Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:39]1([C:42](O)=[O:43])[CH2:41][CH2:40]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O.C(OCC)(=O)C>[CH:39]1([C:42]([N:21]2[CH2:22][C:17]3[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[CH:13][CH:12]=4)=[N:19][C:18]=3[CH2:20]2)=[O:43])[CH2:41][CH2:40]1
Reactant: O=C(O)C1CC1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) (150 mg, 0.38 mmol) in 2-methyl THF (2 mL) and DMSO (1 mL) was added DIPEA (159 uL, 0.92 mmol), cyclopropane carboxylic acid (578 uL, 0.73 mmol) and EDC (139 mg, 0.73 mmol), followed by HOBt (98 mg, 0.73 mmol). The reaction mixture was stirred at room temperature for 4 h then diluted with water and ethyl acetate. The organic layer was concentrated and purified by prep HPLC (low pH) to give a pale yellow solid (65 mg, 0.14 mmol, 37% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[C:30]([O:35][CH3:36])(=[O:34])[C:31]([CH3:33])=[CH2:32]>>[CH3:36][O:35][C:30](=[O:34])[CH:31]([CH3:33])[CH2:32][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[NH:19][S:20]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:14]=1
Reactant: C=C(C)C(=O)OC
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: COC(=O)C(C)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodo-phenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and methyl methacrylate analogous to Example 133. (M+1)+=343. HPLC retention time=0.99 min (Method 14).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2.[CH2:14]([OH:19])[CH:15]([OH:18])[CH2:16]Cl>C(O)C>[OH:18][CH:15]([CH2:14][OH:19])[CH2:16][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: OCC(O)CCl
Agent: [Na]
Solvent: CCO
Product: O=C1CCc2c(cccc2OCC(O)CO)N1
Yield: 29.6 %

Procedure:
0.23 g of sodium metal was dissolved in 40 ml of ethanol, and 1.63 g of 5-hydroxy-3,4-dihydrocarbostyril and 1.1 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 6 hours. After allowing the mixture to cool, the precipitated crystals were filtered, and the filtrate was concentrated to dryness. The residue thus obtained was extracted with 100 ml of chloroform, and the extract was washed with a 5% aqueous sodium hydroxide solution and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethanol to give 0.7 g of 5-(2,3-dihyroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 173° - 175° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][NH:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OC1C2N=NNC=2C=CC=1.CN(C1C=CC=CN=1)C.C(Cl)CCl>O1CCCC1>[C:18]1([NH:17][C:8]([C:7]2[C:2](=[O:1])[NH:3][CH:4]=[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=2)=[O:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c[nH]c1=O
Reactant: Nc1ccccc1
Agent: CN(C)c1ccccn1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)c1cc(-c2ccccc2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 2-Oxo-5-phenyl-1,2-dihydro-pyridine-3-carboxylic acid (44 g, 0.20 mmol) in tetrahydrofuran (5 mL) were successively added aniline (20 μL, 0.23 mmol), hydroxybenzotriazole (30 mg, 0.23 mmol), dimethylaminopyridine (27 mg, 0.23 mmol) and EDC (43 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with DCM containing 10% of MeOH to afford the title compound as a white solid (20 mg, 34% yield). MS (ES+) 291. δH (DMSO-d6) 7.2 (3H, m), 7.9 (1H, t), 8.5 (1H, d), 8.6 (2H, m), 9.3 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>CS(C)=O>[N:15]1([C:6]2[N:5]=[C:4]([NH2:8])[CH:3]=[CH:2][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cc(Cl)ccn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(N2CCCC2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 36.8 %

Procedure:
A mixture of 4-chloro-2-aminopyridine (19.3 g, 0.150 mol), K2CO3 (41.7 g, 0.30 mol) and pyrrolidine (32.0 g, 0.45 mol) in DMSO (150 mL) was stirred at 190° C. for 10 hours. After cooling to room temperature, water (300 mL) was added and extracted with ethyl acetate (150 mL×4). The combined organic layers were washed with water (25 mL×3), dried over Na2SO4 and concentrated in vacuo, the residue was purified by silica gel chromatography (10:1 ethyl acetate/petroleum ether) to obtain 6-(pyrrolidin-1-yl)pyridin-2-amine (9.0 g, 37% yield).
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([Cl:13])=[O:12])=[C:9]([I:14])[C:8]([NH2:15])=[C:7]([I:16])[C:3]=1[C:4]([Cl:6])=[O:5].[C:17](Cl)(=[O:19])[CH3:18].O>CC(N(C)C)=O>[I:1][C:2]1[C:3]([C:4]([Cl:6])=[O:5])=[C:7]([I:16])[C:8]([NH:15][C:17](=[O:19])[CH3:18])=[C:9]([I:14])[C:10]=1[C:11]([Cl:13])=[O:12]
Reactant: CC(=O)Cl
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 8 h
Yield: 99 %

Procedure:
To 2,4,6-triiodo-5-amino-isophthalic acid dichloride (150 g; 0.252 mole) in DMAC (300 ml) is added acetyl chloride (80 ml; 4 times the theoretical amount). The mixture is stirred overnight in an ice-water bath. It is then poured over water (1.5 liter). The resulting material is then filtered and washed twice with water, after which it is dried in an oven at 45° C, to give 159 g of product (i.e., in a yield of 99%).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(Cl)CCl.[C:17]([O:21][C:22]([N:24]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32](O)=[O:33])[S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32]([O:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:33])[S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(CO)OCc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of benzyl 2-hydroxyacetate (0.234 g, 1.410 mmol), EDC (0.541 g, 2.82 mmol) and DMAP (0.086 g, 0.705 mmol) in DCM (25 ml), 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoic acid (0.487 g, 1.410 mmol) was added, and the reaction was stirred at RT for 1 hour. The mixture was washed with HCl 1N and with NaHCO3 5%; the organic phase was dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=80:20 to 70:30) to give 2-(benzyloxy)-2-oxoethyl 3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-4-methoxybenzoate (0.508 g, 1.029 mmol, 73.0% yield, MS/ESI+ 515.9 [MNa]+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[O:19])[CH2:3]1
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1C[C@H](C(=O)OCc2cccc(C(F)(F)F)c2)N(Cc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of (2R,4R)-3-(trifluoromethyl)benzyl 4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D81) (469 mg, 1.05 mmol) in dry DCM (10 ml) was treated with Dess-Martin periodinane (0.57 mg, 1.34 mmol) and stirred at RT 4 hrs. The reaction was quenched with 10% aqueous sodium sulphite solution (10 ml) and extracted with EtOAc (3×10 ml). The organic phases were collected, washed with NaCl sat. sol, dried over Na2SO4 and evaporated to afford a residue which was purified by SPE-Si cartridge (10 g) eluting with a mixture cHex/EtOAc 90/10. Collected fractions after solvent evaporation afforded the title compound (D83) (290 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=4[F:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(F)cccc4F)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,6-difluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=597.6)=80%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:10]=1[CH:11]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(Cl)Cl.O>[F:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:10]=1[CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(F)c(CNc2ccccc2)c(F)c1
Temperature: 70 °C
Yield: 100 %

Procedure:
A mixture of aniline (3.80 mL, 41.7 mmol), 2,4,6-trifluorobenzaldehyde (7.35 g, 45.9 mmol) and glacial acetic acid (6.0 mL, 104.4 mmol) in dichloroethane (100 mL) was heated at 70° C. for 2.5 h. After cooling to rt, sodium triacetoxyborohydride (17.7 g, 83.5 mmol) was added and the mixture stirred at rt for 1.5 h, before the cautious addition of H2O (100 mL), followed by 10M aqueous NaOH (30 mL) and DCM (50 mL). The phases were separated, and the aqueous phase was extracted with DCM (2×100 mL), the combined organic phases were washed with brine (50 mL) and concentrated in vacuo. Purification by gradient column chromatography eluting with 0-6% EtOAc in iso-hexane yielded the title compound (9.90 g, 41.7 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][O:7][N+:8]([O-:10])=[O:9])[C:3](Cl)=[O:4].[C:12]([CH:15]1[CH2:19][S:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:16]1)([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:12]([CH:15]1[CH2:19][S:18][CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]1[C:3](=[O:4])[C:2]([CH3:11])([CH3:1])[CH2:6][O:7][N+:8]([O-:10])=[O:9])([OH:14])=[O:13]
Reactant: CC(C)(CO[N+](=O)[O-])C(=O)Cl
Reactant: O=C(O)C1CSC(c2ccccc2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO[N+](=O)[O-])C(=O)N1C(C(=O)O)CSC1c1ccccc1
Reaction time: 0.75 h
Yield: 38 %

Procedure:
A solution of 5.2 g of 2,2-dimethyl-3-nitroxypropanoyl chloride in 100 ml of tetrahydrofuran was added at 0° C. under nitrogen to a solution of 6.0 g of 4-carboxy-2-phenylthiazolidine and 4.0 g of potassium carbonate in a mixture of 50 ml of tetrahydrofuran and 150 ml of water. After stirring the resulting solution for 45 minutes the mixture was concentrated under reduced pressure to about 150 ml and then acidified to pH=2 with citric acid. The resulting mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate and evaporated. The residue was purified by chromatography (silica, petroleum ether 60-80: ethyl acetate: acetic acid/8:8:1). Yield 38%. Empirical formula C15H18N2O6S. Molecular weight 354. Melting point 35°-38° C. TLC system: petroleum ether 60-80: ethyl acetate: acetic acid/4:4:1. Rf 0.50.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[CH2:33][OH:34].O>CN(C=O)C>[OH:34][CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][N:27]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: OCC1CCCCN1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 49.3 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 2-piperidinemethanol (191 mg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2—(hydroxy-methyl)piperidinomethyl]phenyl]-3—(4-methylphenyl)cinnamamide (Compound 68) (120 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:25])=[O:15])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylic acid (33.00 g), methyl iodide (8.5 mL), potassium carbonate (18.88 g) and N,N-dimethylformamide (300 mL) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (33.48 g, yield 97%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 53-54° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[C:6]([O:12][CH3:13])[CH:5]=1.O.CC(=CC)C.[O-:21]Cl=O.[Na+]>C(O)(C)(C)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:21])=[O:11])=[C:6]([O:12][CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
To a stirred solution of 4-formyl-3-methoxy-benzoic acid methyl ester (5.0 g, 26 mmol) in tert-butyl alcohol (200 mL) was added NaH2PO4-2H2O (3.6 g, 26 mmol), water (50 mL), 2-methyl-2-butene (11 mL, 104 mmol), and finally NaClO2 (7.02 g, 78 mmol). The reaction was allowed to stir at room temperature for 4 hours. The solvent was then removed under reduced pressure. The crude reaction mixture was then dissolved in DCM (200 mL) and the product was extracted with 1N NaOH (200 mL). The aqueous layer was washed with DCM (200 mL) and then neutralized with 6N HCl (˜40 mL) and the product extracted with DCM (200 mL). The organic layer was then washed with water (100 mL), NaCl (sat.) (100 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was sufficiently pure to use without further purification. The product, 2-methoxyterephthalic acid 4-methyl ester, was obtained in 47% yield (2.4 g, 12.3 mmol).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].OS(O)(=O)=O.O>C(O)(C(F)(F)F)=O>[C:12]([C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.3 %

Procedure:
2-Trifluoromethyl-phenol (2.98 g, 18.3 mmol) was dissolved in 12 mL TFA and t-butanol (1.43 g, 19.3 mmol) and H2SO4 (0.24 mL) were added. The reaction was stirred at rt for 48 hrs, after which water was added and the compound was extracted into DCM. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2/1 Hex/EtOAc) to yield 2.01 g of the target compound.
Reaction SMILES: CO[C:3]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:4]=1[CH2:5][CH:6]([C:12]([O:14]CC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[K+]>C(O)C.O>[CH2:10]([O:9][C:7]([CH:6]([CH2:5][C:4]1[CH:3]=[CH:20][C:19]2[O:21][CH2:22][O:23][C:18]=2[CH:17]=1)[C:12]([OH:14])=[O:13])=[O:8])[CH3:11]
Reactant: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(=O)O
Yield: 98.5 %

Procedure:
To a solution of the diethyl 2-(2-methoxy-4,5-methylenedioxybenyl)-malonate (20.0 g, 0.066 mol) of in ethanol (50 ml) was added a solution of potassium hydroxide (3.5 g, 0.066 mol) in water (25 ml). The solution was stirred at reflux for 6 h. After concentrating the aqueous layer was washed with ether and acidified with concentrated HCl to pH 1 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a yellow solid (17.3 g, 89%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[CH3:12]>C1COCC1>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]([CH3:12])=[C:5]([CH2:4][CH2:3][OH:2])[CH:10]=1
Reactant: COC(=O)Cc1cc(N)ccc1C
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1CCO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (5-amino-2-methyl-phenyl)-acetic acid methyl ester 49 (1.4 mmol) in THF (7 mL) at 0° C. is added 1M lithium aluminum hydride THF solution (1.4 mmol). The reaction is stirred at rt for 6 h and subsequently quenched with ice water and partitioned with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and reduced to dryness to yield 2-(5-amino-2-methylphenyl)ethanol 50 as tan crystalline solid, which is used without further purification.
Reaction SMILES: C([Si]([O:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:33])/[CH2:26][CH2:27][CH:28]1[O:32][CH2:31][CH2:30][O:29]1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[O:29]1[CH2:30][CH2:31][O:32][CH:28]1[CH2:27][CH2:26]/[C:25](/[CH3:33])=[CH:24]/[CH:23]=[CH:22]/[CH2:21][CH2:20][CH2:19][OH:18]
Reactant: C/C(=C\C=C\CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCC1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C/C(=C\C=C\CCCO)CCC1OCCO1
Reaction time: 11 h
Yield: 87.6 %

Procedure:
(4E,6E)-9-[1,3]Dioxolan-2-yl-7-methyl-nona-4,6-dien-1-ol was synthesized in the following manner. A solution of tert-butyl-(4E,6E)-(9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dienyloxy)-diphenyl-silane (3.35 g, 7.28 mmol) in 75 mL of THF was cooled to 0° C. and treated dropwise with 10 mL of a 1 M solution of TBAF in THF. The reaction mixture was stirred at 0° C. to room temperature for 11 hours, quenched with a saturated NaHCO3 solution, extracted with Et2O, dried (Na2SO4), and concentrated. Purification of the residue by column chromatography on SiO2 (2:1 hexanes-EtOAc) provided 1.44 g (6.38 mmol, 88%) of oily (4E,6E)-9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dien-1-ol: 1H NMR δ6.28 (dd, 1H, J=14.9, 10.9 Hz), 5.84 (d, 1H, J=10.7 Hz), 5.59 (dt, 1H, J=14.4, 7.0 Hz), 4.86 (t, 1H, J=4.7 Hz), 4.00-3.80 (m, 4H), 3.67 (t, 2H, J=6.5Hz) 2.50-2.38 (m, 1H), 2.25-2.10 (m, 4H), 1.80-1.75 (m, 2H), 1.75 (s, 3H), 1.68 (p, 2H, J=6.7 Hz).
Reaction SMILES: [N:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[N:3][CH:2]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1cnc2ncncc2c1
Product: Clc1ncnc2ncccc12

Procedure:
A mixture of 17.8 g of Pyrido[2,3-d]pyrimidin(4(3H)one and 200 mL of POCl3 was stirred under reflux for one hour. Excess POCl3 was removed under vacuum, and then CH2Cl2, ice, and water were added. A black solid dissolved slowly. The organic layer was then separated, washed with aqueous NaHCO3, and dried over Na2SO4. Solvent was then removed under vacuum to leave a yellow solid, which was recrystallized from toluene/hexane. M.P. 137° dec.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[C:8]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11]>C(O)C>[C:8]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11]
Reactant: CC1(C)CC(OC(=O)CC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=CN1C(C)(C)CC(OC(=O)CC(=O)OC2CC(C)(C)N(C=CC(=O)OCC)C(C)(C)C2)CC1(C)C
Yield: 60 %

Procedure:
150 g of ethyl propiolate were added dropwise to a solution of 270 g of bis(2,2,6,6-tetramethyl-4-piperidinyl) malonate in 400 ml of ethanol at 60° C. The mixture was then refluxed for 4 hours. The solvent was removed by distillation under reduced pressure, and recrystallization of the resulting residue from isopropanol yielded 245 g of the compound of the formula shown below in the form of a colorless solid of melting point 100°-102° C. ##STR23##