Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(CN2C(C3CCCC4C=C(OC)C=CC=4C=3)=CC=CC2=O)=CC=1.ClCCN1CCCCCC1.[N:39]1([CH2:46][CH2:47][O:48][C:49]2[CH:75]=[CH:74][C:52]([CH2:53][N:54]3[C:59]([C:60]4[CH2:66][CH2:65][CH2:64][C:63]5[CH:67]=[C:68]([O:71]C)[CH:69]=[CH:70][C:62]=5[CH:61]=4)=[CH:58][CH:57]=[CH:56][C:55]3=[O:73])=[CH:51][CH:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:46][CH2:47][O:48][C:49]2[CH:50]=[CH:51][C:52]([CH2:53][N:54]3[C:59]([C:60]4[CH2:66][CH2:65][CH2:64][C:63]5[CH:67]=[C:68]([OH:71])[CH:69]=[CH:70][C:62]=5[CH:61]=4)=[CH:58][CH:57]=[CH:56][C:55]3=[O:73])=[CH:74][CH:75]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc2c(c1)CCCC(c1cccc(=O)n1Cc1ccc(OCCN3CCCCCC3)cc1)=C2
Agent: COc1ccc2c(c1)CCCC(c1cccc(=O)n1Cc1ccc(O)cc1)=C2
Agent: ClCCN1CCCCCC1
Product: O=c1cccc(C2=Cc3ccc(O)cc3CCC2)n1Cc1ccc(OCCN2CCCCCC2)cc1
Yield: 72.1 %

Procedure:
Synthesized from 1-(4-hydroxybenzyl)-6-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-1H-pyridin-2-one and 1-(2-chloroethyl)azepane according to an analogous synthetic method to Example 383 described below, 1-[4-(2-azepan-1-ylethoxy)benzyl]-6-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-1H-pyridin-2-one (317 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (222 mg).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([CH3:23])[C:15]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:7]1[C:2]([O:24][C:15]2[C:14]([CH3:13])=[CH:19][C:18]([N+:20]([O-:22])=[O:21])=[CH:17][C:16]=2[CH3:23])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ncc(C(F)(F)F)cc1Cl
Yield: 121.1 %

Procedure:
2,3-Dichloro-5-trifluoromethylpyridine (1.04 g), 0.8 g of 2,6-dimethyl-4-nitrophenol, and 0.5 g of potassium carbonate were added to 3 mL of dimethylacetamide, and the mixture was allowed to react at 155 to 165° C. for one hr. The reaction mixture was cooled, ethyl acetate and distilled water were then added thereto, followed by separation and washing with brine. The ethyl acetate layer was concentrated to give 2.01 g of 3-chloro-2-(2,6-dimethyl-4-nitrophenoxy)-5-trifluoromethylpyridine (yield 100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>CN(C=O)C.O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxybenzoic acid (60.9 g, 50 mmole) in 150 ml DMF was added potassium tert.-butoxide (12.34 g, 110 mmole) and the mixture was stirred at room temperature for one hour. Benzyl bromide (20.5 g, 120 mmole) was added and the mixture was stirred for two days at room temperature. The mixture was evaporated under reduced pressure and 100 ml 1,4-dioxane and a solution of sodium hydroxide (6.0 g, 150 mmole)in 50 ml water was added. The mixture was refluxed for two hours, cooled and evaporated under reduced pressure. Water was added and the mixture was acidified with acetic acid. The product was filtered, washed with cold water and dried. Yield: 10.2 g=89%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@H:29]([OH:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@H:29]([OH:36])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: O=C(O)c1ccc(S(=O)(=O)C[C@H](O)c2ccccc2)cc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)C[C@H](O)c2ccccc2)cc1Cl

Procedure:
150 mg of (R)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 190 mg of (R)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 170 mg of (R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide. MS (Q1) 527.2 (M)+.
Reaction SMILES: [Br-].[CH2:2]([N+:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[CH:3]=[CH2:4].C1(CCN2CCCC(C(C)=O)=C2)C=CC=CC=1>>[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][C:7]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:18])=[CH:6]1)[CH2:3][CH3:4]
Reactant: C=CC[n+]1cccc(C(=O)c2ccccc2)c1
Agent: CC(=O)C1=CN(CCc2ccccc2)CCC1
Agent: [Br-]
Product: CCCN1C=C(C(=O)c2ccccc2)CCC1

Procedure:
1-(2-Propenyl)-3-benzoyl pyridinium bromide was hydrogenated according to the procedure of Part (b) of Example 6 to give phenyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone (10) as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][NH:17][C:18](=[O:20])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[N:11]1([C:14]2[N:15]=[CH:16][NH:17][C:18](=[O:20])[CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]cn2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=c1cc(N2CCNCC2)nc[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.7 %

Procedure:
To a solution of 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (13.5 g, 48.2 mmol) in dichloromethane (200 mL) was added MP-TsOH (available from Aldrich; 81.0 g). The reaction was shaken at room temperature for 4 days. The crude reaction mixture was filtered and the resin was washed with methanol (460 mL). The desired product was eluted from the resin with 2M ammonia in methanol (460 mL) to give 6-piperazin-1-yl-3H-pyrimidin-4-one (8.4 g, 90%). LCMS Purity=96% (Rt=0.22 in the solvent front). 1H NMR (d6-DMSO) δ 7.75 (s, 1H), 5.10 (s, 1H), 2.60-2.42 (m, 4H), 2.38-2.25 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:1]([O:8][C@@H:9]([CH3:13])[C:10]([O:12][CH2:19][CH3:20])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: C[C@H](OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](C)OCc1ccccc1

Procedure:
The water layer at the time of the extraction with ethyl acetate in Example 3 was collected in its entirety, and was then adjusted to pH 2 with 10% hydrochloric acid. The water layer was then extracted twice with ethyl acetate (100 mL). After the organic layers were combined and dried, the solvent was distilled off to obtain (S)-benzyloxypropionic acid [0.83 g (48.0%), 96% ee]. An aliquot (0.8 g, 4.4 mmol) of the (S)-benzyloxypropionic acid was dissolved in ethanol (10 mL), followed by the addition of concentrated sulfuric acid (0.01 mL). The thus-prepared mixture was then heated under reflux. Eight hours later, the solvent was distilled off, and the residue was extracted with ethyl acetate (20 mL). The extract was washed with a 5% aqueous solution of sodium hydrogencarbonate (10 mL) and water (10 mL), the organic layer was dried, and the solvent was distilled off to obtain (S)-ethyl benzyloxypropionate. It was dissolved in toluene (10 mL), and under ice-cooled stirring, sodium ethoxide (0.33 g, 1.1 eq) was added, followed by stirring at room temperature for 14 hours. By gas chromatography making use of an optically active column, completion of the racemization was confirmed. Thereafter, the reaction mixture was added dropwise into a 10% aqueous solution of citric acid (10 mL). After the organic layer was washed with water (10 mL) and then dried, the solvent was distilled off to afford the title compound (0.74 g). 1H-NMR spectrum data of the compound were in conformity with those of the compound in Example 1. This racemate can be used as a feed for such asymmetric ester hydrolysis as in Examples 1 to 4.
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].[C:17]1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:14][CH:15]([CH2:16][CH3:17])[CH2:12][O:11]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:2])[CH3:3]
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC1COC(CN(C(=O)CCl)C(C)C)O1

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), butandiol-1,2 (3.56 ml) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-isopropyl-N-(4-ethyl-1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 140° C. at 1 mm of Hg pressure.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1ccccn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccccn4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(pyridin-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[N:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCCc1ccncc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 465.9 %

Procedure:
To a suspension of NaH (0.4 g) in DMF (8 mL) was added diethyl malonate (0.16 g) at 0° C. The mixture was stirred at RT for 30 min. To the mixture was added a solution of 4-(3-chloropropyl)pyridine (1.2 g) prepared in (1) in DMF (4 mL). The reaction mixture was stirred at 80° C. for 10 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=1/1) to give the title compound (1.3 g, 60%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([CH2:12][C:13]1[N:17]([CH:18]2[CH2:20][CH2:19]2)[C:16]2[CH:21]=[C:22]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:23]([F:25])=[CH:24][C:15]=2[N:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O.[O:51]1CCC[CH2:52]1>>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[CH:12]=[C:13]2[N:17]([CH:18]3[CH2:19][CH2:20]3)[C:16]3[CH:21]=[C:22]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[C:23]([F:25])=[CH:24][C:15]=3[N:14]2[C:52]1=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(=O)NOCc2ccccc2)n3C2CC2)CC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Yield: 5 %

Procedure:
tert-Butyl 4-[2-[[(benzyloxy)carbamoyl]methyl]-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (779 mg, 1.18 mmol) is dissolved in tetrahydrofuran (15 ml) and treated with N,N'-carbonyldiimidazole (480 mg, 2.96 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (225 mg, 1.48 mmol). The suspension obtained is poured into water (200 ml) and then extracted with ethyl acetate. The organic phase is washed in succession with water and 10 percent sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel (eluent: ethyl acetate/n-hexane 8:2). The product is crystallized from ethyl acetate/n-hexane. There are obtained 42 mg (5%) of tert-butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:12]([CH2:16][C:17]#[CH:18])[C:13](Cl)=[O:14])[CH2:10][CH3:11].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:16]([N:12]([CH2:9][C:10]#[CH:11])[C:13]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:14])[CH2:17][CH3:18]
Reactant: CCSc1nc[nH]n1
Reactant: C#CCN(CCC)C(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN(CCC)C(=O)n1cnc(SCC)n1

Procedure:
A mixture of 6.45 g. 3-ethylthio-1,2,4-triazole, 8.1 g. N-propyl-N-prop-2-ynylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to give a residual oil. This residual oil was distilled under reduced pressure to give 1-(N-propyl-N-prop-2-ynylcarbamoyl)-3-ethylthio-1,2,4-triazole, b.p. 124°C./0.05 mm. (97.8% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7](/[CH:19]=[CH:20]\[C:21]([O:23]C)=[O:22])[CH:6]=1.O[Li].O>CO.C1COCC1.O>[CH3:1][N:2]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7](/[CH:19]=[CH:20]\[C:21]([OH:23])=[O:22])[CH:6]=1
Reactant: COC(=O)/C=C\c1cc(CC(=O)N(C)CCc2ccccc2)ccc1OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(CCc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2)c(/C=C\C(=O)O)c1
Reaction time: 12 h

Procedure:
To a solution of 160 mg (0.36 mmoles) of cis-N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbomethoxyvinyl)phenyl]acetamide in 10 ml of a 1:1:1 MeOH/THF/H2O mixture at 0° C. is added 76 mg (1.8 mmoles) of LiOH·H2O. The reaction mixture is allowed to come to room temperature and stirred at room temperatured for 12 hours after which time the eraction mixtured is concentrated down in vacuo, taken up in H2O washed with ether (2 times) and acidified to pH 3-4 with 1N HCl. The aqueous layer extracted with ether (2 times). The ether extracts are combined and are dried with MgSO4, filtered and concentrated down in vacuo to give cis-N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyvinyl)phenyl]acetamide. (m.p. 48°-51° C.)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=O>>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]1[N:15]=[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:14][N:13]2[CH:18]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C(CBr)c1ccc(F)cc1F
Product: CC1(C)OB(c2ccc3nc(-c4ccc(F)cc4F)cn3c2)OC1(C)C

Procedure:
By carrying out the procedure as in stage 4.1, starting from 4.76 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine and 5.09 g of 2-bromo-1-(2,4-difluorophenyl)ethanone, 4.84 g of compound are obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[CH:38]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C1C=CN=CC=1)C.ClCCl>[O:35]1[C:31]2([CH2:30][CH2:29][N:28]([C:26]([N:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)[CH2:15][CH:10]([NH:9][C:43]([CH:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:44])[CH2:11]3)=[O:27])[CH2:37][CH2:36]2)[O:32][CH2:33][CH2:34]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
177 μl of triethylamine (1.27 mmol) and 15.5 mg of DMAP (0.127 mmol) were added to a solution of the amine hydrochloride from Example 62A (200 mg, 0.422 mmol) in dichloromethane (10 ml), and 84 mg of cyclopentanecarbonyl chloride (0.633 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrogen chloride solution and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 112 mg (52% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[C:21](O)(=[O:23])C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:21]=[O:23])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 208.4 g (1.0 mol) of 2,4-di-tert-butylphenol and 283.2 g (2.0 mol) of HMT in 500 mL of glacial acetic acid was heated at 130 C. with stirring for 2 hours. A solution of 500 mL of 20% (vol/vol) aqueous sulfuric acid was then added and the resulting solution was refluxed for 0.5 hour. The solution was cooled to around 60°-80° C. and the organic phase was separated from the aqueous phase. The organic phase was recrystallized twice from 150-200 mL of cold (0°-5° C.) methanol to give 93 to 107 g (40-46% yield) of pure 3,5-di-tert-butylsalicylaldehyde of greater than 95% purity by HPLC. mp 60°-62° C. 1H-NMR (60 MHz, CDCl3): δ9.8 (s,1H); 7.6 (d,1H); 7.3 (d,1H); 1.2-1.5 (d,18H). IR (KBr): 3400, 2980, 1650 cm-1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[NH2:40][O:41][CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:4][CH2:3][C:2](=[N:40][O:41][CH:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH2:7][CH2:6]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: NOC1CCOCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=NOC3CCOCC3)CC2)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), 4-(aminooxy)tetrahydro-2H-pyran (0.45 g) and pyridine (5 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 76%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.C(=O)(O)O.[NH2:17][C:18]([NH2:20])=[NH:19]>C(O)C>[NH2:20][C:18]1[N:19]=[C:8]([OH:10])[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:17]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nc(O)c2c(n1)CCCC2
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a solution of ethyl 2-oxocyclohexane carboxylate (41 g, 241 mmol) in ethanol (200 ml) was added guanidine carbonate (26.0 g, 289 mmol) under stirring at room temperature. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The precipitated crystals were filtered and washed with water, followed with methanol. The crystals were dried in vacuo to give the object compound (35.5 g, 89%).
Reaction SMILES: Br[C:2]([Cl:5])(Cl)[Cl:3].O=[C:7]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:3][C:2]([Cl:5])=[C:7]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1
Reactant: ClC(Cl)(Cl)Br
Reactant: COC(=O)c1ccc2c(c1)C=CC(=O)CO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C=CC(=C(Cl)Cl)CO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
0.046 ml (2 equivalents) of bromotrichloromethane is added to 50 mg (0.23 mmol) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 49, and 214 mg (0.92 mmol) of triphenylphosphine in suspension in 0.5 ml of acetonitrile, which is stirred beforehand at 0° C. for 2 hours. The reaction medium is protected from light and is again stirred at ambient temperature for 15 minutes. After the conventional treatments, purification on a column of silica gel (ethyl acetate/heptane 5/95) provides 48 mg (74%) of methyl 3-(dichloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylate in the form of a white solid; M.p.=119–121° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:10]([O:22][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCO
Reactant: C(OCC1CO1)C1CO1
Product: CCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of dodecanol.