Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](Cl)=[O:26]>N1C=CC=CC=1>[C:2]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:26])[CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccccc1OC1CCNC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1OC1CCN(C(=O)c2ccccn2)C1
Yield: 43.2 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)pyrrolidine hydrochloride (0.26 g, 1.00 mmol) in pyridine (2.5 mL) was added picolinoyl chloride hydrochloride (0.20 g, 1.10 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate (50.0 mL) and water (50.0 mL) and separated. The organic layer was washed with saturated sodium chloride (50.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 80:20 to 50:50 heptane/ethyl acetate) provided (3-(2-tert-butylphenoxy)pyrrolidin-1-yl)(pyridin-2-yl)methanone (0.14 g, 43%) as a pale yellow oil.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=NN)[C:6](=[O:12])[NH:7]2>C(O)C>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2
Reactant: NN=C1C(=O)Nc2cccc(Cl)c21
Agent: [Na]
Solvent: CCO
Product: O=C1Cc2c(Cl)cccc2N1
Yield: 60.1 %

Procedure:
To a stirred solution of 22 g of sodium in 450 ml of anhydrous ethanol was added, portionwise, 43.5 g of 4-chloro-3-hydrazono-2-oxindole, and the resulting solution was heated under reflux for 30 minutes. The cooled solution was then concentrated to a gum, which was dissolved in 400 ml of water and decolorized using activated carbon. The resulting solution was poured onto a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The precipitate which formed was recovered by filtration, dried and recrystallized from ethanol, giving 22.4 g of 4-chloro-2-oxindole, mp 216°-218° C. (dec).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:37])[CH2:28][CH2:29][CH2:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:32]([F:34])([F:35])[C:31](=[O:36])[CH2:30][CH2:29][CH2:28][C:27]([C:24]1[CH:25]=[CH:26][C:21]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:23]=1)=[O:37]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C(CCCC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(CCCC(=O)C(F)(F)F)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 65.4 %

Procedure:
1.0 g 1-naphthaleneboronic acid, 1.0 g potassium carbonate and 0.06 g tetrakis(triphenylphosphine)palladium(0) in 90 ml toluene were combined under a protective gas atmosphere. A solution of 1.0 g 1-(4-bromophenyl)-6,6,6-trifluorohexane-1,5-dione in 10 ml toluene was added dropwise to this initial solution and it was stirred for 3 days at 90° C. It was allowed to cool to RT, 13 ml saturated aqueous sodium hydrogen carbonate solution was added dropwise thereto and the phases were separated. The organic phase was washed in succession with water, aqueous potassium hydrogen sulphate solution, water and saturated aqueous common salt solution. The organic phase was dried over sodium sulphate and the solvent was evaporated in the WV. Purification of the remaining residue by means of flash chromatography (stationary phase: silica gel, mobile phase: n-hexane/EA 3:2 v/v) and subsequent recrystallisation of the combined product fractions from EA/n-hexane (2:3) yielded 0.75 g of the title compound, m.p.=79.7-82.5° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:21]=[C:22]([C:25](O)=[O:26])[NH:23][N:24]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:25]([C:22]3[NH:23][N:24]=[C:20]([CH3:19])[CH:21]=3)=[O:26])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: Cc1cc(C(=O)O)[nH]n1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(C3CCCC3)c2)[nH]n1
Yield: 27.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.33 mmol) and 5-methyl-2H-pyrazole-3-carboxylic acid (41.6 mg, 0.33 mmol) as starting materials. The title compound (33 mg, 23.4%) was isolated as off white solid; MS (ESI): 369 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:29])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]#[N:28])=[N:19]3)[C@@H:12]([CH3:30])[CH2:11]2)=[C:4]([F:31])[CH:3]=1.[NH2:32][OH:33].Cl>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:29])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]([NH:32][OH:33])=[NH:28])=[N:19]3)[CH:12]([CH3:30])[CH2:11]2)=[C:4]([F:31])[CH:3]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(=N)NO)c4cccnc43)C(C)C2)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A mixture of 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.6 g, 3.6 Mmol, 1 eq), NH2OH.HCl (0.84 g, 10.8 mmol, 3 eq), TEA (1.5 mL), and ethanol (10 mL) was stirred at 65° C. overnight. The reaction solution was concentrated in vacuo, and dissolved in ethyl acetate, washed with brine, and concentrated to provide 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:33][O:34][CH2:35][CH:36]([NH2:38])[CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:38][CH:36]([CH3:37])[CH2:35][O:34][CH3:33])=[O:6]
Reactant: COCC(C)N
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (19 mg, 0.045 mmol), 1-methoxypropan-2-amine (8 mg, 0.090 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.090 mmol), and N,N-diisopropylethylamine (31 μL, 0.18 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=496.1
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[F:12].Cl>CO.[Fe]>[F:13][CH:2]([F:1])[C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[F:12])[NH2:9]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)F)c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1ccc(F)c(C(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
A solution of 2-(difluoromethyl)-1-fluoro-4-nitrobenzene (1.2 g, 6.2 mmol) in methanol (20 mL) was added iron powder (4.8 g, 24.8 mmol) followed by conc. HCl (5 mL) dropwise. The reaction mass was stirred at RT for 1-2 h. The reaction mass was quenched in ice-water, basified with NaHCO3 and extracted with DCM. The organic layer was dried and concentrated to afford 0.800 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.25 (s, 2H), 6.66-6.73 (m, 2H), 6.86-7.04 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>CN(C=O)C.O>[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: BrCc1ccc(I)cc1
Reactant: COC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)OCc1ccc(I)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in parafin liquid) (2.22 g, 55.5 mmol) in DMF (25 ml) was added dropwise a solution of methyl 2-hydroxy-isobutyrate (6.44 g, 54.5 mmol) in DMF (12 ml) over a period of 20 minutes (the inner temperature: 20° C.). The reaction solution was stirred at 22-23° C. for 30 minutes (the bath temperature: 23° C.). To this reaction solution was added dropwise a solution of 4-iodobenzyl bromide (15.4 g, 51.9 mmol) in DMF (35 ml) over a period of 20 minutes (the inner temperature: 22-26° C.). This reaction solution was stirred at 22-25° C. for 2.5 hours. To the reaction solution were added toluene (80 ml) and water (50 ml), and the mixture was stirred for 5 minutes. The mixture was transferred into a separatory funnel, and separated. The organic layer was washed with water, and concentrated to give a mixture of methyl ester compounds. A part of the mixture was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](OC)[C:3]=1[C:12](=[O:22])[CH2:13][C:14](C1C=CN=CC=1)=[O:15].C(O)(=O)C.[ClH:27].C([O-])(O)=O.[Na+]>O>[ClH:27].[O:15]1[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[C:12](=[O:22])[CH:13]=[CH:14]1
Reactant: COc1cc(O)c(C(=O)CC(=O)c2ccncc2)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccoc2ccccc12
Temperature: 100 °C
Yield: 13 %

Procedure:
To a solution of isonicotinic acid-2-acetyl-3,5-dimethoxyphenyl ester (2.72 g, 9.03 mmol) in anhydrous THF (50 mL) was added potassium tert-butoxide (1.21 g, 10.8 mmol) in small portions. The reaction mixture was stirred at room temperature for 24 hours. A sat. NH4Cl solution (20 mL) was added. The organic layer was separated and aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phase were washed with water, brine and dried over anhydrous Na2SO4. Removal of solvent gave 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-pyridin-4-yl-propane-1,3-dione (2.4 g, 88%). To a mixture of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-pyridin-4-yl-propane-1,3-dione (2.4 g, 7.96° mmol) acetic acid (10 mL) and conc. HCl (1 mL) was heated at 100° C. for 1 hours. The reaction mixture was cooled to room temperature, diluted with water, neutralized with a sat. aqueous NaHCO3 solution. The solid was filtered off and dissolved in CH2Cl2 (120 mL) and hydrogen chloride in ether (5 mL, 2.0M solution) was added. The formed solid was isolated by filtration, washed with 10% methanol in ether and ether to give 5,7-dimethoxy-2-(pyridin-4-yl))-4H-chromen-4-one hydrochloride (0.335 g, 13%) as a yellow solid; MS (ES) m/z: 283.94 (M); MP 234-235° C.
Reaction SMILES: [N+]([C:4]1[C:15]([CH3:16])=[C:14]([CH3:17])[CH:13]=[C:12]([N+]([O-])=O)[C:5]=1[NH:6][CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-])=O.[N+](C1C(C)=C(C)C=C([N+]([O-])=O)C=1N(N=O)C(CC)CC)([O-])=O.S(=O)(=O)(O)N.Cl>O.C(Cl)CCl>[CH2:8]([CH:7]([NH:6][C:5]1[CH:12]=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[CH:4]=1)[CH2:10][CH3:11])[CH3:9]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: CCC(CC)N(N=O)c1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: NS(=O)(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCC(CC)Nc1ccc(C)c(C)c1
Temperature: 80 °C

Procedure:
To a crude nitration solution comprising 1550 g. of 2,6-dinitro-N-(1-ethylpropyl)-3,4-dimethylaniline and 340 g. of 2,6-dinitro-N-nitroso-N-(1-ethylpropyl)-3,4-dimethylaniline in 3700 mls. of ethylene dichloride was added 212 g. of sulfamic acid and 2850 mls. of 37.7% hydrochloric acid. The mixture was refluxed at 80° C. for six hours, 2-liters of water was added thereto and the aqueous phase was separated. The aqueous phase was extracted with 500 ml. of ethylene dichloride and the organic phases were combined. The combined organic phase was washed with 3-liters of water, the aqueous phase separated and the ethylene dichloride was removed under vacuum at 68° C. to recover 1915 g. of product containing 1820 g. of 2,6-dinitro-N-(1-ethylpropyl)-3,4-dimethylaniline and less than 0.1% of 2,6-dinitro-N-nitroso-N-(1-ethylpropyl)-3,4-dimethylaniline.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:31]([O:32]C(=O)C)[C@H:30]([O:36]C(=O)C)[C@@H:29]([CH2:40][O:41]C(=O)C)[O:28][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=1)[C@@H:6]1[O:28][C@H:29]([CH2:40][OH:41])[C@@H:30]([OH:36])[C@H:31]([OH:32])[C@H:5]1[OH:4]
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a suspension of ethyl (E)-3-[4-(2-hydroxybenzyl)phenyl]acrylate (0.34 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (1.4 g) in dichloromethane (3 mL) and toluene (9 ml) was added boron trifluoride-diethyl ether complex (0.45 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethylacetate=4/1) to give (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.47 g). To a solution of the obtained (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.46 g) in methanol (5 mL) was added sodium methoxide (0.010 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl β-D-glucopyranoside (0.31 g).
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])O[C:7](=O)[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[OH-].[NH4+:13]>>[C:10]1(=[O:11])[C@H:1]2[C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:7][NH:13]1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: [NH4+]
Agent: [OH-]
Product: O=C1NC[C@@H]2CCCC[C@@H]12
Yield: 80 %

Procedure:
A solution of trans-1,2-cyclohexanedicarboxylic anhydride (10 g, 65 mmol) in ammonium hydroxide (conc., 30 ml) was hydrogenated by the method of EXAMPLE 168 to yield 7.4 g (80%) of the title material.
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]([C:8]1[C:9]([Cl:23])=[C:10]2[C:15](=[C:16]([Cl:18])[CH:17]=1)[S:14](=[O:20])(=[O:19])[CH2:13][CH2:12][C:11]2([CH3:22])[CH3:21])(=[O:7])C.C(OCC)(=[O:26])C>O>[Cl:23][C:9]1[C:8]([C:5]([OH:7])=[O:26])=[CH:17][C:16]([Cl:18])=[C:15]2[C:10]=1[C:11]([CH3:22])([CH3:21])[CH2:12][CH2:13][S:14]2(=[O:20])=[O:19]
Reactant: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Reactant: CCOC(C)=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCS(=O)(=O)c2c(Cl)cc(C(=O)O)c(Cl)c21
Temperature: 100 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
1.04 Grams (26.1 mmol) of sodium hydroxide was dissolved in 20 ml of water, and 0.5 ml (8.7 mol) of bromine was added. Further, 0.93 g (2.9 mmol) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman-1,1-dioxide was added, and the mixture was stirred for 3 hours. Then the mixture was heated at 100° C. for 5 hours. After the completion of the reaction, ethyl acetate was added, the mixture was liquid-separated, and hydrochloric acid was added to an aqueous layer to adjust the aqueous layer to a pH of 1. The extraction of the aqueous layer was carried out by adding ethyl acetate, and an organic layer was dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to give 0.84 g (yield 90%) of 5,8-dichloro-4,4-dimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: C([S-])C.[Na+].CN(C=O)C.[Cl:10][C:11]1[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=1[C:19]1[N:23]([CH3:24])[C:22]([C:25]2([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:21][N:20]=1>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:19]1[N:23]([CH3:24])[C:22]([C:25]2([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:21][N:20]=1
Reactant: COc1ccc(-c2nnc(C3(c4cccs4)CCCC3)n2C)c(Cl)c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccc(O)cc2Cl)nnc1C1(c2cccs2)CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
Sodium ethanethiolate was added to a DMF (10 ml) solution of 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-[1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazole (300 mg), followed by stirring at 100° C. for 2 hours. After the reaction solution and chloroform were added to distilled water, the organic layer was separated. Furthermore, the organic layer washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=97:3) and then the resulting solid was recrystallized from isopropanol to obtain 30 mg of 3-chloro-4-{4-methyl-5-[1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenol (colorless solid).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:33]#[CH:34]>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)\[C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:33][CH2:32][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the above ester (480 mg, 0.908 mmol) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and N-propargylmorpholine (237 mg, 1.89 mmol) was added under argon atmosphere. The solution was cooled, tetrakis(triphenylphosphine)palladium (84 mg, 0.073 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture was stirred at ambient temperature for 6 h and then left to stand overnight. The mixture was evaporated in vacuo; the residue was dissolved in dichloromethane (20 mL) and the formed solution was washed with water (2×10 mL). The organic solution was dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1) yielding methyl (Z)-[2-methyl-4-[3(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:14]Cl.[C-:16]#[N:17].[K+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][C:16]#[N:17]
Reactant: COc1cc(Br)c(CCl)cc1OC(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Br)c(CC#N)cc1OC(C)C

Procedure:
1-Bromo-2-(chloromethyl)-5-methoxy-4-(1-methylethoxy)benzene (7.00 g, 23.8 mmol) and potassium cyanide (1.70 g, 26.1 mmol, freshly ground) are stirred in absolute DMSO (70 ml) for 12 hours at room temperature.
Reaction SMILES: [NH2:1][C@@:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1)[C:3](N)=[O:4].C1(CC(N)=[O:24])C=CC=CC=1.Br>O>[CH3:15][C@@:2]([NH2:1])([C:3]([OH:24])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COc1ccc(C[C@](C)(N)C(N)=O)cc1
Reactant: NC(=O)Cc1ccccc1
Agent: Br
Solvent: O
Product: C[C@](N)(Cc1ccc(O)cc1)C(=O)O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a 100 mL flask with a reflux condenser was charged amide 4 (5.50 g of a mixture containing 4 (3.37 g, 16.1 mmol) and phenylacetamide (2.13 g)) and 48% HBr (30 mL). The solution was heated for 5 h at 120° C. and was cooled to room temperature. H2O (60 mL) was added and the solution was washed with EtOAc (3×35 mL). The aqueous phase was concentrated in vacuo to provide a beige paste. The paste was dissolved in H2O (15 mL) and the resulting mixture was heated to 65° C. Activated carbon (300 mg, Type NORIT SX) was added and the mixture was stirred for 15 min, was filtered and the filter pad was washed with water (2×4 mL). The combined filtrates were heated to 55° C. and the pH was adjusted to 5-6 using 32% aq. NH3. The mixture was cooled to 0° C., was stirred for 15 min and was filtered. The collected solids were washed with cold water (2×5 mL) and were dried in vacuo to provide (−)-α-methyl-L-tyrosine (or metyrosine) 1 (2.65 g, 84%) as a white solid. HPLC (Zorbax C18, NaH2PO4 10 mM pH=3/MeCN (100:0) 10 min, (100:0) to (0:100) 15 min, 0:100 5 min) tR=10.1 min. Chiral HPLC (Nucleosil Chiral-1, CuSO4 10 mM/MeCN 10:1) tR=16.9 min. m.p.=320-321° C. [α]546=+201° (c=0.5 Copper complex solution) (lit.2+185-190° Copper complex solution preparation: Solution A (anhydrous NaOAc dissolved in H2O (150 mL) in 250 mL volumetric flask, glacial acetic acid (50 mL) added and diluted to volume with H2O) mixed with Solution B (cupric sulfate (62.5 g) diluted to volume with H2O in a 200 mL volumetric flask) in a 1 L volumetric flask and was diluted to volume with H2O. Metyrosine solution (5 mg/mL) was prepared in this solution.