:26]
Reactant: CCC(=O)NCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of N1-{[4-(4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-ylamino)cyclohexyl]methyl}propanamide (0.380 g, 0.944 mmol) in anhydrous THF (7 ml) was added 1M BH3 in THF (2.0 ml, 2.0 mmol). The solution was stirred for several hours at room temperature. TLC (EtOAc) indicated reaction to be incomplete and an additional 2.5 ml 1M BH3 in THF was added to the solution which was then stirred overnight. 4N HCl (25 ml) was slowly added to the stirred solution and the solution was washed with EtOAc. The aqueous layer was made basic by addition of 20% NaOH. The resulting solution was extracted with EtOAc and the extract washed with water. Upon removal of the solvent, 72% (254 mg) of the product was obtained as a white solid: 1H-NMR (CDCl3) δ 0.88 (3H, t, J=7.3 Hz), 1.12 (4H, m), 1.43 (3H, m), 1.75 (2H, m), 2.14 (2H, m), 2.41 (2H, d, J=6.6 Hz), 2.51 (2H, t, J=7.4 Hz), 2.60 (1H, m), 3.10 (2H, t, J=5.0 Hz), 3.22 (1H, m), 4.27 (2H, t, J=5.0 Hz), 5.35 (1H, m), 6.95 (1H, d, J=7.6 Hz), 7.06 (2H, m), 8.20 (1H, d, J=7.3 Hz); 372 (ESMS, MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:38][O:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[CH3:38][O:39][CH2:40][C:41]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)=[O:42]
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Yield: 89.4 %

Procedure:
To a suspension of 0.13 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 10 ml tetrahydrofurane were added at 0–4° C. 0.21 ml N-ethyldiisopropylamine and 0.037 g methoxyacetyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.126 g (91%) 2-methoxy-1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-ethanone as yellow solid; MS (ISP): m/e=458 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:14])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:15][C:16]([F:30])([F:29])[CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([S:14][CH2:17][C:16]([F:30])([F:29])[F:15])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1SCC(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 3,4-dichloro-2-mercaptobenzoate (7.95 g), 2,2,2-trifluoroethyl-p-toluene-sulphonate (9.66 g) and potassium carbonate (6.56 g) in DMF was heated at 90° C. for 4.5 hours. After cooling, water was added and the reaction mixture extracted with ether. The organic extracts were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography eluting with ether/n hexane to give ethyl 3,4-dichloro-2-trifluoroethylsulphenylbenzoate as a yellow oil, (3.53 g) NMR CDCl3; 1.4 (t,3H), 3.5(q,2H), 4.4(q,2H), 7.45(d,1H), 7.55(d,1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:14]([O:13][C:11](=[O:12])[C:10]([S:9][C:3]1[C:2]([NH:1][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)([CH3:19])[CH3:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ncc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)cnc2SC(C)(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To a 1,2-dichloroethane solution (2 ml) of tert-butyl 2-[(3-amino-5-chloropyridin-2-yl)thio]-2-methylpropanoate (334 mg) and tert-butyl 4-oxopiperidine-1-carboxylate (272 mg) was added at room temperature trifluoroacetic acid (0.084 ml), followed by stirring for 15 minutes. Sodium triacetoxyborohydride (356 mg) was added to the reaction solution, and stirred at 45° C. overnight. Cooling to room temperature, tert-butyl 4-oxopiperidine-1-carboxylate (264 mg) and trifluoroacetic acid (0.084 ml) were added. After the reaction solution was stirred for 10 minutes, sodium triacetoxyborohydride (345 mg) was added, and further stirred at 45° C. overnight. After the reaction solution was cooled to room temperature, 1 N aqueous sodium hydroxide solution was added, and extracted with dichloromethane. The collected organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-({2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-5-chloropyridin-3-yl}amino)piperidine-1-carboxylate (478 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]=[C:18](Cl)[C:19]([F:22])([F:21])[CH3:20])[CH:5]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]2[C:18]([C:19]([F:22])([F:21])[CH3:20])=[N:27][N:26]=[N:25]2)[CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(N=C(Cl)C(C)(F)F)cc(-c2ccc(C)cn2)c1
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2nnnc2C(C)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
3-(1-Chloro-2,2-difluoro-propylideneamino)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.611 g, 1.732 mmol) and NaN3 (0.225 g, 3.464 mmol) were added to 10 mL acetonitrile, and the mixture was stirred at room temperature for 90 minutes. Solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc. The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give 0.605 g of 3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as a white powder, MS (M+H)=360.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=3[C:22]#N)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)=[O:36]>O=[Pt]=O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:21]=3[CH:22]=[O:36])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=CO
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C#N
Agent: O=[Pt]=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzonitrile (242.1 mg, 0.488 mmol) in 88% aqueous formic acid (5.86 mL) was added PtO2 (57 mg, 0.251 mmol). The reaction was heated to 60° C. After 2 hours, additional PtO2 (57 mg, 0.251 mmol) was added. After 2 more hours, a third portion of PtO2 (57 mg, 0.251 mmol) was added. Heating of the reaction at 60° C. was continued for 18 more hours, and then the reaction was cooled to room temperature. The catalyst was removed by filtration through celite with THF (50 mL). The filtrate was diluted with EtOAc (100 mL) and washed with H2O (2×50 mL), 1:1 saturated NaHCO3/brine (2×50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (5 to 35% EtOAc/hexanes) afforded 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde. Rf=0.23 (25% EtOAc/hexanes). LCMS=500.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 10.26 (s, 1H), 7.79-8.02 (m, 6H), 5.74 (d, J=8.1 Hz, 1H), 5.08 (d, J=16.5 Hz, 1H), 4.91 (d, J=16.7 Hz, 1H), 4.18 (m, 1H), 0.81 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]([CH2:5][C@@H:6]([C:25]([O:27]C)=[O:26])[NH:7][C:8](=[O:24])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]([CH2:5][C@@H:6]([C:25]([OH:27])=[O:26])[NH:7][C:8](=[O:24])[CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:3]1
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccc(Oc3ccccc3)cc2)C(=O)O)c2ccccc21
Yield: 89.9 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 27 (0.93 g), 1 mol/L of an aqueous sodium hydroxide solution (3.1 mL), and methanol (30 mL), to give the captioned compound (0.81 g, 90%) as crystals.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>C(Cl)Cl.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(CBr)cc2)cc1
Reaction time: 12 h

Procedure:
A solution of 4-(bromomethyl)benzenesulfonyl chloride (5.6 mmol) in 5 mL of CH2Cl2 at 25° C. is treated with Et3 N (8.4 mmol) followed by bis-(4-methoxy-benzyl)-amine (5.8 mmol). The reaction is stirred for 12 hours, diluted with H2O, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. The resultant crude material is purified by silica flash chromatography (20% EtOAc/hexanes) to yield 4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide: 1H NMR (400 MHz, CDCl3): δ 7.72 (apparent t, J=8.4 Hz, 2H), 7.44 (dd, J1=1.6 Hz, J2=8.4 Hz, 2H), 6.91-6.86 (m, 4H), 6.69 (d, J=8.8 Hz, 4H), 4.5 (s, 2H), 4.19 (s, 4H), 3.71 (s, 3H); LC/MS: (ES+) 490.1 (M+1)+.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[NH2:2].[CH2:12]([CH2:14][CH2:15][CH2:16][C:17](CC([O-])=O)=[O:18])[CH3:13]>>[O:18]=[C:17]1[N:1]([C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])[N:2]=[C:15]([CH2:14][CH2:12][CH3:13])[CH2:16]1
Reactant: NNc1ccccc1C(=O)O
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccccc2C(=O)O)C(=O)C1

Procedure:
From the reaction of 2-hydrazinobenzoic acid and ethylbutyrylacetate, 2-(4,5-dihydro- 5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yields 2-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid, Mp 126.9° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][C:5](Cl)=[O:6].Cl.Cl.[CH3:10][N:11]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)=[N:20][CH:21]=2)=[N:12]1>C(Cl)Cl.O>[Cl:3][CH2:4][C:5]([N:25]1[CH2:24][CH2:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[CH:15][N:11]([CH3:10])[N:12]=3)=[CH:21][N:20]=2)=[CH:27][CH2:26]1)=[O:6]
Reactant: O=C(Cl)CCl
Reactant: Cn1cnc(-c2ccc(C3=CCNCC3)nc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)CCl)CC3)nc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Added 1N NaOH (50 ml, 50 mmol) and Chloroacetyl chloride (3 ml, 37.7 mmol) in CH2Cl2 (50 ml) dropwise to a solution of 5-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine dihydrochloride (5BX) (1 g, 3.60 mmol) in CH2Cl2 (50 ml at 0° C., maintaining pH at >12. Mixture was stirred for 2 hours at 0° C., then reaction was diluted with CH2Cl2 (200 ml) and H2O (100 ml). The organic layer was separated, washed with H2O (50 ml), dried (Na2SO4), filtered and solvent evaporated yielding title product as a white solid (1.1 g, 100%) MS (MH, 318)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[N:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[Br:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22]Br>>[Br:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][N:10]([C:11]1[C:16]([Cl:17])=[N:15][CH:14]=[CH:13][N:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: BrC/C=C/CBr
Reactant: O=[N+]([O-])c1ccccc1Nc1nccnc1Cl
Product: O=[N+]([O-])c1ccccc1N(C/C=C/CBr)c1nccnc1Cl

Procedure:
Similar to Production Example 132, 5.04 g of 2-[(2-nitrophenyl)amino]-3-chloropyrazine was treated with (E)-1,4-dibromo-2-butene to thereby give 0.34 g of the title compound.