Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:39])[OH:31])=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC.[NH4+].[OH-]>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:39])=[O:31])=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(C)c1C(O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of oxalyl chloride (0.46 mL, 5.4 mmol) in CH2Cl2 (20 mL), was added dropwise DMSO (0.94 mL, 13.2 mmol), at −78° C. Subsequently, a solution of [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dimethyl-phenyl)-methanol (1.6 g, 4.1 mmol) in CH2Cl2 (30 mL) was added, dropwise, at −78° C. After the addition was complete the mixture was stirred for 30 min., at −78° C., and then Et3N (2.9 mL, 20.8 mmol) was added. After complete addition the mixture was allowed to warm to room temperature, overnight. Next, a 2M aqueous NH4OH solution (30 mL) was added, and the mixture extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dimethyl-phenyl)-methanone (1.5 g), which was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C1COCC1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=3)[C:10](=[O:11])[NH:12]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
204 mg (1.0 mmol) N-[3-(trifluoromethyl)phenyl]urea, 108 mg (0.77 mmol) 4-chlorobenzaldehyde and 100 mg (0.77 mmol) ethyl 3-oxobutanoate are suspended in 2 ml of THF, and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [C:1]([N:4]1[C:10]([CH3:11])=[CH:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[C:10]([CH3:11])=[CH:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C=C1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)ccc2C=C1C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
0.78 g (2.1 mmoles) of 3-acetyl-8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine are dissolved in the mixture of 15 ml of methanol and 15 ml of dichloromethane, and about 0.5 g of wet Raney-nickel catalyst and 0.26 ml (5.25 mmoles) of 98% hydrazine hydrate are subsequently added to it under vigorous stirring. The mixture is stirred for further 1 hour. The catalyst is filtered off, washed with dichloromethane, the filtrate is evaporated and the residue is solidified by rubbing with 15 ml of water. The crude product is recrystallized from ethanol. Thus 0.56 g (79%) of the desired compound melting at 209-211° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[CH3:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N1C=CC=CC=1.FC(F)(F)C(O[C:33]1[C:38]([F:39])=[C:37]([F:40])[C:36]([F:41])=[C:35]([F:42])[C:34]=1[F:43])=O>CN(C)C=O.CCOCC>[F:39][C:38]1[C:33]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[C:3]([F:21])=[C:4]([F:20])[C:5]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[CH3:19])=[C:34]([F:43])[C:35]([F:42])=[C:36]([F:41])[C:37]=1[F:40]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc(Br)c(F)c1F
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1Nc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(Br)c(F)c1F
Yield: 90.5 %

Procedure:
To a solution of 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (prepared as described in WO 99/01426) (1.61 g, 3.4 mmol) and pyridine (0.31 mL, 3.83 mmol) in anhydrous dimethylformamide (7 mL) was added 10 pentafluorophenyl trifluoroacetate (0.71 mL, 4.13 mmol). The resultant solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with ether (100 mL) and washed with water (40 mL), 0.1 M aqueous hydrochloric acid (40 mL), saturated aqueous sodium bicarbonate (40 mL), and saturated brine (40 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a foam that was purified on silica gel. Elution with hexanes-ethyl acetate (19:1) afforded 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.95 g, 89%) as a pale-yellow powder: 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.24 (d, J=5.8 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.70 (dd, J=8.4, 5.3 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:14].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>O1CCCC1.O>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: Clc1ccccc1CCBr
Reactant: CCc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(CCc1ccccc1Cl)c1ccncc1
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
In a 200-ml flask, 0.94g (9.35 mmol) of diisopropyl amine and 15 ml of tetrahydrofuran were placed and cooled to -50° C. Then 6.5 ml (10.3 mmol) of n-butyl lithium (15% n-hexane solution) was added thereto under nitrogen atmosphere. The resulting mixture was stirred for 10 minutes, and a solution of 1.0 g (9.35 mmol) of 4-ethylpyridine dissolved in tetrahydrofuran was added dropwise. After stirring for 30 minutes at -50° C., the reaction temperature was gradually raised up to -10° C., which was kept for 30 minutes, and lowered again to -50° C. A solution of 2.05 g (9.35 mmol) of 2-chlorophenethyl bromide dissolved in tetrahydrofuran was added dropwise to the reaction mixture, and after stirring for 30 minutes at -50° C., the temperature was raised up to room temperature. Subsequently, water was added, tetrahydrofuran was distilled away under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, then dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, to obtain an oil. Said oil was purified by silica gel column chromatography, to obtain 1.35 g of the desired compound (yield: 58.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCC(=O)O)cc1
Yield: 100.5 %

Procedure:
10% Palladium-on-carbon (200 mg) was added to a solution of 5.34 g of 4-methoxycinnamic acid in methanol, and the mixture was stirred under hydrogen until hydrogen gas absorption ceased. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 5.43 g of 3-(4-methoxyphenyl)propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2(O)[CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[C:4]([F:14])[C:3]=1[C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1.FC1C=C(C2(O)CCOC2)C=C(F)C=1C1SC=C(C(O)=O)N=1.FC(F)(F)C(O)=O>ClCCl>[O:10]1[CH2:11][CH:12]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:15]3[S:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=3)=[C:4]([F:14])[CH:5]=2)[CH2:9]1
Reactant: COC(=O)c1csc(-c2c(F)cc(C3(O)CCOC3)cc2F)n1
Agent: O=C(O)c1csc(-c2c(F)cc(C3(O)CCOC3)cc2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(-c2c(F)cc(C3=CCOC3)cc2F)n1
Temperature: 120 °C
Yield: 24.1 %

Procedure:
To a solution of methyl 2-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]thiazole-4-carboxylate (250 mg, 0.732 mmol, precursor to Intermediate 144) in dichloromethane (1 mL) was added TRIFLUOROACETIC ACID (1 mL) The mixture was heated at 120° C. in microwave for 2 h. After in vacuo concentration, purification by CombiFlash (0 to 100% EtOAC in heptane) provided methyl 2-(4-(2,5-dihydrofuran-3-yl)-2,6-difluorophenyl)thiazole-4-carboxylate (57 mg, 24% yield) as a mixture of olefin isomers.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[OH:22].[CH2:23]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH2:29]Br)[CH3:24]>CS(C)=O>[Cl:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:22][CH2:29][CH2:28][O:27][C:26]([NH:25][CH2:23][CH3:24])=[O:31]
Reactant: CCNC(=O)OCCBr
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)OCCOc1ccc(Oc2ccc(F)cc2)cc1Cl
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 1.41 g of potassium tert-butylate in 20 ml of dimethyl sulfoxide is added dropwise with stirring at 10°-15° C. to 2.86 g of 2-chloro-4-(4-fluorophenoxy)phenol in 10 ml of dimethyl sulfoxide. 2.92 g of 2-bromoethyl ethylcarbamate in 10 ml of dimethyl sulfoxide are subsequently added dropwise at room temperature and the mixture is then stirred for 18 hours at 40° C. The reaction mixture is then poured into 300 ml of ice-water and extracted several times using ether. The combined ether phases are washed to neutrality using a small amount of water and dried over sodium sulfate and the solvent is evaporated in vacuo. The crude product is purified on silica gel using diethyl ether/hexane (1:9) as eluent. This gives the title compound of melting point 42°-43° C.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].[N+]([O-])(O)=O.C(O)(=O)C>C(O)(=O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2[N+](=O)[O-])N1
Reaction time: 19 h
Yield: 41 %

Procedure:
A suspension of the product of Example 352C (100 mg, 0.352 mmol) in glacial acetic acid (3 mL) was treated at room temperature with a solution of concentrated nitric acid in glacial acetic acid (1.43 M, 0.305 mL, 0.436 mmol) and stirred at this temperature for 19 hours. Added additional 1.43 M nitric acid/acetic acid (0.020 mL, 0.029 mmol) and let stir for 1.5 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 8% methanol/dichloromethane to give the title compound as a light yellow solid (47 mg, 41%). MS (ESI−) m/z 328 (M−H)−. 1H NMR (300 MHz, PYRIDINE-d5) δ 0.98 (t, J=7.17 Hz, 3 H) 3.86 (s, 2 H) 4.01 (q, J=7.23 Hz, 2 H) 7.11 (d, J=8.82 Hz, 1 H) 7.22 (d, J=8.82 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[C:19]#N.C([Al]CC(C)C)C(C)C.C[OH:31]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[CH:19]=[O:31]
Reactant: CO
Reactant: Cc1cn(-c2cc(C#N)c(N)c(C(F)(F)F)c2)c(C)n1
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc(C=O)c(N)c(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C

Procedure:
To an ice-cooled stirred solution of 1-(4-amino-3-cyano-5-trifluoromethylphenyl)-2,4-dimethylimidazole (0.7 g) in tetrahydrofuran (10 cm3) was added 3.5 cm3 of a 1.5M solution of diisobutyl aluminium in toluene. The mixture was heated at 40° for 2 hours, cooled in ice, treated with methanol (2 cm3), and evaporated in vacuo. The residue was treated with water (25 cm3) and 2M hydrochloric acid (5 cm3), and heated on a steam bath for five minutes. The solution was then cooled, basified to pH 8 with aqueous sodium carbonate solution, and extracted with chloroform:methanol, 20:1 (3×30 cm3). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 50:1, to afford 1-(4-amino-3-formyl-5-trifluoromethylphenyl)-2,4-dimethylimidazole, m.p. 200°-202°, (0.391 g).
Reaction SMILES: Cl[S:2][N:3]([CH3:10])[C:4](=[O:9])[O:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:16]=[CH:15][C:13]=1[NH2:14].C(N(CC)CC)C>C(OCC)C>[Cl:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=1[O:19][C:17]1[CH:16]=[CH:15][C:13]([NH:14][S:2][N:3]([CH3:10])[C:4](=[O:9])[O:5][CH2:6][CH2:7][CH3:8])=[C:12]([F:11])[CH:18]=1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: CCCOC(=O)N(C)SCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCOC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Yield: 97.7 %

Procedure:
A solution of propyl N-chlorosulphenyl-N-methylcarbamate (12.1g) in diethyl ether (20 ml) was added to a stirred solution of the compound of Example 1 (18.3 g) and triethylamine (7 g) in the same solvent (70 ml) over 20 minutes, the temperature being maintained at 15°-20° C. with cooling. Stirring was continued at room temperature for a further 11/2 hours. The reaction mixture was then diluted with diethyl ether (200 ml), washed with water, dried and stripped of solvent. The residue was added to 100 mls toluene, and the toluene was removed under reduced pressure to leave 26.5 g of the desired product in crude form as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([CH3:17])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2ccc(Cl)nn12
Yield: 12.9 %

Procedure:
12.9 g of 3-amino-6-chloropyridazine was suspended in 250 ml of ethanol; 18.1 g of ethyl 2-chloro-3-oxobutanoate was added, followed by thermal refluxing for 6 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was ajusted to pH 7 by the addition of aqueous sodium bicarbonate; ethyl ether was added; the precipitated was collected by filtration and extracted with ethyl ether; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; ethanol-1 N aqueous solution of sodium hydroxide (1:1) was added; the crystal precipitated was collected by filtration; the filtrate was concentrated again. The residue was crystallized by the addition of ethyl acetate and collected by filtration to yield 3.09 g of the title compound.
Reaction SMILES: CO.[CH:3]1([S:6]([NH:9][C:10]([C@@:12]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][C@H:13]2[CH:15]=[CH2:16])=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1.CCCCCCC>CCOC(C)=O.[Ru]>[CH:3]1([S:6]([NH:9][C:10]([C@@:12]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][C@H:13]2[CH2:15][CH3:16])=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Agent: [Ru]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CO
Product: CC[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 40 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
A hydrogenation vessel was charged with a MeOH (1000 mL) slurry of t-butyl ((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)carbamate (164 g, 0.50 mol) (U.S. Pat. No. 6,995,174) and 5% Ru/C (dry, 7.5 wt %, 12.4 g) and stirred. The vessel was placed under N2 (20 psi) and vented to atmospheric pressure (3×) to remove residual oxygen. The vessel was then placed under H2 (50 psi). After 20 hours, the vessel was vented to atmospheric pressure. The reaction slurry was then transferred out of the reaction vessel and filtered through SOLKA FLOK (34 g, wetted with 100 mL MeOH) to yield a clear, light brown solution. The SOLKA FLOK was rinsed with MeOH (200 mL×2). The combined MeOH solutions were concentrated under reduced pressure to yield crude product as a white solid (153 g). The crude product was slurried in EtOAc (800 mL), warmed to 40° C. and aged 30 minutes. The solution was then seeded, aged 30 minutes, and heptane (500 mL) was added via addition funnel over 30 minutes. The partially crystallized solid was cooled to RT and aged overnight, after which additional heptane (500 mL) was added. After 1 hour, additional heptane (250 mL) was added via addition funnel, and the white slurry aged for 1 hour. The solution was filtered, and the solid was rinsed with heptane/EtOAc (500 mL, 4:1) and dried under reduced pressure to give t-butyl ((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)carbamate (125.9 g).
Reaction SMILES: C(P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH3:34])([CH3:33])[CH2:26][CH2:27][C:28]2([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH3:35])(=O)[CH3:19].[CH3:36]N(C)C=O>>[CH3:33][C:25]1([CH3:34])[C:24]2[C:29](=[CH:30][C:21](/[C:18](/[CH3:36])=[CH:19]/[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:22]([CH3:35])[CH:23]=2)[C:28]([CH3:32])([CH3:31])[CH2:27][CH2:26]1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C/C(=C\c1ccccc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diethyl benzylphosphonate in 30 ml of dimethylformamide is added at room temperature to a suspension of 3.7 g of NaH (50% in mineral oil) in 50 ml of dimethylformamide. After stirring at room temperature for 15 minutes a solution of 12.6 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin in 60 ml of dimethylformamide is added dropwise thereto in the course of 2 hours. The reaction mixture is stirred at room temperature overnight and subsequently heated to 60° for a further 1 hour. After cooling the mixture is poured on to ice, extracted with ether, dried and evaporated. After chromatography of the crude product (silica gel elution agent hexane) and crystallization from hexane there are obtained 3.9 g of 1,2,3,4-tetrahydro-1,1,4,4,7-pentamethyl-6-[(E)-α-methylstyryl]naphthalene in colourless crystals, melting point 75°-77°.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C1C=CC=CC=1.[CH3:48][Si:49]([C:52]#[CH:53])([CH3:51])[CH3:50]>C(OCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[C:53]#[C:52][Si:49]([CH3:51])([CH3:50])[CH3:48])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c2ccccc2cc2ccccc12

Procedure:
To a solution of 9-bromoanthracene (1.35 g, 5.25 mmol), triphenylphosphine (138 mg, 0.53 mmol), copper iodide (50 mg, 0.26 mmol), and bis(triphenylphosphine)palladium dichloride (74 mg, 0.11 mmol) in 1:1 triethylamine/benzene (35 mL) was added trimethylsilylacetylene (1.11 mL, 7.85 mmol) and the solution was heated at reflux 1 h. The cooled solution was diluted with ethyl ether (100 mL) and filtered. The organic was washed with H2O (3×100 mL), dried over Na2SO4, and filtered. Solvents were removed under reduced pressure to yield crude 9-anthracenyltrimethylsilylacetylene. The crude oil was dissolved in methanol (150 mL) and 3.5 M KOH(aq) (2 mL) was added and stirred 1 h. The reaction was quenched with H2O (150 mL) and the product was extracted with hexane (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and solvents were removed under reduced pressure to yield crude 9-anthracenylacetylene. The crude oil was dissolved in benzene (10 mL) and added to a solution of 4-bromophthalic anhydride (0.908 g, 4.0 mmol), triphenylphosphine (105 mg, 0.40 mmol), copper iodide (39 mg, 0.20 mmol), and bis(triphenylphosphine)palladium dichloride (56 mg, 0.08 mmol) in 2:1 triethylamine/benzene (30 mL) by cannula transfer and heated at reflux 1 h. The cooled solution was filtered and the precipitate was diluted with 0.5 M NaHCO3(aq) (100 mL) and stirred vigorously 1 h. The mixture was diluted with acetone (50 mL) and filtered. The crude product was recrystallized from toluene and dried under reduced pressure to yield 4-(9-anthracenylethynyl)phthalic anhydride (1.03 g, 73.8%) as a deep red solid. 1H NMR (DMSO-d6, 300 MHz) δ7.77 (t, J=7.1 Hz, 2H), 7.88 (t, J=7.2 Hz, 2H), 8.29-8.34 (m, 3H), 8.56 (d, 7.8 Hz, 1H), 8.75 (s, 1H), 8.83 (d, J=8.7 Hz, 2H), 8.92 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([O:32][Si](C(C)(C)C)(C)C)[CH2:29][N:28]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(OCC)(=O)C>CN(C)C(=O)C>[C:43]([O:42][C:40]([N:28]1[CH2:29][C@H:30]([OH:32])[CH2:31][C@H:27]1[CH2:26][CH2:25][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCl
Reactant: Oc1ccc(F)cc1CCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
687 mg of 4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenol (prepared as described in Preparation 6) were dissolved in 12 ml of N,N-dimethylacetamide, and then 212 mg of potassium t-butoxide were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred for 10 minutes, after which 687 mg of (2S,4R)-2-(2-chloroethyl)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine were added. The resulting mixture was then stirred at room temperature for 14 hours. At the end of this time, 135 mg of potassium t-butoxide were added to the reaction mixture, and the mixture was stirred at 40° C. for 4 hours, after which 300 ml of ethyl acetate were added. The resulting reaction mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 571 mg (yield 74%) of the title compound as a colorless oily substance.