Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:9]=[CH:8][C:6]=2[N:7]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Fc1ccc(Oc2cc3c(Cl)nc(Cl)nc3cn2)c(F)c1
Reactant: N
Solvent: CO
Product: Nc1nc(Cl)nc2cnc(Oc3ccc(F)cc3F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (1E) (1.75 g, 5.33 mmol) was placed in a sealed-tube, and 7 N ammonia in MeOH (Aldrich Chemical Co.) (30 mL) was added. The tube was tightly capped, and the resulting homogeneous mixture was stirred at room temperature overnight. The next morning, TLC confirmed that the reaction was complete. The mixture was transferred to a round-bottom flask and concentrated under reduced pressure at 55° C. The residue was taken up in EtOAc (700 mL) and water (250 mL). The layers were partitioned and then separated. The organic layer was washed with water (2×250 mL) and brine (1×250 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and pumped to give the title compound (1F) as an off-white powder (1.859 g, (M−H)−=307, Mp>300° C.).
Reaction SMILES: C(Cl)(Cl)Cl.O=O.[CH2:7]([OH:11])[CH2:8][CH:9]=[CH2:10].B(CC)(CC)CC.[CH2:19]=[CH:20][CH:21]1[O:23][CH2:22]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1COCC1>[CH3:22][CH:21]([O:23][C@H:8]([CH:9]=[CH2:10])[CH2:7][OH:11])[CH:20]=[CH2:19]
Reactant: C=CC1CO1
Reactant: C=CCCO
Agent: CCB(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CC(C)O[C@H](C=C)CO
Temperature: 25 °C
Reaction time: 0 h
Yield: 81577.8 %

Procedure:
To an oven dried test tube was added Pd2dba3.CHCl3 (5.2 mg, 5.0 μmol), chiral ligand (S,S)-9 (11.8 mg, 15 μmol), DMAP (6.2 mg, 50 μmol) and a stirbar. Several drops of CH2Cl2 were then added to wet the catalyst, and the test tube was immediately placed under reduced pressure (vacuum pump) for 10 sec and refilled with Ar. This purging procedure was repeated five times to ensure no oxygen remained in the reaction vessel. After being placed under an Ar atmosphere, freshly distilled and degassed methylene chloride was added (10 mL) and the resulting dark purple mixture was stirred at room temperature until it turned a deep orange color (roughly 15 min). During this time, the 3-butenol (172 μL, 2.0 μmol) and a 1.0 M solution of Et3B in THF was added (5.0 μL, 5.0 μmol). To the solution of catalyst and alcohol was added neat butadiene monoepoxide (81 μL, 1.0 μmol) and the solution immediately turned pale yellow. Stirring was continued for 4 h. The solvent was removed in vacuo. Flash chromatography of the crude material (silica gel, 4:1 pentane-ether) afforded 116 mg (82%) of 27 as a colorless oil in 90% ee (separated by chiral GLC, Cyclosil B column, isothermal 100° C., (S)-(+)-isomerrt=11.97 min, (R)-(−)-isomerrt=12.20 min). [α]D=−50.0° (c 2.20, CHCl3); 1H NMR (300 MHz): δ 2.09 (br s, 1H), 2.28-2.35 (m, 2H), 3.32-3.40 (m, 1H), 3.46-3.66 (m, 3H), 3.77-3.83 (m, 1H), 5.01 (d, IH, J=11 Hz), 5.10 (d, 1H, J=17 Hz), 5.23 (d, 1H, J=10 Hz), 5.28 (d, 1H, J=17 Hz), 5.60-5.84 (m, 2H); 13C NMR (75 MHz): δ 34.2, 65.3, 67.9, 81.7, 116.6, 118.7, 135.2, 135.2. Anal. Calcd. for C8H14O2: C, 67.57; H, 9.92; found C, 67.36; H, 9.80.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28]>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Reactant: CC(C)(C)COC(=O)Cl
Product: CC(C)(C)COC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1

Procedure:
From 0.45 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and neopentyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 156 mg of 2′-(2,2-dimethylpropoxycarbonylaminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained. MS (ES+): m/e=445 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].[CH2:24]([NH:31][CH2:32][CH3:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH3:33])[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCNCc1ccccc1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22](/[C:15](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2cccnc2)cc1
Yield: 63.5 %

Procedure:
As before in Example 134, a solution of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.61 g) and 3-pyridinebutanamine (0.61 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. After the usual workup, the crude product was crystallized form ethyl acetate to provide 1.05 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=4)[CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(O[C@@H]2C[C@H]3CNCCN3C2)nc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)c1cccc(N2CCN3C[C@H](Oc4ccc(Cl)cn4)C[C@H]3C2)n1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
To a solution of Example 57 (76.2 mg, 0.3 mmol) in dimethyl sulfoxide (0.3 mL) was added 2-chloro-6-(trifluoromethyl)pyridine (87 mg, 0.48 mmol) and sodium carbonate (64 mg, 0.6 mmol). The mixture was stirred at 100° C. for 4 days and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (m, 2H), 2.22-2.36 (m, 3H), 2.58 (m, 1H), 2.90-3.08 (m, 2H), 3.62 (m, 1H), 4.30 (m, 1H), 4.44 (m, 1H), 5.31 (m, 1H), 6.83 (d, 1H, J=7 Hz), 7.05 (d, 1H, J=7 Hz), 7.15 (d, 1H, J=7 Hz), 7.78 (m, 2H), 8.22 (s, 1H); MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH:20][C:21]([C:23]2[C:24]3[CH:31]=[N:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:25]=3[CH:26]=[N:27][CH:28]=2)=[O:22])[CH2:18][CH3:19])[CH2:13][CH:12]1[C:39](=[O:41])[NH2:40])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:39]([CH:12]1[CH2:13][CH:14]([C@@H:17]([NH:20][C:21]([C:23]2[C:24]3[CH:31]=[N:30][N:29]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[C:25]=3[CH:26]=[N:27][CH:28]=2)=[O:22])[CH2:18][CH3:19])[CH2:15][CH2:16][NH:11]1)(=[O:41])[NH2:40]
Reactant: [H][H]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCNC(C(N)=O)C1
Reaction time: 8 h

Procedure:
A solution of 2-carbamoyl-4-((S)-1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-piperidine-1-carboxylic acid benzyl ester (340 mg, 0.61 mmol) in MeOH (10 mL) was added to a flask containing 10% palladium on carbon (52 mg, 0.05 mmol) under nitrogen and then the mixture was placed under 1 atmosphere of hydrogen. The reaction was monitored by HPLC-MS indicating 50% conversion. After stirring overnight, the mixture was filtered, and concentrated. The reaction was re-subjected to the above condition for an additional 5 hours at which time the mixture was filtered through diatomaceous earth, rinsed with MeOH, filtered and concentrated. The crude material was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 uM 30×150 mm column, eluted with 15-85% acetonitrile in water, with 0.1% TFA). Fractions containing the desired product were concentrated in vacuo, made basic with a few drops of saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@:13](C)([CH2:14][CH2:15][C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1.O>C(O)(=O)C>[CH3:1][C@H:2]1[C@H:3]2[C@H:4]3[C@:8]([CH3:9])([CH2:10][CH2:11][C@@H:12]2[C:13]2[CH:14]=[CH:15][C:16]([OH:20])=[CH:17][C:18]=2[CH2:19]1)[C:7](=[O:22])[CH2:6][CH2:5]3
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 60 °C
Yield: 82 %

Procedure:
To a solution of 114 g of 7α-methylandrost-4-ene-3,17-dione 45a in 1,500 mL of glacial acetic acid was added 106 g of CuCl2. The mixture with stirring was heated to 60° C. for 72 h. The reaction mixture was poured into H2O (500 mL reaction mixture to 3,500 mL H2O) and the precipitate collected by filtration and air dried for 18 h. The solid was dissolved in methylene chloride (2 L) and washed with sat. NaHCO3 (2 L), H2O (2 L), and sat. NaCl (2 L). The methylene chloride solution was dried over MgSO4, and filtered. The methylene chloride solution was filtered (suction chromatography) through 1.5 kg of flash chromatography silica gel 60 (230-400 mesh). The pad of silica gel was further eluted with additional MeCl2. The MeCl2 solutions were combined and then treated with Norite, filtered through a pad of celite and then after evaporation at reduced pressure there was obtained 91.3 g of pure 13 (82%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11](=[CH:15][O:16]CC)[C:12]([CH3:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:23]O.[OH-].[Na+]>C(O)C.O>[CH3:14][C:12]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)=[O:19])=[CH:15][O:16][N:23]=1
Reactant: NO
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nocc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-(ethoxymethylene)-acetoacetamide (4 g) is suspended in 10 mL of ethanol treated with 1.5 g of hydroxylamine hydrochloride in 10 mL of water which has been adjusted to pH 5 with sodium hydroxide. The mixture is stirred and warmed to 40° C. for 2 hours, then cooled to room temperature and the precipitate collected by vacuum filtration. Sodium hydroxide (1 g) is added to the filtrate which is stirred for 30 minutes. The mixture is acidified to pH 2 with 6 N hydrochloric acid and the precipitate collected by vacuum filtration. The filtrate is then diluted with 100 mL of water and allowed to stand at 4° C. overnight. The precipitate is collected by vacuum filtration, washed with ethanol:water 2:1 and dried to give 300 mg of crude 3-methyl-4-[4-(trifluoromethyl)-phenylaminocarbonyl]isoxazole. The crude is purified on a column of silica gel eluting with ethyl acetate:hexane 1:4 to give 100 mg of 3-methyl-4-[4-(trifluoromethyl)phenylaminocarbonyl]-isoxazole, an off-white solid.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl.CCOCC>[O:8]1[CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:17]
Reactant: C=CCCCCCO
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: OCCCCCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
A mixture of 3 (1.4 g, 12 mmol) and m-chloroperbenzoic acid (2.92 g, 14.4 mmol) in methylene chloride (40 mL) was stirred at room temperature overnight. It was then diluted with ether, washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Removal of the solvent afforded 1.64 g of the crude 6,7-epoxy-1-heptanol (5).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][O:22][C:23](=O)[O:24]C>C1COCC1>[O:3]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:23]([O:22][CH3:21])=[O:24])[C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a suspension of NaH (1.02 g of 60% NaH in mineral oil washed with hexanes, 0.61 g, 25.6 mmol) in dry THF (30 mL) was added methyl (4-phenoxyphenyl)acetate (2.7 g, 11.1 mmol ) in dry THF (10 mL). The resulting mixture was stirred at room temperature for 30 minutes and then dimethylcarbonate (4.0 g, 3.75 mL, 44.4 mmol) was added . The reaction mixture was heated to reflux overnight and then cooled to room temperature, quenched with 1N HCl (60 mL), and extracted with ether (2×100 mL). The combined organic extracts were washed with water, then brine, dried (Na2SO4), concentrated, and purified using HPLC (porasil) eluted with 15% EtOAc/hexanes to give 2.56 g of dimethyl 2-(4-phenoxyphenyl)malonate as a white solid: 1H NMR (200 mHz, CDCl3) δ 7.39-6.92 (9H, m), 4.65 (1H, s), 3.75 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([OH:18])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]2=O)=[CH:5][CH:4]=1.[N:20]1([C:26]([CH:28]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:10]([CH2:28][C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:27])[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:17]2=[O:18])=[CH:7][CH:8]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCCC1
Reactant: COc1ccc(N2C(=O)C3=C(CCCC3)C2O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)C3=C(CCCC3)C2CC(=O)N2CCCCC2)cc1
Yield: 50.8 %

Procedure:
2-(4-Methoxyphenyl)-3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one (2.59 g) and piperidinocarbonylmethylenetriphenylphosphorane (4.6 g) were dissolved in 50 ml of dry toluene and the solution was refluxed gently for 20 hours. After cooling, the solvent was distilled off and the residue was purified by silica gel column chromatography. Fractions eluted with dichloromethaneethyl acetate (5:1) were collected and concentrated to give crude crystals. This product was recrystallized from ether-hexane (1:3) to give 1.87 g of 2-(4-methoxyphenyl)-3-piperidinocarbonylmethyl-4,5,6,7-tetrahydroisoindolin-1-one.
Reaction SMILES: C1(N2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)C=N2)C=CC=CC=1.C(C1C=C2C(=CC=1)/C(=N/O)/CCC2)=C.[C:45]1([C:51]2C(C(F)(F)F)=C(C(OC)=O)[S:53][N:52]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:51]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[S:53][N:52]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)c1snc(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: C=Cc1ccc2c(c1)CCC/C2=N\O
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1snc(-c2ccccc2)c1C(F)(F)F

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1) and methyl 3-phenyl-4-(trifluoromethyl)isothiazole-5-carboxylate (Preparation 103E) as starting materials. The compound had an HPLC retention time=4.25 min. (condition C); LC/MS M+1=424.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([CH2:14]O)=[CH:12][CH:11]=[CH:10][N:9]=1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:14][C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1-c1ccccc1Cl
Product: ClCc1cccnc1-c1ccccc1Cl
Reaction time: 1 h
Yield: 92 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of [2-(2-chlorophenyl)pyridin-3-yl]methanol (1 g, 4.55 mmol, 1.00 equiv) in thionyl chloride (5 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum to yield 1 g (92%) of 3-(chloromethyl)-2-(2-chlorophenyl)pyridine as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].I[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1>C(O)C>[CH2:2]([NH:4][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1)[CH3:3]
Reactant: CCN
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 74.2 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.1 g (13.4 mmol) of ethylamine hydrochloride, 1.85 g (13.4 mmol) of potassium carbonate and 800 mg (1.34 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 511 mg of ethyl 4′-(3-ethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=148° C., yield=74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH:19](OC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:3]=1.B(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH:19]([Cl:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(OC)c1ccccc1F
Reactant: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(Cl)c1ccccc1F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 20.1 g of 3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole in 250 ml methylene chloride is added 54 ml of a 1.4 molar boron trichloride solution in methylene chloride, and the mixture is stirred during 16 hours. Ice/water is then added; the organic layer separated, washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The aqueous layers are reextracted with methylene chloride. After removal of the solvent, the 3-[4-chloro-2-(α-chloro-2-fluoro-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole is obtained as the solid residue, which is directly used in the next step.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:17]([N:7]1[CH2:8][C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C@@H:5]([CH2:3][OH:2])[CH2:6]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (5.8 g, 0.018 mol) were dissolved in THF (180 mL). At 0° C. LiAlH4 (0.70 g, 0.0185 mol) was added portion wise. After stirring at 0° C. for 4 h water (5 mL), then 5N NaOH (5 mL) and additional water (15 mL) was added. After stirring at ambient temperature for 30 min the mixture was extracted with ethyl acetate (3×10 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a light yellow oil (5.2 g, 98%) and directly used in the next step. ES-MS m/e: 302.8 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].CCN=C=NCCCN(C)C.[C:42](O)(=[O:45])[CH2:43][CH3:44]>CN(C1C=CN=CC=1)C.ClCCl>[C:42]([NH:25][S:22]([C:20]1[S:21][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:26])(=[O:24])=[O:23])(=[O:45])[CH2:43][CH3:44]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NS(=O)(=O)c1sc(C(CC)(CC)c2ccc(OCC(=O)C(C)(C)C)c(C)c2)cc1C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide (330 mg, 0.73 mmol), EDCI (210 mg, 1.1 mmol), propionic acid (82 μL, 1.1 mmol) and DMAP (50 mg) in dichloromethane (10 ml) is stirrred overnight. The reaction is diluted with dichloromethane and washed with 1N HCl. The organic phase is concentrated and chromatographed (Hex to 30% EtOAc/Hex) to give the title compound (92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:26]N1C(=O)CCC1=O>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][Br:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Solvent: CC(Cl)Cl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Yield: 71 %

Procedure:
A solution of 3-(3-bromo-4-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.2 g), N-bromosuccinimide (0.54 g) and 2,2′-azobisisobutylonitrile (0.05 g) in dichloroethane (20 mL) was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, the residue was diluted with t-butylmethylether, and the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to yield 3-[3-bromo-4-(bromomethyl)-phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.0 g).