Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH:23]=[O:24]>C1COCC1>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH:23]([OH:24])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7]
Reactant: C=CCCCCBr
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=CCCCCC(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A flame-dried round-bottomed flask was charged with magnesium turnings (1.23 g, 50.75 mmol) and stirred under vacuum for 15 minutes and then applied under nitrogen atmosphere. THF (70 mL) was added followed by 1,2-dibromoethane (381 mg, 2.03 mmol), and the mixture was brought to the boiling point for 1 minute, then and cooled down to room temperature. A solution of 6-bromohexene (8.28 g, 50.75 mmol) in THF (30 mL) was transferred via cannula to the magnesium flask and the mixture was refluxed overnight and cooled to −78° C. A solution of 2-naphthaldehyde (6.10 g, 39.04 mmol) in THF (30 mL) was transferred via cannula to the Grignard reagent and the mixture was slowly warmed to 0° C. over 3 hours and kept at that temperature for 2 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution and THF was evaporated in vacuo. The aqueous residue was poured into a separating funnel containing water and the compound was extracted with diethyl ether (2×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (10% to 15% ethyl acetate in hexane), affording the title compound 181 in 89% yield (8.33g). 1H NMR: (300 MHz, CDCl3) δ: 7.85-7.78 (m, 4H), 7.51-7.44 (m, 3H), 5.85-5.72 (m, 1H), 5.02-4.91 (m, 2H), 4.87-4.82 (m, 2H), 2.08-2.01 (m, 2H), 1.94-1.80 (m, 2H), 1.53-1.23(m, 4H). MS (ESI)=223 (MH+—H2O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=425.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]2[N:32]=[C:33]([NH2:35])[S:34][C:30]=2[CH:29]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:35][C:33]3[S:34][C:30]4[CH:29]=[C:28]([F:27])[CH:37]=[CH:36][C:31]=4[N:32]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nc2ccc(F)cc2s1
Yield: 37.4 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 6-fluorobenzo[d]thiazol-2-amine (0.067 g, 0.397 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of desired product. 1H NMR (DMSO-d6): δ 3.99 (s, 3H), 7.32 (t, J=7.2 Hz, 1H), 7.51 (t, J=9.3 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.68-7.80 (m, 4H), 7.94 (t, J=6.3 Hz, 2H), 11.98 (s, 1H), 12.83 (br s, 1H); MS (m/z): 512.97 [M−H]−.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Cl:26])=O)C1C=CC=CC=1.[N:27]1[C:36]2[C:31](=[N:32][C:33]([CH:37]=O)=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.N1CCCCC1>CC(O)C>[Cl:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:37][C:33]2[CH:34]=[CH:35][C:36]3[C:31](=[CH:30][CH:29]=[CH:28][N:27]=3)[N:32]=2)[C:14](=[O:16])[N:13]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(F)cc2Cl)=N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccc(F)cc2Cl)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.1 mg, 0.19 mmol), 1,5-naphthyridine-6-carboxaldehyde (28.7 mg, 0.18 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-1,5-dihydro-imidazol-4-one as a light yellow solid, 30.6 mg (43.0%). HR-ES (+) m/e calcd. for C19H13FClN5O: (M+H)+ 382.0866. Found: 382.0866.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of 3.13 g (0.010 mole) of 4-[5-(3,4-dichlorophenyl)-2-furanyl]-4-oxobutanoic acid and 50 ml of 95% dioxane/water was treated portionwise with 0.95 g (0.025 mole) of NaBH4 while maintaining the temperature below 20° by means of an ice bath. The resulting near solution was allowed to stand overnight at room temperature and was then added to ice/water. After acidifying with 20% hydrochloric acid, the resulting oily mixture was extracted with ether and the ethereal extract dried over MgSO4. The ether was removed on a Calab evaporator yielding 3 g (96%) of product as a residual oil.
Reaction SMILES: [NH:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.I[CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:9]([N:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1)([CH3:11])[CH3:10]
Reactant: CC(C)I
Reactant: O=Cc1cnc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cncc1C=O
Temperature: 50 °C
Yield: 95.9 %

Procedure:
A mixture of 1H-imidazole-5-carbaldehyde (800 mg, 8.3 mmol), 2-iodopropane (1.7 g, 10 mmol) and potassium carbonate (1.4 g) in DMF (30 mL) was heated to 50° C. overnight. The mixture was evaporated under reduced pressure, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to give 1-isopropyl-1H-imidazole-5-carbaldehyde (1.1 g), LC-MS (ESI) m/z: 139 (M+1)+. This compound (1.1 g, 8.0 mmol) and (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (1.7 g, 7.2 mmol) were added in ethyl propionate (50 mL) then sodium ethoxide was added under 0° C. The mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was extracted with ethyl acetate (100 mL×4). The organic layer dried over anhydrous sodium sulfate, purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1) to give ethyl 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (770 mg, yield 30%). LC-MS (ESI) m/z: 404 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:13]([O:30][CH:31]([CH3:33])[CH3:32])[CH:12]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:39]>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N+:16]([O-:39])=[C:15]([CH3:17])[C:14]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:13]([O:30][CH:31]([CH3:33])[CH3:32])[CH:12]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc(OC(C)C)c(COc2cc(C(C)C)ccc2C)c(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc(OC(C)C)c(COc2cc(C(C)C)ccc2C)c(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine (250 mg, 0.56 mmol) and 3-chloroperoxy-benzoic acid (77%, 150 mg, 0.67 mmol) in CH2Cl2 (10 mL) is stirred at room temperature for 2 hours. The mixture is diluted with CH2Cl2 (20 mL) and washed with saturated Na2CO3, brine dried over sodium sulfate, and concentrated in vacuo. The residue is purified on PTLC (1:1 hexane EtOAc) to give 6-(2,6-diethyl-phenyl)-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine 1-oxide. 1H NMR (CDCl3) 7.90 (m, 1H), 7.50-7.04 (m, 3H), 6.90-6.71 (m, 3H), 5.18 (m, 2H), 4.55 (m, 1H), 3.95 (m, 1H), 2.78 (s, 3H), 2.52-2.20 (m, 4H), 2.20 (s, 3H), 1.35 (d, 6H), 1.25 (d, 6H), 1.08 (t, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3].[CH3:14][O:15][CH2:16][C:17](OC)=[O:18]>C(OC)(C)(C)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C@H:2]([NH:1][C:17](=[O:18])[CH2:16][O:15][CH3:14])[CH3:3]
Reactant: CC(N)c1ccc2ccccc2c1
Reactant: COCC(=O)OC
Solvent: COC(C)(C)C
Product: COCC(=O)N[C@H](C)c1ccc2ccccc2c1
Yield: 34.8 %

Procedure:
39 g (0.23 mol) of racemic 1-amino-1-(β-naphthyl)ethane were dissolved in 200 ml of methyl tert-butyl ether. The solution was treated with 29.5 g (0.25 mol) of methyl methoxyacetate, the reaction was started by adding 0.5 g of lipase (approximately 1,000 U/mg, Pseudomonas spec. DSM 8246), and the batch was mixed during the reaction on a vibrating table. After the reaction rate had reached 50% (check by means of gas chromatography), which was the case after approximately 48 hours, the enzyme was filtered off. The filtrate was concentrated and the concentrate taken up in dilute hydrochloric acid (300 ml) and diethyl ether (300 ml). After the ether phase had been separated off, the acid phase was re-extracted using diethyl ether. After the ether phases had been combined, dried and concentrated, 18.7 g (0.08 mol) of (R)-N-[1-(β-naphthyl)ethyl]methoxyacetamide were obtained. After addition of sodium hydroxide solution until the pH is alkaline, it was possible to extract (S)-1-amino-1-(β-naphthyl)ethane from the aqueous phase with diethyl ether. Drying and evaporation of the organic phase gave 15 g of (0.09 mol) of (S)-1-amino-1-(β-naphthyl)ethane. After reaction to give the trifluoroacetamide, the enantiomeric excess (=ee) was determined on a chiral GC column (20 m Chiralolex B-Ph) as 89.5%.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][C:5]([O:7]CC)=O.Cl[C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH2:13]>CCO.CCOC(C)=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:11]2[S:3][CH2:4][C:5](=[O:7])[NH:13][C:12]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CSc2ccc([N+](=O)[O-])cc2N1

Procedure:
A solution of 2.44M aqueous NaOH (24 mL, 58 mmol) was added to a stirring solution of ethyl 2-mercaptoacetate (19 mL, 174 mmol) in EtOH (150 mL). The mixture was added to the stirring solution of 2-chloro-5-nitroaniline (10 g, 58 mmol) in EtOH (68 ml). The resulting mixture was heated at reflux overnight. After this time the reaction was diluted with EtOAc and washed with water. The separated organic layer was dried over Mg2SO4, filtered and evaporated in vacuo. The crude residue was triturated with EtOAc to give 6-nitro-2H-benzo[b]-[1,4]thiazin-3(4H)-one. Mass Spectrum (ESI) m/e=257 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29](OCC1C=CC=CC=1)=[O:30])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1>>[C:1]([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29](=[O:30])[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1)[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CN1CCc2cc(F)ccc21
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)N[C@@H](CC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CN2CCc3cc(F)ccc32)c1
Yield: 92 %

Procedure:
This material was prepared in 92% yield in an analogous fashion to example 158 except that 3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester was deprotected and m-anisic acid was used as the acid; 1H NMR (CDCl3, 400 MHz) δ 0.95 (s, 9H), 1.40 (s, 9H), 1.57 (dd, 1H, J1=8.5, J2=14.5), 1.88 (dd, 1H, J1=4.0, J2=14.5), 2.51 (dd, 1H, J1=5.9, J2=16.3), 2.61 (dd, 1H, J1=5.1, J2=16.3), 2.81-2.96 (m, 2H), 3.07 (dd, 1H, J1=7.4, J2=13.8), 3.22 (dd, 1H, J1=6.5, J2=13.8), 3.34 (dd, 1H, J1=8.5, J2=17.1), 3.44 (dd, 1H, J=8.6, J2=16.3), 3.82 (s, 3H), 4.34-4.43 (m, 1H), 4.64 (ddd, 1H, J=4.0, J2=J3=8.5), 6.39 (dd, 1H, J=4.1, J2=8.5), 6.57 (d, 1H, J=8.4), 6.66-6.75 (m, 1H), 6.73-6.78 (m, 1H), 6.97 (d, 1H, J=8.5), 6.98-7.04 (m, 1H), 7.23-7.33 (m, 3H); HPLC-MS calcd. for C31H42FN3O5 (M+H+) 556.3, found 556.5.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: O=[N+]([O-])O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a 1000 mL RB flask fitted with magnetic stirrer was charged with 150 mL of HNO3, cooled to 0° C., was added (1R,2R)-2-phenylcyclopropanecarboxylic acid (15 g, 92.593 mmol) portion wise for half an hour, RM brought to RT and stirred for 3 h. After the completion of reaction, RM was poured into ice cold water, stirred for 30 min and filtered off the product and dried under vacuum. The obtained product was white color solid (15 g, yield: 78.2%).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][NH3+:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C=O)C.O>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[CH:20][CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)C[NH3+]
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1
Reaction time: 12 h
Yield: 69 %

Procedure:
A solution of 2-(tert-butoxy)-2-oxoethanaminium chloride (3.00 g, 17.9 mmol) and potassium carbonate (4.95 g, 35.8 mmol) in DMF (20 mL) was stirred at room temperature for 2 min. To the reaction mixture was added 4-(bromomethyl)benzonitrile (3.19 g, 16.3 mmol) and stirring continued for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (3×20 mL). The combined organic extract was dried over MgSO4 then concentrated. Purification of the crude product by a silica gel column (DCM/MeOH) gave 2.77 g (68%) of tert-butyl 2-((4-cyanobenzyl)amino)acetate INT-31 as a yellow oil. LCMS-ESI (m/z) calculated for C14H18N2O2: 246; found 247 [M+H]+, tR=0.92 min (Method 3).
Reaction SMILES: C(N(CC)[CH:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])C.[C:20]([O:23][C:24]1[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>C(C(C)=O)C>[CH2:4]([N:6]([CH2:5][CH2:4][N:6]1[CH2:11][CH2:10][N:9]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][C:20](=[O:22])[CH3:21])[CH2:8][CH:7]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCN(CC)C(C)N1CCNCC1c1ccccc1
Solvent: CCC(C)=O
Product: CCN(CC)CCN1CCN(C(=O)c2ccccc2OC(C)=O)CC1c1ccccc1

Procedure:
4-Diethylaminoethyl-3-phenyl-1-(o-acetoxy benzoyl)piperazine is prepared by boiling under reflux 15 g. of 1-diethylaminoethyl-2-phenyl-piperazine dissolved in 100 ml. of methyl ethyl ketone with 11 g. of acetyl salicyclic acid chloride dissolved in 50 ml. methyl ethyl ketone, for 6 hours. The solvent is removed by distillation. The residue is dissolved in water. The aqueous solution is extracted with benzene. Ammonia is added to the aqueous layer until its reaction is alkaline and the thus precipitated oil is extracted with benzene. The benzene extract is dried by means of potassium carbonate and the benzene is distilled off. The residue is distilled in a vacuum. Boiling point: 190° C./0.01 mm. (bath temperature). Light yellow, viscous oil.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>C(#N)C>[Br:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]2[CH2:3][CH2:2][CH:1]([C:7]([OH:9])=[O:8])[C:4]2=[O:5])=[CH:13][CH:12]=1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: Nc1ccc(Br)cc1
Solvent: CC#N
Product: O=C(O)C1CCN(c2ccc(Br)cc2)C1=O

Procedure:
30 g of 1,1-cyclopropanedicarboxylic acid and 50 g of 4-bromoaniline were added to 50 ml of acetonitrile, followed by refluxing for 7 hours with heating and stirring.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][F:30])=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCCO)c(C(F)(F)F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCCCF)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
[4-(4-Hydroxybutyl)-3-trifluoromethylphenyl]carbamic acid tert-butyl ester (190 mg, 0.57 mmol) was dissolved in DCM (2 mL), and DAST (153 mg, 0.95 mmol) was added thereto. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give [4-(4-fluorobutyl)-3-trifluoromethylphenyl]carbamic acid tert-butyl ester (96 mg, 50%) as a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[Li+].[BH4-]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:16][CH2:17]2)=[N:4][CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(CO)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of (S)-methyl 5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinate (0.20 g, 0.38 mmol) in THF (20 mL) was added LiBH4 (2 M in THF, 0.19 mL, 0.38 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with DCM (50 mL) and the organic layer was washed with water (20 mL), 1 N HCl (10 mL), 1 N NaOH (10 mL) and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using EtOAc as eluent to yield a solid, which was further triturated with isopropanol/hexanes to give (S)-1-(1-(3-chloro-5-(hydroxymethyl)pyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.021 g, 0.043 mmol, 11% yield). Mass spectrum (apci) m/z=497.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C(C2C=CC([C:62]([F:65])([F:64])[F:63])=CC=2)=C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]2([C:26]3[CH:31]=[CH:30][C:29]([C:62]([F:65])([F:64])[F:63])=[CH:28][CH:27]=3)[CH2:24][CH2:25]2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cc(C3(c4ccccc4)CC3)nnc2OCc2ccccc2)cc1
Reactant: C=C(c1ccc(C(F)(F)F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1ccc(C2(c3cc(OCc4ccccc4)c(OCc4ccccc4)nn3)CC2)cc1
Yield: 38 %

Procedure:
Prepared according to the method for 3,4-bis(benzyloxy)-6-(1-phenylcyclopropyl)pyridazine (Intermediate 26) from 3,4-bis(benzyloxy)-6-{1-[4-(trifluoromethyl)phenyl]ethenyl}-pyridazine (Intermediate 67) in 38% yield.
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>CO>[OH:1][CH:2]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-hydroxy-3-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (14.7 g, 38.4 mmol) in methanol (60 ml) was added 2N aqueous sodium hydroxide solution (38.5 ml, 77 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-hydroxy-3-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (11.7 g, 86%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[C:23]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([CH:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC(C)(C)C1CCNCC1
Product: CC(C)(C)C1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 4-tert-butylpiperidine to give 252. MS: (ESI+)=427.1