Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([OH:14])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([O:14][C:16](=[O:18])[CH3:17])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(O)c1ccc(C)nc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(OC(C)=O)c1ccc(C)nc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 100.9 %

Procedure:
45.9 g (0.22 mol) of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester was dissolved in 100 ml of ethyl acetate, and 50 ml (0.53 mol) of acetic anhydride and 0.1 g (0.82 mmol) of 4-dimethylaminopyridine were added. The solution was stirred for 6 hours at 20° C. and then evaporated. The residue was dissolved in 50 ml methylene chloride and 50 ml of 5 percent sodium hydroxide solution, the phases were separated and the organic phase was evaporated. 55.8 g of raw 3-acetoxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester was obtained. This raw product was dissolved in 300 ml of acetic acid with 3.0 g of 5 percent palladium on carbon and fed into a 1-liter autoclave. The autoclave was put under 8 bars of hydrogen and stirred at 70° C. Hydrogenation was ended after 6 hours. The autoclave was cooled and opened, and the solution was filtered and evaporated. The residue was dissolved in 50 ml of water and brought to pH 8 by potassium carbonate. The solution was extracted three times with 100 ml of methylene chloride and the organic extracts were evaporated. 42.5 g of raw 2-methyl- pyridine-5-propionic acid ethyl ester was obtained. The raw product was distilled (b.p. 100°-110° C./1.0 mbar). 22.0 g of 2-methylpyridine-5-propionic acid ethyl ester was obtained, with a GC content of 92 percent. The yield, in relation to the 6-methyl nicotinoyl propionic acid ethyl ester, was 62.9 percent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[C:4](=[O:15])[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:37][CH2:36][CH2:35]1>>[C:36]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[C:4](=[O:15])[N:3]=1)(=[O:37])[CH3:35]
Reactant: C1CCOC1
Reactant: C[C@@H](O)[C@H](CO)Cn1ccc(N)nc1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(=O)Nc1ccn(C[C@@H](CO)[C@@H](C)O)c(=O)n1
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 45 (1.3 g, 2.7 mmol) in 38 ml of THF was added 2.3 ml of 1M TBAF in THF. The reaction was stirred for 24 hrs, concentrated and chromatographed on silica eluting with, first, 10% MeOH in dichloromethane and, second, with 15% MeOH in dichloromethane. Concentration of the pure product fractions afforded 0.5 g (72%) of 46 as white amorphous solid. 1H NMR (DMSO-d6): δ10.81 (s, 1H), 7.98 (d, J=7 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 4.58 (d, J=5 Hz, 1H), 4.48 (t, J=5 Hz, 1H), 3.82 (d, J=7 Hz, 2H), 3.67 (m, 1H), 3.46 (m, 1H), 3.38 (m, 1H), 2.09 (s, 3H), 1.89 (m, 1H), 1.09 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]C)=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH:13]=[O:14])[CH:4]=1.C(O)C[OH:17]>>[C:13]([OH:14])(=[O:17])[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: OCCO
Product: COc1cc(C(=O)O)cc(OC)c1O
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
106 g (0.5 mole) of TMBA, 66 g (1.6 mole) of soda in pellets in 200 g of ethylene glycol, are heated under nitrogen. Solution is complete towards 160° C. Distillation commences and stops at the end of 30 minutes, at around 195° C. This temperature is held for 30 minutes. After cooling under nitrogen, it is diluted with 1 l of water and acidified to pH 3 with 170 ml of 10 N sulphuric acid, with heating to bring it to reflux. It is then cooled and left to crystallize for 1 hour. By filtration, 163.3 g of moist, crude product are isolated and this recrystallized in 900 ml of water. After washing and drying, 76.4 g of recrystallized syringic acid are obtained, namely a yield of 77.2% with respect to the TMBA. The acid obtained has a melting point of 210° C. Analysis by liquid-liquid chromatography indicates that it contains less than 1% of residual TMBA and that it is free of 3-hydroxy 4,5-dimethoxybenzoic acid and of dihydroxymonomethoxybenzoic acid.
Reaction SMILES: [OH-].[Na+].BrBr.NC([C:8]1[C:9]([Cl:19])=[N:10][C:11]([CH3:18])=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])=O.[NH2:20]C(C1C=NC=CC=1)=O>O>[NH2:20][C:8]1[C:9]([Cl:19])=[N:10][C:11]([CH3:18])=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1cc(C(F)(F)F)c(C(N)=O)c(Cl)n1
Reactant: NC(=O)c1cccnc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(F)(F)F)c(N)c(Cl)n1
Temperature: 75 °C

Procedure:
To a solution of 6.6 g of sodium hydroxide in 60 ml of water at 5° C. was added 9.3 g of bromine. When a clear solution was obtained, 9.2 g of 3-aminocarbonyl-2-chloro-6-methyl-4-(trifluoromethyl)pyridine was added quickly, maintaining the temperature below 5° C. The resulting mixture was stirred until the 3-(aminocarbonyl)pyridine dissolved (~30 min). The cooling bath was removed and the mixture was then warmed to 75° C. for 30 min. After cooling to room temperature, the 3-aminopyridine product was extracted with ethyl acetate, dried (magnesium sulfate), filtered, and evaporated to give 4.9 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1N
Yield: 72 %

Procedure:
1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine (60 mg, 0.18 mmol, as prepared in the previous step) was stirred with 40 mg 5% Pd—C in MeOH (5 mL) under H2 (1 atm) for 2 h. The reaction was filtered through Celite and concentrated in vacuo to afford 40 mg (72%) of 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine as a brown solid, which was used immediately without further purification. Using a procedure similar to Example 9, step (c), 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine (40 mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)) in the presence of DIEA (61 μL, 0.34 mmol) to afford 18.9 mg (36%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 2.13 (s, 3H), 2.38 (s, 3H), 2.59-2.62 (m, 4H), 3.24-3.27 (m, 4H), 6.92 (d, 1H, J=2.8 Hz), 7.06 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.7 Hz), 7.02 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=5.1 Hz), 8.11 (s, 1H), 8.34 (d, 1H, J=9.0 Hz); Mass spectrum (ESI, m/z): Calcd. for C22H22N4O2S, 407.1 (M+H), found 407.1.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:31])[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[C:8]([O:10]CC)=[O:9])C>O.C(O)C>[OH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:7]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])([C:8]([OH:10])=[O:9])[C:6]([OH:31])=[O:5]
Reactant: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)(C(=O)O)C(=O)O
Yield: 60.1 %

Procedure:
To a stirred solution of KOH (4.83 g, 75 mmol) in water (4.2 mL) and ethanol (15 mL) was added 2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester (15 g). The reaction mixture was heated to reflux for 14 h, then concentrated in vacuo, and extracted with chloroform. The aqueous layer was acidified with HCl until pH 1 and extracted with diethyl ether (3×50 mL). The ethereal solution was dried over anhydrous MgSO4 and concentrated in vacuo to afford get 2,2-bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid (7.8 g, 82.3%) as a yellow solid. 1H NMR (300 MHz, CD3OD/TMS): (ppm) 4.86 (s, 4 H), 3.22 (s, 4 H), 1.9-1.8 (m, 4 H), 1.36-1.10 (m, 12 H), 0.84 (s, 12 H). 13C NMR (75 MHz, CD3OD/TMS): (ppm) 176.0, 72.0, 58.7, 39.8, 36.0, 34.1, 26.5, 25.5, 24.5. Mp.: 178-180 C.
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:16](OCC1C=CC=CC=1)=O.C[O:28][C:29](=O)[C@@H:30]1CC(=C)CN1C(OCC1C=CC=CC=1)=O>>[CH2:9]([C@@H:7]1[CH2:6][N:5]2[C@H:4]([CH2:3][C:29](=[O:28])[CH2:30][CH2:16]2)[CH2:8]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@@H]1CC(=Cc2ccccc2)CN1C(=O)OCc1ccccc1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Product: O=C1CCN2C[C@@H](Cc3ccccc3)C[C@H]2C1
Yield: 4 %

Procedure:
In a similar manner to the procedures described in Preparative Examples 8(ii)′, 8(iii)′, 8(iv)′, 8(v)′ and 8(vi)′ above, reactions were conducted in turn, using (S)-1-benzyloxycarbonyl-4-benzylideneproline methyl ester [prepared as described in Preparative Example 26′ above] instead of (S)-1-benzyloxycarbonyl-4-methylideneproline methyl ester, to give the title compound as a brown oil (yield: 4%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccnn1C
Yield: 109.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.20 g, 0.34 mmol) prepared in Example 43b, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (4.0 mL), to yield the title compound (0.16 g, 98%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:55]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])(=[O:58])[CH:56]=[CH2:57]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1)([CH3:63])([CH3:62])[CH3:61]
Reactant: CCCOc1ccc(Br)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc(/C=C/C(=O)OC(C)(C)C)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 378 %

Procedure:
To a solution of 5-(5-bromo-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (1.0 g, 0.0025 mol) and triethylamine (0.38 g, 0.0038 mol) in acetonitrile (2 ml), was added palladium(II) acetate (0.03 g, 0.00013 mol), tri-o-tolylphosphine (0.076 g, 0.00025 mol) and t-butyl acrylate (0.48 g, 0.00038 mol). The mixture was heated under reflux for 4 hours, then cooled and evaporated under vacuum. The residue was suspended in water (30 ml) and extraction with dichloromethane (3×20 ml) effected. The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum to give a yellow-green solid. Chromatography on silica gel (12 g), using a methanol in dichloromethane elution gradient (0-2% methanol), followed by crystallisation from ethyl acetate-hexane gave the title compound as a white solid (0.65 g, 58%), m.p. 167°-168° C. Found: C,66.47; H,7.00; N,12.31. C25H32N4O4 requires C,66.35; H,7.13; N,12.38%.
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-])=O)[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:23]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([NH:11][C:3](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mg of 5% palladium-carbon was added to a mixed solution of 4.0 mL of methanol and 8.0 mL of ethyl acetate containing 50 mg of tert-butyl 2-(benzamido)-4-(2-nitroanilino)benzoate and stirred under hydrogen atmosphere at room temperature for 1 hour and 30 minutes. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 46 mg of tert-butyl 4-(2-aminoanilino)-2-(benzamido)benzoate as pale yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[CH:10][C:11]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[C:2]1=[O:27].Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH:33][C:23](=[O:24])[CH:22]([O:21][C:18]1[CH:19]=[CH:20][C:11]([CH:10]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:27])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)[CH3:26]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Reaction time: 15 h
Yield: 44.1 %

Procedure:
To a solution of 2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy]propionic acid (100 mg, 0.28 mmol), L-alanine methyl ester hydrochloride (40 mg, 0.29 mmol) and triethylamine (0.4 ml) in THF (10 ml) was added N, N'-dicyclohexylcarbodiimide (60 mg, 0.29 mmol) at room temperature under stirring. The stirring was continued for 15 h, then the mixture was filtered and the filtrate evaporated under vacuum. The residue was chromatographed on silica gel using as eluant ethylacetate methanol (9:1) to give pure title compound in 44.1% yield (55 mg).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+]>[C:9]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(OC(=O)c2ccccc2)c1

Procedure:
Metacresyl benzoate was prepared by vigorously shaking a mixture of metacresol (1 equivalent, 5 grams) and benzoyl chloride (1.2 equivalents, 7.1 grams) in a 10% aqueous solution of sodium hydroxide (100 ml) in a stoppered flask for 15 minutes. The white crystalline solid thus formed was removed by filtration, washed with water and dried to yield metacresyl benzoate.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C([NH:15][C@H:16]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17]([OH:19])=[O:18])(OC(C)(C)C)=O>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:15][C@H:16]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 ml of TFA were added to a solution of (R)-N-Boc-2-amino-3-cyclohexylpropanoic acid (3.0 g, 11.1 mmol) in 20 ml of CH2Cl2, and the mixture was stirred at RT overnight. After deprotection was complete, the CH2Cl2 was evaporated off, and the remaining solid was mixed with 50 ml of H2O and lyophilized. Yield: 2.84 g (90%) of (R)-2-amino-3-cyclohexylpropanoic acid trifluoroacetate as colorless solid.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:14]C(=O)N(C)C)[CH:13]=1)[CH2:9][OH:10])=O.[OH-].[Na+]>>[SH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([SH:14])[CH:13]=1)[CH2:9][OH:10]
Reactant: CN(C)C(=O)Sc1cc(CO)cc(SC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: OCc1cc(S)cc(S)c1

Procedure:
3,5-Bis (dimethylcarbamoylthio) benzyl alcohol was treated with sodium hydroxide according to the ordinary method to give 3,5-dimercaptobenzyl alcohol. This alcohol was then brominated in a manner similar to that in EXAMPLE 17, giving 3,5-dimercaptobenzyl bromide, followed by the reaction with urea according to the ordinary method giving 3,5-dimercaptobenzyl mercaptan.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][N:19]3C(OC(C)(C)C)=O)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][NH:19]3)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of (2S,4R)-tert-butyl 2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1.3 g, 2.1 mmole) in DCM was added trifluoroacetic acid (TFA, 5 mL) at room temperature. The reaction mass was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to get crude compound (2S,4R)—N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxamide (1.05 g, 97.2%) as a TFA salt. The crude compound was taken to the next step without further purification. MS: MS m/z 501.3 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]/[C:16]([O-])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=C\C(=O)[O-])c1ccc(-c2cccc(C)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cccc(C)c2)cc1

Procedure:
(E)-3-(3′-Methyl-biphenyl-4-yl)-but-2-enoate (0.74 g, 2.64 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52b to give (E)-3-(3′-methyl-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid; 0.63 g (85%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.OO.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([OH:20])(=[O:19])[CH3:18]>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][O:20][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: Cc1ccnc(C)c1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(=O)OCc1cc(C)ccn1

Procedure:
24.3 ml of 2,4-dimethylpyridine were dissolved in 80 ml of glacial acetic acid, the solution was mixed with 30 ml of 30% hydrogen peroxide and refluxed for 25 hours. The solution was then adjusted to approximately pH 8 with saturated sodium carbonate solution, the solution was extracted with dichloromethane and the organic phase rotated in. The residue was mixed with 90 ml of acetic anhydride and refluxed for 1.5 hours. The pH-value of the solution was adjusted to approximately 8 with 40% NaOH and the solution was extracted with trichloromethane. 30 g of crude 4-methyl-2-acetoxymethylpyridine were obtained.
Reaction SMILES: [CH2:1]([OH:11])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][CH2:9][C@@H:7]2[O:8][C@H:2]([CH2:1][O:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:3]([OH:4])[C@@H:5]2[OH:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O[C@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In accordance with Flowchart C, 2,5-anhydro-D-glucitol 19 is reacted with trityl chloride in pyridine, giving 2,5-anhydro-1,6-bis-O-(triphenylmethyl)-D-glucitol 20, which is then reacted with sodium hydride and benzyl bromide in dimethylformamide, giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-1,6-bis-O-(triphenylmethyl)-D-glucitol 21. Compound 21 is then reacted with acetic acid at about 80° C., giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol 22, which is then reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving 2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol, 1,6-bis(diphenyl phosphate) 23. Substitution of other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 23 is then hydrogenated in methanol/acetic acid over palladium on carbon, giving the product of Formula I where R', R", R'" and R"are phenyl, 2,5-anhydro-D-glucitol, 1,6-bis(diphenyl phosphate) 24. which may then be hydrogenated in methanol over platinum oxide, giving the product of Formula I where R', R", R'" and R"" are hydrogen, 2,5-anhydro-D-glucitol, 1,6-bis(dihydrogen phosphate) 25. Compounds 24 and 25 are disclosed in Voll et al., Carbohydrate Research, 95, 145-154 (1981), but are prepared by a different process. ##STR16##
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:27])[C:17](=[O:18])[C:16]2[C:19]([Sn](C)(C)C)=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:19]2[C:16]3[C:17](=[O:18])[C:13]([CH3:12])([CH3:27])[O:14][C:15]=3[CH:22]=[CH:21][CH:20]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Oc2cccc([Sn](C)(C)C)c2C1=O
Reactant: Cc1c(I)cnc(N)c1C#N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)cnc(N)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.8 grams (0.007 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine, 2.3 grams (0.007 mole) of (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)trimethyltin (prepared in Step D of this Example), and 0.5 gram (catalyst) of tetrakis(triphenylphosphine)palladium(O) in 25 mL of toluene is heated at reflux for about 22 hours. After this time the reaction mixture is cooled to ambient temperature and diluted with 50 mL of ethyl acetate. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to a residue. The residue is purified using column chromatography, yielding 2-amino-3-cyano-4-methyl-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)pyridine.