Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:24]([O:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)=[CH:29][CH:28]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 81.1 %

Procedure:
A solution of compound D (31.5 g; 0.1278 mol), tert-butyl 4-aminobenzoate (48 g; 0.248 mol), N,N-diisopropylethylamine (50.3 g; 0.39 mol) in 400 mL of dioxane was refluxed for 72 h under magnetic stirring. The reaction mixture was filtered, concentrated and taken up with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=9/1) to yield compound E (41.8 g; 81%).
Reaction SMILES: C([N:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][N:7]=[C:6]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:5]1=[O:24])C=C.C[N+]1([O-])CC[O:29]CC1.[O:33]1[CH2:37][CH2:36][CH2:35]C1>C(OCC)(=O)C.C(Cl)(Cl)Cl.CO.[Os](=O)(=O)(=O)=O>[C:20]([O:19][C:17]([NH:16][C:6]1[C:5](=[O:24])[N:4]([CH2:35][CH:36]([OH:29])[CH2:37][OH:33])[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][N:7]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Reactant: C=CCn1c(-c2ccccc2)cnc(NC(=O)OC(C)(C)C)c1=O
Agent: O=[Os](=O)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2)n(CC(O)CO)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
4-Allyl-2-t-butyloxycarbonylamino-3-oxo-5-phenyl-3,4-dihydropyrazine (850 mg, 2.60 mmol) was dissolved in tetrahydrofuran (10.4 ml), and 4-methylmorpholine N-oxide (1.22 ml, 5.19 mmol) and 4% aqueous osmium tetroxide (0.83 mol. 0.13 mmol) was added to it, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate and then washed successively with saturated aqueous sodium thiosulfate, distilled water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=50/1) whereby title compound (750 mg, 80% yield) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15])([O-])=O.[H][H]>NC1C(C)=CC=CC=1.O>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: Cc1ccccc1N
Solvent: O
Product: CCOc1ccc(N)cc1N
Yield: 89.1 %

Procedure:
112 g (0.529 mol) of 2,4-dinitrophenetole were hydrogenated, in a 700 ml stirred autoclave, in 300 ml of o-toluidine with 15 g of water-moist palladium catalyst (0.5% by weight of palladium on charcoal), corresponding to 6 g of dry catalyst, at a temperature of about 80° C and a hydrogen pressure of between 5 and 10 bars. After 31/2 hours, the hydrogen absorption and the reaction had ended. After filtering off the catalyst, the solvent and the water of reaction formed were distilled off under normal pressure and the residue which remained was then fractionally distilled in vacuo. 71.7 g (89.3% of theory) of 2,4-diaminophenetole of solidification point 64.2° C were obtained in the boiling range of 150° - 180° C/5 mm Hg. 4.5 g of a higher-boiling residue remained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:59])([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:49]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:59])([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:49]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CCC(O)(CC)C1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(O)(CC)C1CCCN(C(=O)c2cnoc2-c2ccc(C)cc2)C1
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.010 mmol, 2 equ) in DMF (0.3 mL) was added to 3-piperidin-3-ylpentan-3-ol hydrochloride (10 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H28N2O3: 356.2100, found 356.2099.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: BrCc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 30 mg, 1.175 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (160 mg, 0.470 mmol) in N,N-dimethylformamide (6 mL) at 0° C. After 30 min, 2-bromomethylpyridine (0.125 mg, 0.494 mmol) was added. After 1 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (202 mg). MS 432.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12](=[CH2:13])[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:3][CH:4]=1)#[N:10]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: N#CCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1

Procedure:
A mixture of 5 g of p-bromophenylacetonitrile, 4.6 ml of t-butyl acrylate, 57 mg of palladium diacetate, 310 mg of tri-o-tolylphosphine and 12 ml of triethylamine is refluxed for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 10% HCl and saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo to yield t-butyl p-(cyanomethyl)-phenylacrylate. This material is dissolved in ethanol and hydrogenated over 1.1 g of 10% palladium on carbon catalyst for 3 days at 3 atmospheres pressure of hydrogen. After filtration the solvent is removed in vacuo and the residue is chromatagraphed on silica gel with ether/hexane (1:1) as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-phenyl-acetonitrile; 2.8 g of this material is dissolved in 90 ml of tetrahydrofuran and 50 ml of methanol and to this is added 6.2 g of cobalt chloride in 90 ml of water followed by 2.1 g of sodium borohydride in small portions. After filtration and removal of solvent, the residue is chromatagraphed on silica gel with 7.5% ammonia saturated methanol in methylene chloride as the eluent to afford p-(2-t-butoxy-carbonyl-ethyl)-2-phenethylamine as an oil.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>[OH-].[Na+].O>[C:9]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])(=[O:11])[CH3:10]
Reactant: Cc1ccccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccccc1C
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
Ice (300 g) was added to o-cresol (21.6 g, 0.2 mol) dissolved in a solution of sodium hydroxide (12 g, 0.3 mol in water (100 ml). Acetic anhydride (30.6 g, 0.3 mol) was then added and the mixture was shaken for 1 min. The product was extracted into ether and then purified by reduced pressure distillation.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[CH:20]=O>C(O)C.Cl.C(O)(C)C.O>[OH:25][C:24]1[C:23]([CH3:26])=[CH:22][C:19]([CH2:20][CH2:8][C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:4]=2)=[O:9])=[CH:18][C:17]=1[CH3:16]
Reactant: CC(=O)c1cc(-c2ccccc2)c(C)s1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1O
Reaction time: 6 h
Yield: 52.9 %

Procedure:
A solution of 1-(5-methyl-4-phenyl-thiophen-2-yl)-ethanone (419 mg, 1.94 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (350 mg, 2.33 mmol) in ethanol (4 mL) and 5 N HCl in isopropanol (2 mL) is stirred at it for 1 h. The dark green solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in ethanol (10 mL) and treated with Pd/C (60 mg, 10% Pd). The slurry is hydrogenated under 1.4 bar of H2 for 6 h. The mixture is filtered, the solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-methyl-4-phenyl-thiopen-2-yl)-propan-1-one (360 mg) as a colourless resin; LC-MS: tR=1.09 min, [M+1]+=351.25; 1H NMR (CDCl3): δ 7.60 (s, 1H), 7.46-7.30 (m, 5H), 6.85 8s, 2H), 4.48 (s, 1H), 3.14 (dd, J=7.0, 8.2 Hz, 2H), 2.92 (dd, J=7.0, 8.2 Hz, 2H), 2.52 (s, 3H), 2.21 (s, 6H).
Reaction SMILES: Cl.[C:2]([C:5]1[C:6]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[NH:4])[NH2:3].Br[CH2:21][C:22](=O)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:16]1([C:6]2[C:5]([C:2]3[NH:3][C:22]([CH2:23][CH3:24])=[CH:21][N:4]=3)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:15])[CH:7]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1cc(C(=N)N)c(C2CCC2)cc1C
Reactant: CCC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound 245.1, 350 mg, 1.11 mmol, 1.00 equiv, 90%) in ACN (50 mL). 1-Bromobutan-2-one (186 mg, 1.23 mmol, 1.00 equiv) and potassium carbonate (513 mg, 3.53 mmol, 3.00 equiv, 95%) were added to the reaction. The resulting solution was stirred overnight at 80° C. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and washed with 3×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to furnish 290 mg (83%) of methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH2:14])[CH2:4][CH2:3]1.C[C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1.C[C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1.[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][C:54]=1[CH:55]=O)[N:51]([CH3:57])[C:50](=[O:58])[CH2:49][CH2:48]2>>[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][C:54]=1[CH2:55][NH:14][CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[NH:7][CH:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:51]([CH3:57])[C:50](=[O:58])[CH2:49][CH2:48]2
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Reactant: CC1CCC(N)C(c2ccccc2)N1
Agent: C[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: C[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: COc1cc2c(cc1CNC1CCC(C)NC1c1ccccc1)N(C)C(=O)CC2

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-methyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-methyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-methyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][C:22](=[O:30])[C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][CH:22]([OH:30])[C:23]([F:28])([F:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCCC(F)(F)C(=O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-oxooctyl)-3-(2-tetrahydro pyranyloxy)cyclopentyl]heptanate (15) (71.01 g, 133.3 mmol) in methanol (284 ml) was cooled to approximately −20° C., and sodium borohydride (5.08 g, 134 mmol) was added thereto. After stirring for approximately 40 minutes, acetic acid (7.6 ml, 133 mmol) was added drop wise, and the reaction mixture was concentrated under reduced pressure. The residue was supplemented with water (325 ml) and extracted three times with ethyl acetate (228 mL). The organic layers were combined, washed with 3% aqueous sodium chloride (325 ml) and saturated aqueous sodium chloride (325 ml), and dried with anhydrous magnesium sulfate (51 g). The solution was concentrated under reduced pressure to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (16) (70.64 g; 132.1 mmol; yield: 99.1%) as a colorless oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.C(=O)(O)[O-].[Na+]>O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[C:21]1[S:22][C:23]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:24][CH:25]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc2ncnc(-c3cccs3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 60 °C

Procedure:
14.4 mL chlorosulfonic acid and 14.42 mL thionyl chloride were added to 7.78 g of 6-bromo-4-(2-thienyl)quinazoline (compound in Production Example 96) under ice-cooling in a stream of nitrogen, and the mixture was heated at 60° C. for 16 hours, then poured into iced water, neutralized by adding a sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The residue was recrystallized from ether/hexane, to give 2.47 g of the title compound (pale skin-colored crystals).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].C(Cl)[Cl:35]>>[ClH:35].[ClH:35].[CH3:1][N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1
Reactant: ClCCl
Reactant: Cc1ccc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OC[C@@H]2CCN2C)cn1
Product: Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 1.3 g sample of the compound from step 59a above was dissolved in 6 mL of methylene chloride, the solution was cooled to 0° C., and 4 mL of TFA was added. The reaction mixture was stirred at 0° C. for 3 hours, then poured into a satd solution of K2CO3. The organic layer was separated, the aqueous layer extracted with additional methylene chloride, the organics combined, and the solvent removed. The residue was dissolved in ethanol, the solution was cooled to 0° C., and excess NaCNBH3 was added. Two mL of HCHO were added, the pH was adjusted with acetic acid, using bromocresol as an indicator, and the reaction mixture was stirred for 16 hours. The reaction was quenched by pouring it into satd K2CO3 solution. The mixture was extracted with methylene chloride, the extract was dried over MgSO4, and the solvent was removed. The residual oil was purified by chromatography on silica gel, eluting with 100: 1 to 95:5 CHCl3 :methanol containing 0.5% NH4OH. This compound was treated with HCl in ether according to Example 14c to afford 362 mg of the title compound. MS (DCI/NH3) m/e: 193 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.33 (d, J=2.2 Hz, 1H), 7.92 (dd, J=2.6, 8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 4.87-4.77 (m, 1H), 4.57-4.44 (m, 2H), 4.33-4.23 (m, 1H), 4.01 (q, J=9.6 Hz, 1H), 3.00 (s, 3H), 2.73-2.61 (m, 2H), 2.64 (s, 3H). Anal. Calc. for C11H16N2O·2 HCl·0.4 H2O: C, 49.88; H, 6.84; N, 10.56; Found C, 48.25; H, 6.96; N, 10.28.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1>Cl>[CH3:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[N:12]=1
Reactant: CNc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Product: CNc1nc(CSCCN)cs1
Yield: 35 %

Procedure:
Cysteamine hydrochloride (2.8 g; 24.6 mmoles) and 2-methylamino-4-chloromethylthiazole (4.0 g; 24.6 mmoles) [prepared from N-methylthiourea and 1,3-dichloro-2-propane] were dissolved in 20 ml of concentrated hydrochloric acid and the solution was heated at an oil bath temperature of 100°. After 30 hours of heating, the reaction mixture was evaporated under reduced pressure and the residue made basic with 40% NaOH solution. The aqueous phase was extracted with methyl acetate, dried, filtered and evaporated to give 1.75 g of the title compound as an oil which was used without further purification in Step B.
Reaction SMILES: B.[C:2]([N:12]1[CH2:19][CH:18]([OH:20])[CH2:17][C@H:13]1[C:14](O)=[O:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].O>C1COCC1>[OH:15][CH2:14][C@@H:13]1[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]1[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To 200 ml (0.2 mol) of borane. THF complex was added 27.8 g (0.1 mol) of 1-(carbobenzyloxy)-4-hydroxy-L-proline in 50 ml of THF at 0° C. After 16 hours of stirring at room temperature, 100 ml of water was added carefully followed by 12 ml of 6N aqueous HC1 solution and the mixture was extracted with 3 x 100 ml of methylene chloride. The combined organic extracts were dried over MgSO4 and evaporated to yield 22.6 g of the product (oil, 90% yield). NMR(CDC13) 7.40 (m,5H), 5.10 (m,2H), 4.90 (m,1H), 4.65 (m,1H), 4.35 (m,1H), 4.17 (m,1H), 3.60 (m,3H), 2.05 (m,1H), 1.70 (m,1H).
Reaction SMILES: B(O)(O)O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:31])[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=2)C(OC)=O)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.C1(C)C=CC=CC=1>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:31])[CH2:16][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COC(=O)C(C(=O)c1cc(OC)cc(OC)c1)c1ccc(OC(C)C)cc1
Agent: OB(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(OC)cc(C(=O)Cc2ccc(OC(C)C)cc2)c1
Temperature: 152.5 °C
Reaction time: 3 h

Procedure:
9.65 g of boric acid (0.16 mol) and 58 g of crude methyl 3-(3,5-dimethoxyphenyl)-2-(4-isopropyloxyphenyl)-3-oxopropionate (0.16 mol) prepared according to Example 25 are introduced into a round-bottomed flask. The mixture is heated with stirring at 150-155° C. for 3 h and then cooled to approximately 80° C. 200 ml of toluene and then 150 ml of water are added. Separation by settling is carried out and the organic phase is recovered. The aqueous phase is re-extracted with 20 ml of toluene. The organic phases are concentrated to recover 48.8 g of crude 1-(3,5-dimethoxyphenyl)-2-(4-isopropyloxyphenyl)ethanone in the form of a viscous oil with a dark brown color.
Reaction SMILES: [CH2:1]([N:5]([C:17]1[N:22]=[C:21]([N:23]([CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:20]=[C:19]([N:39]([CH2:48][CH:49]([CH2:54][CH3:55])[CH2:50][CH2:51][CH2:52][CH3:53])[CH2:40][CH:41]([CH2:46][CH3:47])[CH2:42][CH2:43][CH2:44][CH3:45])[N:18]=1)[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([OH:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)[CH2:2][CH2:3][CH3:4].N(O[C:59]([CH3:62])([CH3:61])C)=O.[Br:63][C:64]1[CH:70]=[C:69]([Br:71])[CH:68]=[CH:67][C:65]=1N>N1C=CC=CC=1>[CH2:24]([N:23]([C:21]1[N:22]=[C:17]([N:5]([CH:6]2[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][C:61]3[CH:59]=[CH:62][C:64]([Br:63])=[CH:70][C:69]=3[Br:71])[C:8]([CH3:15])([CH3:16])[CH2:7]2)[CH2:1][CH2:2][CH2:3][CH3:4])[N:18]=[C:19]([N:39]([CH2:48][CH:49]([CH2:54][CH3:55])[CH2:50][CH2:51][CH2:52][CH3:53])[CH2:40][CH:41]([CH2:46][CH3:47])[CH2:42][CH2:43][CH2:44][CH3:45])[N:20]=1)[CH:28]1[CH2:29][C:30]([CH3:37])([CH3:38])[N:31]([O:36][C:68]2[CH:67]=[CH:65][C:64]([Br:63])=[CH:70][C:69]=2[Br:71])[C:32]([CH3:34])([CH3:35])[CH2:33]1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc(Br)cc1Br
Reactant: CCCCC(CC)CN(CC(CC)CCCC)c1nc(N(CCCC)C2CC(C)(C)N(O)C(C)(C)C2)nc(N(CCCC)C2CC(C)(C)N(O)C(C)(C)C2)n1
Solvent: c1ccncc1
Product: CCCCC(CC)CN(CC(CC)CCCC)c1nc(N(CCCC)C2CC(C)(C)N(Oc3ccc(Br)cc3Br)C(C)(C)C2)nc(N(CCCC)C2CC(C)(C)N(Oc3ccc(Br)cc3Br)C(C)(C)C2)n1
Yield: 43.4 %

Procedure:
The procedure of Example 1 is repeated using 10 g (13 mmol) of 2,4-bis[N-butyl-N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)amino]-6-[N,N-bis(2-ethylhexyl)amino]-s-triazine, 6.18 g (60 mmol) of tert-butyl nitrite, 7.8 mg (0.013 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 140 mL of pyridine and 13.05 g (52 mmol) of 2,4-dibromoaniline at 85° C. The crude product obtained is purified by vacuum flash chromatography (2% ethyl acetate/heptane) to give 7 g of the title compound as a light yellow solid in 43.4% yield. The structure is confirmed by 1Hnmr and elemental analysis.