Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[CH2:20]([O:27][C:28]1[CH:48]=[CH:47][C:31]([CH2:32][N:33]2[CH:37]=[C:36]([CH:38]=O)[C:35]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[N:34]2)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH2:20]([O:27][C:28]1[CH:48]=[CH:47][C:31]([CH2:32][N:33]2[CH:37]=[C:36]([CH2:38][C:10]#[N:11])[C:35]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[N:34]2)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: N#CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
A solution of p-toluenesulfonylmethylisocyanide (3.08 g) in dimethoxyethane (15 ml) was added to a mixture of potassium t-butoxide (3.37 g) and dimethoxyethane (15 ml) at −78° C., and the resultant was stirred for 5 minutes. A solution of 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (5.80 g) in dimethoxyethane (30 ml) was added to the mixture. After stirring at the same temperature, the mixture was stirred for 1 hour while raising the temperature. Methanol (45 ml) was added to the mixture, which was refluxed for 1 hour. After cooling, the reaction mixture was poured into saturated aqueous ammonium chloride solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-ylacetonitrile (4.52 g, yield 76%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 86–87° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]([N:16]=[O:17])[CH2:13][CH2:12][CH2:11]2)(=[O:5])[CH3:4].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)Cl>O.C(O)C>[C:19]1([CH:18]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]([N:16]=[O:17])[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cccc2c1N(N=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=NN1CCCc2cccc(C(=O)C=Cc3ccccc3)c21
Temperature: 10 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
20 g (0.5 mol) of sodium hydroxide were dissolved in 120 ml of water. A cold solution of 109 g (0.5 mol) of 8-acetyl-1-nitroso-1,2,3,4-tetrahydroquinoline and 53 g (0.5 mol) of benzaldehyde in 300 ml of ethanol was added at 0°-5° C. The mixture was stirred at 10° C. for 1 hour, 600 ml of methylene chloride were then added and the mixture was stirred for 1 hour at 10°-20° C. 500 ml of water were then added, the organic layer was separated, dried, and the solvent was distilled off. 153.5 g of crude 8-(3-phenyl-2-propen-1-on-1-yl)-1-nitroso-1,2,3,4-tetrahydroquinoline were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:38][C:11]3[C:12](=[O:37])[N:13]([CH2:16][C:17]4[N:22]=[C:21]([O:23][CH:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)[CH:20]=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:38][C:11]3[C:12](=[O:37])[N:13]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([O:23][CH:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)[N:22]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC2CCNCC2)n1
Reaction time: 1 h

Procedure:
tert-butyl 4-[(6-{[2-(4-chlorophenyl)-7-oxothieno[2,3-d]pyridazin-6(7H)-yl]methyl}pyridin-2-yl)oxy]piperidine-1-carboxylate (0.22 g, 0.39 mmol) was dissolved in DCM/TFA 5:1 (6 mL) and stirred for 1 hour. The reaction mixture was co-evaporated with toluene, dissolved in DCM (20 mL) and washed with sat. NaHCO3(aq.)/water 1:1 (30 mL). The resulting water phase was extracted with DCM (3×20 mL). The combined organics were dried over a phase separator and concentrated in vacuo to give the product. Yield: 0.16 g (89%). MS (ESI+) 453.06 (M+1H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].ClCCl.[Cl:25][C:26]1[N:30]2[N:31]=[C:32](Cl)[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Ba+2]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Temperature: 80 °C
Yield: 18.5 %

Procedure:
a mixture of 4.16 g of 4-fluorophenylboronic acid, 9.37 g of barium hydroxide octahydrate, 2.20 g of [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) in a complex with dichloromethane (1:1) and 5.1 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine in 40 cm3 of N,N-dimethylformamide containing 10 cm3 of water is heated in a bath at 80° C. for 1.5 h. The beigey-brown suspension obtained is cooled to 20° C. and then poured into approximately 200 cm3 of water. The insoluble material is spin-filter-dried and washed successively with water and with ether, and then dried under vacuum at 20° C. The resulting beige solid is made into a paste in dichloromethane, spin-filter-dried, and dried under vacuum at 20° C. 1.24 g of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine are thus obtained. 30 g of silica are added to the combined mother liquors and the mixture is evaporated to dryness under vacuum. This residue is deposited onto a bed of 10 g of silica in a sintered glass filter and elution is carried out with dichloromethane. An additional 1.60 g of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine are thus recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[CH2:14]([OH:18])[CH:15]=[CH:16][CH3:17].O>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([CH3:17])[CH2:15][CH:14]=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: CC=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(CC=O)c1cccc(Cl)c1
Temperature: 130 °C

Procedure:
A mixture of 3-chloroiodobenzene (2.38 g), palladium acetate (20 mg), sodium bicarbonate (1.01 g) and crotyl alcohol (1.28 ml) in N-methylpyrrolidone (4 ml) was stirred and heated at 130° C. for 2 hours. The reaction mixture was allowed to cool, water (50 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). The combined organic extracts were dried and the residue obtained on removal of the solvent was purified by chromatography through silica eluting with a mixture of ethyl acetate and methylene chloride (1:20) to give the title compound as an oil, yield 519 mg, M−H=181
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.ClCCl>CO>[CH2:2]([O:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)[CH:3]=[CH2:4]
Reactant: COc1ccc2nccc(Br)c2c1
Reactant: C=CCO
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: C=CCOc1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
Sodium (1.22 g, 52.9 mmol, 2.1 eq) is added portionwise at 0° C. to a stirred solution of allyl alcohol (117.1 g, 201.6 mmol, 80.0 eq). After 30 minutes stirring at 0° C., 4-bromo-6-methoxy-quinoline (6.0 g, 25.2 mmol, 1.0 eq) is added to the reaction mixture that is heated under reflux for 5 hours. The reaction mixture is then cooled down to room temperature, and filtered. The filtrate is evaporated under reduced pressure to give a residue that is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 60:1, v/v) to afford 4-allyloxy-6-methoxy-quinoline as a white solid (4.0 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](I)[CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH2:25][C:26]#[CH:27])[CH3:24].CCN(CC)CC>CN(C=O)C.O.C(OCC)(=O)C.[Cu]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>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]#[C:26][CH2:25][N:23]([CH3:24])[CH3:22])[CH:8]=2)[N:3]=1
Reactant: C#CCN(C)C
Reactant: Fc1ccc(Nc2nc(Cl)nc3ccc(I)cc23)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
In a 50 mL round-bottomed flask was added 2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine (200 mg, 0.46 mmol), N,N-dimethylpropargylamine (99 mL, 0.92 mmol), NEt3 (0.26 mL, 1.84 mmol), CuI (0.88 mg, 4.6 mmol) and PdCl2(PPh3)2 (6.5 mg, 9.2 mmol) in DMF (3 mL) to give a light yellow suspension. The mixture was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was diluted with water (10 mL) and ethyl acetate (10 mL) and then a precipitate formed. The resulting precipitate was removed by filtration through Celite. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (1×15 mL) and brine (1×15 mL) and was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2/MeOH 1:0 to 9:1). The desired product was washed with CH2Cl2 to give 61 mg of 2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine, as pale yellow solid in a 34% yield. LCMS m/z=389 (M+1) (Method C) (retention time=2.2.4 min). 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 8.68 (s, 1H), 8.07 (dd, J=2.7, 6.9 Hz, 1H), 7.86 (dd, J=1.8, 8.7 Hz, 1H), 7.81-7.70 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.49 (t, J=9.2 Hz, 1H), 3.52 (s, 2H), 2.28 (s, 6H).
Reaction SMILES: C(C1C=C(C(NS(C2C=CC(F)=C(F)C=2)(=O)=O)C)C=CC=1C1C=C(F)C=CC=1OC)C=C.[F:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1.[CH3:50][C:51]1[C:55]([S:56](Cl)(=[O:58])=[O:57])=[C:54]([CH3:60])[O:53][N:52]=1>>[F:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:43]=[CH:44][C:45]([CH2:46][NH:47][S:56]([C:55]3[C:51]([CH3:50])=[N:52][O:53][C:54]=3[CH3:60])(=[O:58])=[O:57])=[CH:48][CH:49]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: COc1ncc(F)cc1-c1ccc(CN)cc1
Agent: C=CCc1cc(C(C)NS(=O)(=O)c2ccc(F)c(F)c2)ccc1-c1cc(F)ccc1OC
Product: COc1ncc(F)cc1-c1ccc(CNS(=O)(=O)c2c(C)noc2C)cc1

Procedure:
Di-tert-butyl dicarbonate (3.5 g, 16 mmol) and triethylamine (13 ml, 9.4 mmol) were added to a stirred solution of 4-aminomethylphenylboronic acid (3 g, 16 mmol) in tetrahydrofuran (100 ml). The reaction was stirred under reflux for 1 hour, then the solvent evaporated and the residue partitioned between water and ethyl acetate. The organic phase was concentrated under reduced pressure to give tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (2.67 g, 10.6 mmol) as a white solid. Toluene (16 ml), ethanol (4 ml), 2M sodium carbonate solution and tetrakis(triphenylphosphine) palladium (0) were added to tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (1.349 g, 5.4 mmol) and 3-bromo-5-fluoro-2-methoxy-pyridine (0.505 g, 2.45 mmol) and the mixture stirred under reflux for 24 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was separated and the solvent evaporated. The residue was purified on silica gel eluting with 3:1 heptane/ethyl acetate to give [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester as a yellow oil. Trifluoroacetic acid (2 ml, 0.026 mmol) was added to a solution of [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester (0.8 g, 2.41 mmol) in dichloromethane (4 ml) and the reaction mixture stirred for 2 h. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated and the solvent evaporated to give 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine. The title compound was prepared in a similar manner to N-[1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-3,4-difluoro-benzenesulfonamide (Example 34) using 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. MS (ESI) m/z: 392 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:16])/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Si:17]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]I)=[CH:28][CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>C1COCC1.CCOCC>[Si:17]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][O:16][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CI)cc1
Reactant: CCCCCCCCCC/C=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC/C=C\COCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with 60 mg of a 60% dispersion of NaH in oil. The dispersion was washed with three 2-mL portions of THF. The NaH was suspended in 5 mL of THF and cooled to 0° C. A solution Of cis-2-tridecen-1-ol (206 mg, 1.1 mmol, 1.1 equiv) in THF (1 mL) was slowly added to the mixture. After 25 minutes the cold bath was removed and stirring was continued for an additional 10 minutes. At this time a solution of (40) (361 mg, 1 mmol) in THF (1 mL) was added and stirring was continued for 12 hours. The mixture was poured into water (20 mL) and ether (25 mL). The organic layer was separated and washed with three 10-mL portions of water. The ether extract was dried (MgSO4) filtered and concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (95:05 petroleum ether/EtOAc) afforded 341 mg (85%) of the coupled produced (41) as a clear colorless oil: Rf 0.80 (9:1 petroleum ether/EtOAc); 1H NMR (CDCl3) δ 7.20 (s, 4 H), 5.61 (m, 2H), 4.76 (s, 2H), 4.52 (s, 2H), 4.08 (d, J=4.8 Hz, 2H), 2.05 (m, 2H), 1.29 (m, 16 H), 0.97 (s, 9 H), 0.91 (t, J=6.9 Hz, 3 H), 0.12 (s, 6 H); 13C NMR (CDCl3) δ 140.76, 137.04, 127.71, 126.04, 125.98, 71.86, 65.58, 64.80, 31.92, 29.62, 29.56, 29.52, 29.24, 29.36, 27.61, 25.94, 22.69, 18.57, 14.12, -5.25. ##STR8##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a solution of 1.2 g of 3-hydroxybenzaldehyde in 50 ml of N,N-dimethylformamide were added 2.4 g of 4-chlorobenzyl chloride and 2.1 g of potassium carbonate. The mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was treated with ethyl acetate-water. The resulting ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=102) to obtain 1.9 g of 3-(4-chlorobenzyloxy)benzaldehyde.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([O:17]C)[CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[CH2:11][CH2:10][C:9]3(C)C)[CH2:3][CH2:2]1.[C-]#N.[Na+].C#N.Cl>CS(C)=O.CCCCCC.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([OH:17])[CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9]3)[CH2:2][CH2:3]1
Reactant: COc1cc(C2CC2)c2c(c1)C(C)(C)CCC2=O
Agent: C#N
Agent: Cl
Agent: [C-]#N
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(O)cc(C3CC3)c21
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of 8-cyclopropyl-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 156, 1.5 g, 6.14 mmol) and sodium cyanide (2 g, 40.8 mmol) in anhydrous dimethylsulfoxide (25 mL) was heated at 230° C. overnight under argon. The reaction mixture was then cooled to ambient temperature, poured into ice and acidified (Caution! Hydrogen cyanide evolution!) with dilute hydrochloric acid and extracted with ethyl acetate (×2). The combined organic extract was washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated to afford a dark brown oil. Flash column chromatography on silica gel (230-400 mesh) using 25% ethyl acetate in hexane as the eluent afforded the title compound as a solid (1.1 g, 78%).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of Boc-isonipecotic acid (40 g, 0.17 mol) and N-methylmorpholine (19 mL, 0.17 mol) in tetrahydrofuran (900 mL) stirring at −10° C., ethyl chloroformate was slowly added (17 mL, 0.17 mol) via addition funnel. After 30 min, sodium borohydride was added (19.8 g, 0.5 mol) in one portion. The reaction mixture was stirred at −10° C. for 1 h; then it was slowly quenched with methanol. The solvent was removed in vacuo: the resulting residue was diluted with 10% aqueous acetic acid and partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with additional ethyl acetate (2×500 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid residue which was chromatographed on silica gel. Elution with ethyl acetate-hexanes (1:9 to 1:1) provided the title compound (33.8 g, 90%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:14]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
To a mechanically stirred mixture of tert-butyl 2-(hydroxy)ethylcarbamate (32.2 g, 200.4 mmol) and sodium hydroxide (300 mL of 50%) was added benzyltrimethylammonium chloride (3.79 g, 20.4 mmol) and benzyl bromide (23.8 mL, 200.4 mmol). After stirring at room temperature for 12 hours TLC monitoring, using 1/1 hexane/ethyl acetate and ninhydrin stain, indicated complete reaction. The resulting clear solution was diluted with ice water (1 L), and the organic layer was separated. The aqueous layer was washed with chloroform (4×). The organic layers were combined and washed with water (2×) and brine (2×), dried with sodium sulfate, and concentrated under reduced pressure to provide 45.4 g of clear liquid. NMR analysis confirmed the product, which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SC)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of 2-chloro-5-methylsulfanylbenzoic acid (20.2 g, 100 mmol) in N,N-dimethylformamide (200 ml) were added potassium carbonate (15.2 g, 110 mmol) and methyl iodide (6.8 ml, 110 mmol). After stirring at room temperature for 3 hr, diethyl ether (300 ml) was added. The organic layer was washed successively with water (200 ml×3) and saturated brine (200 ml), and dried over magnesium sulfate. Filtration and concentration gave methyl 2-chloro-5-methylsulfanylbenzoate (18.5 g, yield 86%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]OC(OC)(C)C.O>CO>[CH3:22][O:15][C:14]([C@H:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9]1)=[O:16]
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Yield: 86 %

Procedure:
A mixture of 26 g (117.5 mmol) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid, 0.66 ml of sulfuric acid, and 100 ml of dimethoxypropane in 700 ml of methanol are heated to reflux for 3 hours. For the working-up, the reaction mixture is reduced to ⅘ of its volume, then the residue is added under stirring to a mixture of ice and water. The precipitated product is collected on a filter funnel, washed with cold water and finally dried under high vacuum to yield 23.7 g (86% of theory) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M−H)+; optical integrity: 97.4% e.e. .
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.Br([O-])(=O)=[O:15].[K+].[N+]([O-])([O-])=O.[NH4+].[Ce]>O.O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 0 °C
Yield: 88.8 %

Procedure:
A solution of 1,2,3,4-tetrahydro-1,1,7-trimethyl-naphthalene (9.60 g, 55 mmol), potassium bromate (9.17 g, 55 mmol), cerium ammonium nitrate (1.50 g) in water (28 mL) and dioxane (44 mL) was heated under argon at 85° C. for 6 hours. The mixture was then cooled to 0° C., diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with water (2×), saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (6.5×17 cm, 10% ethyl acetate/hexane) to give the title material (9.2 g, 89%) as a colorless oil.