Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[C:12]([CH:13]=[C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][S:17][C:16]4[CH:25]=[C:26]([C:29](OC)=[O:30])[CH:27]=[CH:28][C:15]3=4)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC.C1COCC1>[OH:30][CH2:29][C:26]1[CH:27]=[CH:28][C:15]2[C:14](=[CH:13][C:12]3[N:8]([C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:9]=[N:10][N:11]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][S:17][C:16]=2[CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)SCc1ccccc1C2=Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc2c(c1)SCc1ccccc1C2=Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 21-b (3.8 g, 6.4 mmol) was dissolved in a mixture of 80 ml of ether and 40 ml of THF, and 250 mg (6.6 mmol) of lithium aluminium hydride was added to the solution under ice cooling, followed by stirring at room temperature for one hour and a half. To the mixture was added 1 ml of a saturated aqueous solution of sodium sulfate and insoluble matters were filtered off. The filtrate was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (5/1)] to give the E form (21-c-E; 40%) and the Z form (21-c-Z; 41%) as colorless oily substances.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[NH:17]([C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18]>C(O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[N:17]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:18]1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: NNc1ncccn1
Solvent: CCO
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ncccn1

Procedure:
A solution of 2.36 g of ethyl 4-chloroquinoline-3-carboxylate and 1.46 g of 2-hydrazinopyrimidine in 80 ml of ethanol is refluxed for 2 hours and 30 minutes. The resulting slurry is cooled down to 5°, then filtered and the resulting product is taken up in 20 ml of N sodium hydroxide and sufficient water to effect solution. Ammonium chloride (10 g) is added, the resulting precipitate is collected, and is washed three times with ethanol and three times with ether to yield 2-(2-pyrimidyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, m.p. above 360°; IR (KBr) 800, 817, 844, 886 cm-1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:1]([O:17][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C([O-])c1ccccc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
The synthesis of tetratelluride catalysts based on dendritic wedge 3 is shown in FIG. 15. Benzyl alcohol 16 (Francavilla et al., J. Am. Chem. Soc., 123:57 et al. (2001), which is hereby incorporated by reference in its entirety) was converted to the benzoate 17 in 93% isolated yield with benzoic anhydride as previously described. The four silyl groups were removed with HF-pyridine to give tetraol 18 in 88% isolated yield. As before, the hydroxyl groups were converted via the mesylate to the corresponding bromides (Wendler et al., Tetrahedron, 3:144 et al. (1958), which is hereby incorporated by reference in its entirety) to give tetrabromide 19 in 52% overall yield. The addition of excess PhTeNa to 19 gave tetratelluride 20a in 65% isolated yield; 4-Me2NC6H4TeNa, tetratelluride 20b in 92% isolated yield; and n-C6H13TeNa, tetratelluride 20c in 51% isolated yield.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][C:24](=[O:26])[CH3:25])[N:15]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].[ClH:42]>CO.C(Cl)Cl.CCOCC.[Pd]>[ClH:42].[ClH:42].[OH:37][C@H:33]1[C:29]2[N:30]=[CH:31][N:32]=[C:27]([N:15]3[C:16]4[C:21](=[C:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[CH:19]=[CH:18][CH:17]=4)[C:11]4([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:14]3)[C:28]=2[C@H:35]([CH3:36])[CH2:34]1
Reactant: CC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(=O)NCc1cccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Yield: 77 %

Procedure:
To a solution of N-((1′-benzyl-1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)acetamide (19 mg, 0.038 mmol) in MeOH (0.4 mL) was added ammonium formate (24 mg, 0.38 mmol) and 10% Pd/C (4 mg, 20% weight). The mixture was allowed to stir at reflux for 4 h. After cooling, the reaction mixture was filtered through Celite. The filtrate was evaporated in vacuo. The crude residue was purified by column chromatography (4% 7 N ammonia in MeOH/DCM) to yield the free base, which was taken up in DCM and acidified with 2N HCl in Et2O. Removal of the solvents afforded N-((1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)acetamide dihydrochloride as a solid (12 mg, 77%). LCMS (APCI+) m/z 408 [M+H]+; Rt=1.74 min.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(OC(=O)C)(=O)C>[C:8]([N:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]([C:11](=[O:10])[CH3:12])[C:5]1=[O:7])(=[O:9])[CH3:3]
Reactant: CCOC(=O)c1[nH]c(=O)[nH]c1C
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(C)n(C(C)=O)c(=O)n1C(C)=O

Procedure:
A mixture of 54.5 g of ethyl 2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate and 240 ml of acetic anhydride is refluxed for 13 hours. The mixture is distilled to remove 150 ml of acetic anhydride and acetic acid this is replaced by fresh acetic anhydride and refulxing is resumed. After a total of 22 hours of reflux, excess acetic anhydride is evaporated under reduced pressure and the resulting residue is triturated with cyclohexane and then recrystallized from cyclohexane to give ethyl 1,3-diacetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate melting at about 56°-58° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(CCO)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCOS(C)(=O)=O)cc1OC
Reaction time: 4 h
Yield: 102.6 %

Procedure:
A solution of 18.2 g (0.1 mole) of 3,4-dimethoxyphenethyl alcohol in 150 ml of methylene chloride was cooled to -5° C. To the solution was added 13.9 ml (0.1 mole) of triethylamine followed by 7.7 ml (0.1 mole) of methanesulfonyl chloride keeping the temperature below 0° C. The reaction was stirred for 4 hr, poured into water, washed with brine, dried over Na2SO4, and evaporated to give 26.7 g of product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.[NH2:25][C@@H:26]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:25][C@H:26]([CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.62 mmol) [Prepared in Example 95], N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine]in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol, 53% yield) as a clear oil: LCMS (ES) m/e 511, 513 (M, M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[N:12]2[N:16]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[N:18]=[C:11]2[CH:10]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:35][C:13]1[N:12]2[N:16]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
530 mg (1.30 mmol) of 7-(2,4-dichlorophenyl)-2-[1-(1-methylethyl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidin-5(6H)-one were initially charged in phosphorus oxychloride (16 ml), and 1.19 g (5.22 mmol) of benzyltriethylammonium chloride were added. The mixture was then stirred at 120° C. for 2.5 h. The reaction mixture was poured onto saturated aqueous sodium bicarbonate solution (150 ml), and solid sodium bicarbonate was added until a pH of 7 had been reached. The mixture was extracted with dichloromethane (3×50 ml), and the combined organic phases were washed with water (50 ml), dried over magnesium sulfate and concentrated. This gave 502 mg (89% of theory) of the product as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](Br)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>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.O>[C:11]1([C:7]2[N:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2ccccc2)nc1
Yield: 51 %

Procedure:
5-acetyl-2-bromopyridine 38 (0.656 g, 3.28 mmol), phenylboronic acid (0.800 g, 6.56 mmol), Na2CO3 (0.243 g, 2.29 mmol), Pd(PPh3)2Cl2 (0.115 g, 0.16 mmol, 5% Pd), acetonitrile (26 mL) and H2O (26 mL) were added to 50 mL screw cap pressure vessel. The mixture was stirred, degassed by purging with argon for 15 min, sealed and placed in an 80° C. oil bath for 14 h (overnight). The dark colored mixture was cooled and extracted with ether. The organic layer was filtered through a pad of celite, rinsed with ether, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by flash column chromatography (SiO2, 20 g, 5% EtOAc/hexanes) to afford the coupled ketone 40 as a white solid (0.33 g, 52%): TLC Rf=0.4 (25% EtOAc/hexanes); mp 124.9126.2° C.; 1H NMR (500 MHz, CDCl3) δ 9.22 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.10-7.99 (m, 2H), 7.83 (d, J=8.3 Hz, 1H), 7.55-7.40 (m, 3H), 2.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.6, 161.1, 150.2, 138.2, 136.7, 130.9, 130.4, 129.2, 127.6, 120.4, 26.9; IR (neat cm−1) 3062, 2999, 2960, 2322, 1673, 1557, 1382, 1016, 736; HRMS (DART, M++H) m/z 198.0906 (calculated for C13H12NO, 198.0919).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:20])[CH2:7]1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: COc1ccc(CNC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1

Procedure:
Example 2 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-4-methoxybenzene (19.5 μl) to give the title compound (0.0257 g). LC-MS (System A): Rt 2.23 mins, Mass Spectrum m/z 438 [MH+].
Reaction SMILES: CC(C)=O.C(S)C.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[C:14]([O:27]C)[CH:13]=1>O.C1C=CC=CC=1>[CH3:26][CH:18]([C:16]1[CH:17]=[C:12]([O:11][CH3:10])[CH:13]=[C:14]([OH:27])[CH:15]=1)[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(C)C(C)c1cc(OC)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCS
Product: CCCCCC(C)C(C)c1cc(O)cc(OC)c1

Procedure:
To 750 ml. cold dimethyl formaldehyde (DMF) was added 100 g. (1.06 mol.) ethanethiol. To this was added slowly 48 g. (1.14 mol.) of 57% NaH in mineral oil (which had been freed of mineral oil by washing with benzene). Then 90 g. (0.34 mol.) 1,3-dimethoxy-5(1,2-dimethylheptyl) benzene was added under a nitrogen atmosphere. The reaction mixture was refluxed overnight. Ice and water (4 l.) was added and the mixture was extracted with ether. The ether extracts were washed twice with 100 ml. 10% H2SO4, twice with water, dried (Na2SO4) and distilled. The product had b.p. 134/0.15 mm n25 =1.5090. Yield 71.5 g. (86%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].Cl.[OH2:27]>C(#N)C.N.N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+]>[CH3:10][C:4]1[C:5](=[O:27])[C:6]([CH3:9])=[C:7]([CH3:8])[C:2](=[O:1])[C:3]=1[CH:11]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1cc(C)c(C(CCCCCC(=O)O)c2ccccc2)c(O)c1C
Reactant: O
Agent: Cl
Agent: N
Agent: [K+]
Solvent: CC#N
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Reaction time: 2 h
Yield: 94.1 %

Procedure:
7-(2-hydroxy-3,4,6-trimethylphenyl)-7-phenylheptanoic acid (5.0 g) was dissolved in a mixed solution of acetonitrile (25 ml), water (10 ml) and 25% aqueous ammonia (1 ml), to which 3% aqueous solution (280 ml) of potassium nitrosodisulfonate (Fremy's salt) was added. The mixture was stirred at a temperature of 2° to 4° C. for 2 hours. The reaction mixture was acidified with hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water twice. Ethyl acetate was distilled off under reduced pressure, and the residue was recrystalized from a mixed solution of acetonitrile and water (6:4) to give 7-(3,5,6-trimethyl-1,4-benzoquinone-2-yl)-7-phenylheptanoic acid (4.90 g, 94.1%) as yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]5[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=5[CH:29]=4)[CH:21]=3)=[C:15]([CH3:42])[CH:14]=2)[CH2:9]1.C(N(CC)CC)C.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>ClCCl>[CH3:19][C:17]1[CH:18]=[C:13]([O:12][CH:10]2[CH2:11][N:8]([C:50](=[O:53])[CH2:51][CH3:52])[CH2:9]2)[CH:14]=[C:15]([CH3:42])[C:16]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]2[CH:41]=[CH:40][C:31]3[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=3[CH:29]=2)[CH:21]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CNC5)cc4C)c3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)OC)c3)c(C)c2)C1
Reaction time: 12 h
Yield: 94.4 %

Procedure:
The crude (S)-methyl 2-(6-((4′-(azetidin-3-yloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2,2,2-trifluoroacetate 14c (40 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of triethylamine (0.1 mL, 0.26 mmol) and propionyl chloride (11 mL, 0.13 mmol) successively. The reaction solution was stirred for 12 hours. The resulting solution was mixed with 10 mL of dichloromethane, washed with saturated sodium chloride solution (5 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-methyl 2-(6-((2′,6′-dimethyl-4′-((1-propionylazetidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 14d (45 mg) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1.O>CC#N.C1(C)C=CC=CC=1>[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1)=[O:5]
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)Cc1ccc(C=O)cc1
Reaction time: 5 h

Procedure:
To a mixture of N-methylmorpholine-N-oxide (63.9 g, 545 mmol) in MeCN (848 g) and toluene (742 g), was added a solution of methyl [4-(bromomethyl)phenyl]acetate (53.0 g) in toluene (212 g) at 0 to 25° C. After stirring for 5 hr, water (106 g) was added to the reaction mixture. The aqueous layer was removed and remaining MeCN in the organic layer was removed under reduced pressure. The remaining toluene solution was washed with water twice (530 g×2), and concentrated under reduced pressure at a temperature below 40° C. until the weight of the solution was 233 g. An activated charcoal (3 g) was added to the solution and removed by filtration. To the solution was added 2,6-dibutyl-4-hydroxytoluene (152 mg), and concentrated under reduced pressure to give the subtitle compound. Yield 30.9 g, 79% from methyl [4-(bromomethyl)phenyl]acetate; 1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.87 (d, 2H), 7.86 (d, 2H), 3.83 (s, 2H), 3.63 (s, 3H)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13](=[CH2:16])[CH2:14][SH:15].C(N(CC)CC)C>O1CCCC1>[CH3:16][C:13](=[CH2:12])[CH2:14][S:15][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C=C(C)CS
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)CSc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 5.0 g (0.031 mole) of 2,4-difluoronitrobenzene and 2.8 g (0.031 mole) of 2-methyl-2-propenethiol in 25 ml of tetrahydrofuran at room temperature was added dropwise 3.1 g (0.031 mole) of triethylamine. The reaction mixture was stirred at room temperature for forty-eight hours and then at 50° C. for eight hours. The tetrahydrofuran was removed under reduced pressure, and water was mixed with the residue. This aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried, and the chloroform evaporated under reduced pressure, leaving an oily residue. Distillation of this residue under reduced pressure yielded 6.0 g of 2-(2-methyl-2-propenylthio)-4-fluoronitrobenzene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: O.[CH3:2][NH:3][CH2:4][CH2:5][NH:6][CH3:7].[NH2:8][C:9]1[C:10](Cl)=[C:11](Cl)[C:12](=[O:16])[N:13]([CH3:15])[N:14]=1.C(Cl)(Cl)Cl>CO>[NH2:8][C:9]1[C:10]2[N:3]([CH3:2])[CH2:4][CH2:5][N:6]([CH3:7])[C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[N:14]=1
Reactant: CNCCNC
Reactant: Cn1nc(N)c(Cl)c(Cl)c1=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(C)c2c1c(N)nn(C)c2=O
Yield: 82.3 %

Procedure:
Water (9 ml) and N,N'-dimethylethylenediamine (0.8 ml, 7.7 mmol) were added to 6-amino-4,5-dichloro-2-methyl-3(2H)-pyridazinone (500 mg, 2.6 mmol) as described in Chemical Pharmaceutical Bulletin, 30, 832 (1982), and the mixture was refluxed under heating for 3 hours. The reaction mixture was concentrated, added with chloroform, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was subjected to silica gel column chromatography (chloroform:methanol=40:1) to give 448 mg of 8-amino-1,2,3,4-tetrahydro-1,4,6-trimethylpyrazino[2,3-d]pyridazin-5(6H)-one.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(C(C)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A stirred solution of methyl 5-acetyl-2-ethoxy-benzoate (9.6 g, 0.043 mol) in a mixture of 1,4-dioxane (80 ml) and water (80 ml) was treated with 5N aqueous sodium hydroxide solution (44 ml, 0.217 mol). The mixture was stirred at room temperature for 18 hours then the solvents evaporated under vacuum. The residue was dissolved in water (100 ml), then this solution was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (4×100 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum. Crystallization of the residue from ethyl acetate gave the title compound as a colourless solid (5.4 g, 60%), m.p. 122-125° C.
Reaction SMILES: Cl/[C:2](/[N+]([O-])=O)=[CH:3]\[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][CH:5]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[N:19]=[CH:18][N:17]=1.N12CCCN=C1CCCCC2>C(O)C>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]2[C:21]3[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=3[O:15][CH:2]=2)=[CH:5][CH:6]=1)[CH3:11]
Reactant: Oc1cc(O)ncn1
Reactant: CCc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCc1ccc(-c2coc3nc[nH]c(=O)c23)cc1
Reaction time: 15 h

Procedure:
Analogously to the literature method [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 11.9 g (85% purity, 47.6 mmol) of 1-[(Z)-2-chloro-2-nitrovinyl]-4-ethylbenzene and 5.9 g (52.3 mmol) of 4,6-dihydroxypyrimidine in 200 ml of ethanol at 60-70° C. for 30 minutes. Then slowly add 14.4 ml (14.6 g, 96.1 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir the resulting reaction solution under reflux for six hours and then at 60° C. for 15 hours. After concentration under reduced pressure, take up the residue in dichloromethane and chromatograph it on silica gel (eluent: cyclohexane/ethyl acetate 1:1→1:5). Stir the resulting solid in diethyl ether and filter. 5.0 g (44% of theory) of the target compound are obtained.