Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([O:10][CH3:19])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(=Cc1ccc(O)cc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)=Cc1ccc(O)cc1

Procedure:
To 4-hydroxy-α-methylcinnamic acid (55 g), absolute methanol (400 ml) and conc. sulfuric acid (10 ml) were added and refluxed for 12 hours. After the reaction mixture was allowed to cool, it was concentrated under reduced pressure. To the residue was added water (300 ml), and the mixture was neutralized with sodium hydrogen carbonate, and the resulting precipitate was collected by filtration, washed with water, and recrystallized from ethyl acetate/nhexane to give methyl 4-hydroxy-α-methylcinnamate (53 g). mp. 103°-104° C.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])CC2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCN(CCCCc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)CCNCCCCc1ccccc1

Procedure:
27.13 g (0.085 mol) of this hydrochloride are hydrogenated in 300 ml of ethanol over 3 g of 5% palladium-on-charcoal catalyst at 20°-25° under normal pressure until the uptake of hydrogen has ended. The catalyst is filtered off with suction, the filtrate is evaporated and the residue is crystallized from acetone. 3-[N-(4-Phenylbutyl)-amino]-propionic acid hydrochloride is obtained, melting point 135°-137°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([OH:37])(=[S:36])[CH3:35].[CH2:38]([N:45]1[CH2:48][CH:47](O)[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([N:45]1[CH2:48][CH:47]([S:36][C:34](=[O:37])[CH3:35])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: OC1CN(Cc2ccccc2)C1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Triphenylphosphine (3.08 g, 11.76 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (30 ml). Oxygen was completely removed by passing nitrogen through the mixture, and the mixture was cooled to 0° C. Diisopropylazodicarboxylate (2.3 ml, 11.76 mmol) was added thereto, and stirred at 0° C. for 1 hour. Added slowly to the mixture in succession were thioacetic acid (840 μl, 11.76 mmol) and 1-benzyl-azetidine-3-ol (960 mg, 5.88 mmol) prepared in Preparation Example 37 and dissolved in tetrahydrofuran (20 ml). The resulting solution was heated to room temperature, stirred for 2 hours and concentrated under a reduced pressure to remove the solvent. The concentrate was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue was purified by column chromatography (eluent−ethyl acetate/normal hexane=1/1) to obtain 1.1 g (yield: 83%) of the title compound.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=4)(=[O:28])=[O:27])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3=CCN4CCCC4C3)c3cnccc32)cc1

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 4-methyl-benzenesulfonyl chloride (20 mg, 0.105 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([O:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:23]=[C:22]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1OCc1ccccc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cccn2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74.7 %

Procedure:
To 0.180 g pyrazole in 5 mL DMF is added 0.105 g NaH. After stirring 50 minutes at room temperature, 0.200 g of the material from Step A, above, is added all at once with 5 mL DMF. After 2 hours at room temperature, the reaction is quenched with water and Concentrated in vacuo. The residue is redissolved in ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography eluting with toluene provides 0.181 g (74.8%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.[I:11]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([I:11])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccnc(N)c1C#N
Solvent: CN(C)C=O
Product: Cc1c(I)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 4, using 8.3 grams (0.063 mole) of 2-amino-3-cyano-4-methylpyridine (prepared as in Step B of Example 4) and 14.2 grams (0.063 mole) of N-iodosuccinimide in 250 mL of N,N-dimethylformamide, yielding 2-amino-3-cyano-5-iodo-4-methylpyridine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(N(CC)CC)C.C(=O)=O>CCOCC>[C:2]1([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: Ic1ccccc1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: c1ccc(-c2cccs2)cc1
Reaction time: 64 h
Yield: 49 %

Procedure:
Bis{di(1H,1H,2H,2H-perfluorooctyl)phenylphosphino}palladium dichloride (89 mg, 0.05 mmol), iodobenzene (0.11 ml, 1 mmol), thiophene-2-boronic acid (128 mg, 1 mmol) and triethylamine (0.15 ml, 1.1 mmol) were placed in a 10 ml stainless steel cell. The cell was sealed and pressurised to approximately 5520 kPa (800 psi) (i.e. full of carbon dioxide). The cell was then heated to 100 C. for 64 hrs and then allowed to cool. When the pressure had dropped below 13800 kPa (2000 psi) the cell was vented into ether (100 ml), the cell was opened once atmospheric pressure was reached and washed out with dichloromethane (20 ml). The organic fractions were combined and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography on silica gel, eluting with hexane to give a white crystalline solid (78 mg, 0.49 mmol, 49%); δH (250 MHz; CDCl3) 7.09-7.66 (8H, m, aryl and thienyl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:14]2[CH:15]=[CH:16][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:12][CH:13]=2)[CH:20]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.Cl.CN([CH:20]=[O:21])C>>[CH:20]([C:10]1[S:6][C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)=[O:21]
Reactant: c1csc(-c2cccs2)c1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In a round bottom flask, phosphorus oxychloride (1.83 g) was added at 0° C. to 15 mL of DMF. After 30 minutes, 2,2′-bithiophene (500 mg) was further added and the solution stirred at room temperature for 30 minutes before heating to 50° C. until completion. Diluted hydrochloric acid was added at 0° C., the solution warmed to room temperature and the crude product extracted with ethyl acetate. Purification by flash chromatography (SiO2) yielded the title product as a light brown powder (81%). 1H-NMR (300 MHz, [D] acetone): δ=9.89 (s, 1H), 7.70 (d, 1H, 3J=3.9 Hz), 7.39 (d, 2H, 3J=4.3 Hz), 7.28 (d, 1H, 3J=3.9 Hz), 7.11 (t, 1H, 3J=4.4 Hz). 13C-NMR (50 MHz, [D] acetone): δ=183.0, 147.6, 142.1, 137.8, 136.5, 128.8, 127.5, 126.6, 124.7. EI-MS: m/z ([M]+, 100%).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=1)[CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[CH2:11]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[C:19]=1[CH:4]=[O:5])[CH2:12][CH2:13][CH3:14]
Reactant: CN(C)C=O
Reactant: CCCCc1cc2ccccc2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of DMF (59 g, 0.805 mol) in anhydrous DCM (300 mL) was added slowly at 0° C. under N2 atmosphere phosphorous oxy-chloride (123 g, 0.84 mol). The mixture was stirred at rt for 2 h. To this was added slowly 2-butyl-1-benzofuran (35 g, 0.21 mol) in anhydrous DCM (100 mL). The reaction mixture was slowly heated to 60° C. for 72 h, cooled to rt and poured into ice and extracted with EtOAc. The organic layer was washed with water, brine and dried over MgSO4. The solvent was removed under vacuum and the crude product purified by column chromatography over silica gel (PetEther/EtOAc) to give 2-butyl-1-benzofuran-3-carbaldehyde (30 g, 74%) as a light brown liquid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](F)=[O:19].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])[OH:28])[OH:26].C(=O)(O)[O-].[Na+].Cl>CC(C)=O.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([O:23][C@@H:24]1[O:32][C@H:31]([C:33]([OH:35])=[O:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]1[OH:26])=[O:19]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 61.1 %

Procedure:
Retinoyl fluoride (2.4 g, 7.9 mmol) was dissolved in 200 ml of acetone. D-glucuronic acid (6 g, 31 mmol) dissolved in 50 ml of water and sodium bicarbonate (970 mg) dissolved in 50 ml of water were added to the retinoyl fluoride solution. The mixture was stirred at room temperature for 20-24 hrs. The solution was neutralized with 1N HCl, diluted with water, and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness in a rotary evaporator. The residue was dissolved in 2-3 ml of diethyl ether and transferred to a silica gel (for dry column chromatography, wet packed with hexane) column. The column was developed with hexane containing diethyl ether (5-50%) to remove retinoic acid and other products. The major yellow band containing retinoyl glucuronide was next eluted with a mixture of CH2Cl2 /CH3OH (1:1). The solvent was evaporated to dryness to give solid retinoyl β-glucuronide (2.3 g, 60%). This preparation consisted mainly of the all-trans isomer, and can be used as such.
Reaction SMILES: C([N:3](CC)CC)C.[CH3:8][C:9](C)([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10](O)=O.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[CH3:8][C:9]([NH2:3])([CH3:10])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(CC(C)(C)C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46.2 %

Procedure:
Triethylamine (16.8 g, 166 mmol) and 2,2-dimethyl-3-(4-methoxyphenyl)propionic acid (32.6 g, 157 mmol) were dissolved in 30 mL of water and enough acetone to maintain solubility at 0° C. A solution of ethyl chloroformate (20.1 g, 185 mmol) in acetone (100 mL) was then added dropwise. An aqueous solution (95 mL) of sodium azide (12.9 g, 198 mmol) was then added dropwise and the resulting reaction mixture stirred 45 minutes at room temperature. The intermediate acyl azide was then extracted into toluene (200 mL). The organic extract was washed with water, dried over anhydrous magnesium sulfate, and heated at 100° C. until the evolution of nitrogen ceased (˜45 min). The toluene was removed under vacuum and replaced with benzyl alcohol. The solution was then heated at 100° C. for 16 hours. The excess benzyl alcohol was removed under vacuum. The resulting benzyl carbamate was dissolved in absolute ethanol (200 mL) and reduced in the presence of palladium hydroxide (2 g) under 90 p.s.i. hydrogen for 4 hours at room temperature. The reaction was filtered and concentrated to a yellow oil. Vacuum distillation afforded 13.0 g of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 180 (M+1, 1), 164 (5), 121 (25), 91 (5), 78 (19), 58 (100).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][N:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:18]3[CH:19]=[C:14]([N:12]([CH3:13])[CH3:11])[CH:15]=[CH:16][CH:17]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Brc1nn2c(I)cnc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 95 °C
Yield: 21.4 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.150 g, 0.455 mmol, 1 eq), 3-(N,N-dimethylamino)phenylboronic acid (0.113 g, 0.682 mmol, 1.5 eq), Cs2CO3 (0.296 g, 0.909 mmol, 2 eq) and Pd(PPh3)4 (0.032 g, 0.027 mmol, 0.06 eq) were dissolved in Dioxane (8 mL) and water (2 mL). The reaction mixture was heated at 95° C. for 24 h. Additional amounts of 3-(N,N-dimethylamino)phenylboronic acid (1.5 eq) and Pd(PPh3)4 (0.06 eq) were added and the reaction mixture was heated at 95° C. for 3 days. The solvent was removed in vacuo, redissolved in DCM/water (150 mL) and extracted with DCM (2×80 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (20-70% EtOAc in cyclohexane) to afford the desired product (36 mg, 21%) as a yellow solid. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.73 min, [M+H]+ m/z 371.1.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:5]1([CH2:4][O:3][C:1](=[O:2])[NH:11][CH:12]([CH3:13])[C:14](=[O:16])[NH:17][N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nn1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Reaction time: 20 h
Yield: 66 %

Procedure:
To a stirred solution consisting of carbobenzyloxy-D,L-alanine (10.0 g) and N-aminopyrrole (3.68 g) in dry DCM (224 ml) was added DCC (9.71 g) at room temperature under nitrogen. After stirring for 20 hours, the reaction mixture was filtered through a pad of celite and the solid DCU was washed with DCM. Concentration of the filtrate gave the crude product. Purification via flash column chromatography (silica gel, 30% ethyl acetate/hexane) afforded 8.50 g of the product as a solid, m.p. 153°-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:10]2[CH:9]1[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)(O)[O-].[Na+].IC>CN(C)C=O>[CH3:25][O:18][C:17]([C:16]1[N:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH3:24])[C:10]=12)=[O:19]
Reactant: O=C([O-])O
Reactant: CC1c2c(C(=O)O)nc(C(F)(F)F)n2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nc(C(F)(F)F)n2c1C(C)N(C(=O)OC(C)(C)C)CC2
Yield: 137.6 %

Procedure:
8-Methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 39a (0.349 g, 1 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and sodium bicarbonate (0.84 g, 10 mmol) was added to the solution under stirring. Iodomethane (0.43 g, 3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 40 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 39b (0.5 g, yield 100%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Reactant: O=C(O)c1ccncc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)c3ccncc3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 86b) and isonicotinic acid as brown solid (41%). MS 409 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:52]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])=[CH:22][N+:21]=1[O-:52])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 125 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-2-yl]methyl}-L-glutamate (0.19 mmol; see Example XB) in dichloromethane (10 mL) was added 51 mg meta-chloro peroxybenzoic acid (70%), and the mixture was stirred for 3 h at room temperature. The mixture was extracted with aqueous sodium bicarbonate, followed by re-extraction of the aqueous layer with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo, and the residue was purified by preparative HPLC. (Method D) to give 104 mg of the target compound as colourless foam (81% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH2:11])[N:10]=[C:4]2[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][C:21](=[O:23])[CH3:22])[N:10]=[C:4]2[CH:3]=1
Reactant: Nc1nc2cc(Br)ccn2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc2cc(Br)ccn2n1
Temperature: 50 °C
Reaction time: 22 h
Yield: 95 %

Procedure:
To a solution of 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared using the procedure in WO2006038116) (0.150 g, 0.704 mmol), diisopropylethylamine (0.363 g, 2.81 mmol), catalytic DMAP (0.09 g, 0.07 mmol) in anhydrous THF (4 mL) was added acetic anhydride (0.216 g, 2.11 mmol). The reaction mixture was stirred at 50° C. for 22 h under N2 (g). After cooling to room temperature the mixture was concentrated, diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate (40 mL), brine (40 mL), and dried over anhydrous sodium sulfate. Filtration and concentration followed by column chromatography of the residue on silica (95:5 dichlormethane/methanol) afforded N-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (0.170 g, 95% yield) as a brown oil. MS (EI) for C8H7BrN4O: 256 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)c2ccccc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Benzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-benzoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:8](OCC)=[O:9]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH:8]=[O:9]
Reactant: CCOC=O
Reactant: NCCCCCO
Product: O=CNCCCCCO
Temperature: 90 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
2.06 g (20.0 mmol) of 5-amino-1-pentanol was dissolved in 5 mL of ethyl formate and the mixture was stirred at 90° C. for 4 hours. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: ethyl acetate/methanol=100/0-70/30) to obtain 1.90 g (yield: 73%) of the title compound as a pale yellow-oil.