Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:8][S:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5].CC(C[AlH]CC(C)C)C.CC(O)C.C(=O)=O>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:7]2[C:6]([CH:4]=[O:5])=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9][N:8]=2)=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=Cc1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 14 (359 mg) in 4 ml of THF is cooled to −78° C. under N2 and to this is added 1.5 ml of DIBALH (1M in hexane). After stirring for 30 min at −78° C., only starting material is observed. The iPrOH/CO2 bath is replaced for an ice bath and stirring is continued at 0° C. for 2 h. TLC shows complete conversion. The mixture is re-cooled to −78° C. and the reaction mixture is quenched with 1N HCl (5 ml). The cooling bath is removed and the reaction mixture is diluted with 1N HCl (50 ml) and EtOAc (50 ml). The layers are separated and the organic layer is washed once more with 1N HCl (50 ml). The organic layer is washed with brine, dried and concentrated. 286 mg of 15 are obtained as a white solid with melting point: 148-149° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].CC(=O)C(=[O:14])C.[C:16]1(C)C=C[CH:19]=[CH:18][CH:17]=1>CO>[CH3:16][C:17]1[N:9]=[C:3]2[C:4](=[N:8][C:18]=1[CH3:19])[N:5]=[CH:6][N:7]=[C:2]2[OH:14]
Reactant: Nc1ncnc(Cl)c1N
Reactant: CC(=O)C(C)=O
Reactant: Cc1ccccc1
Solvent: CO
Product: Cc1nc2ncnc(O)c2nc1C
Yield: 72 %

Procedure:
A mixture of 6-chloropyrimidine-4,5-diamine (1.4 g, 10 mmol) and 2,3-butanedione (2.0 g, 23 mmol) in toluene (35 mL) and methanol (10 mL) was stirred at reflux for 1 h. Upon cooling, the product precipitated and was collected by suction filtration and rinsed with a MeOH/Et2O mixture (ca. 1:2), then air dried to afford 6,7-dimethylpteridin-4-ol (1.4 g, 72%) as a gold powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:5][CH:4]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.Cl>O.C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:24])[C:13]2=[O:23])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccn(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: COc1ccc2ccn(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2c1

Procedure:
A mixture of 0.2 g 1B, 0.25 g potassium carbonate and 15 ml acetonitrile is treated with 0.2 g methyl iodide at room temperature. After stirring over night the mixture is poured into water, acidified with aqueous hydrochloric acid and extracted with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[CH3:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[S:38])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 87%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[CH3:32][S:29]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)(=[O:31])=[O:30]
Reactant: O=C(N[C@H](CO)C[C@H]1CCCOC1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H](C[C@H]1CCCOC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 138.5 %

Procedure:
To a solution of benzyl (5)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (26 g, 69.99 mmol) and triethylamine (21.21 g, 210 mmol) in CH2Cl2 at 0° C. was added mesyl chloride (16.1 g, 140 mmol) dropwise. The reaction mixture was stirred at room temperature until the staring material disappeared. The reaction was quenched with ice-cold water, extracted with CH2Cl2 (3×100 ml), washed with water (3×50 ml), dried over Na2SO4, and concentrated in vacuo to give the product (36 g), which was used for the next step without purification.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[NH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][C:25]1[C:26]([I:40])=[C:27]([CH2:33][CH:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36])[C:28]([I:32])=[CH:29][C:30]=1[I:31])=[O:23])=[O:15]>O>[C:35]([CH:34]([CH2:38][CH3:39])[CH2:33][C:27]1[C:26]([I:40])=[C:25]([NH:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[CH2:13][N:12]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][N:9]([CH2:2][C:3]([OH:5])=[O:4])[CH2:8][CH2:7][N:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:2][C:3]([OH:5])=[O:4])[C:30]([I:31])=[CH:29][C:28]=1[I:32])([OH:37])=[O:36]
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CNCCNCCN)c1I)C(=O)O
Reactant: O=C(O)CBr
Solvent: O
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O)c1I)C(=O)O
Yield: 41.3 %

Procedure:
According to the procedure described in Example 1, 52.1 g of bromoacetic acid (0.375 mol) are reacted with 62 g of compound (B) 3-[6- [[[2-[(aminoethyl)amino]ethyl]amino]acetylamino]-1-oxohexyl]amino-α-ethyl-2,4,6-triiodobenzenepropanoic acid (0.075 mol) in 400 ml of H2O. 32.9 g of 18-[[3-(2-carboxybutyl)-2,4,6-triiodophenyl]amino]-3,6,9-tris(carboxymethyl)-11,18-dioxo-3,6,9,12-tetraazaoctadecanoic acid (0.031 mol) are obtained.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P([O-])([O-])(O)=O.[Na+].[Na+].[Br:20]Br>O.C(O)(=O)C>[C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:20])=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1ccccn1
Reactant: BrBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)Nc1ccc(Br)cn1
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To 53.6 g of an aqueous solution containing 0.2 mol of 2-butanamido pyridine (If), a solution containing 71 g (0.5 mol) of disodium hydrogenphosphate dissolved in 490 g of water was added. To this mixture, a solution containing 54.2 g (0.34 mol) of bromine dissolved in 54 g of acetic acid was added with stirring at 10°-17° C. for 5 hours. After having been stirred at room temperature for one hour and then at 60° C. for one hour, the mixture was cooled. The crystal precipitated thereby was filtered. After the crystal was washed with water and dried, 43.7 g (yield: 89.8%) of 2-butanamido-5-bromopyridine (IIf) was obtained as a pale brown crystal.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OC)(C)(C)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:14]
Reactant: COc1cccc(CO)c1F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1cccc(CCl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.79 g (158.75 mmol) of 2-fluoro-3-methoxybenzyl alcohol is dissolved in 35 ml of dichloromethane. While being cooled slightly, 58.4 ml of thionyl chloride is added in drops, and the batch is then stirred overnight at room temperature. The reaction mixture is spun in until a dry state is reached, the residue is dissolved in methyl tert-butyl ether, and it is shaken twice with semi-saturated potassium carbonate solution. The aqueous phase is extracted once with methyl tert-butyl ether. The combined organic extracts are worked up as usual. The residue that is obtained is incorporated in crude form into the next stage.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C@H:14]1(O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1.O>[C@@H:14]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: O[C@@H]1CCc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(O[C@H]2CCc3ccccc32)cc1
Temperature: -30 °C
Reaction time: 23 h
Yield: 67.5 %

Procedure:
Methyl 4-hydroxybenzenepropanoate (4.1 g, 22 mmol) was dissolved in tetrahydrofuran (50 mL) and the mixture was stirred at −30° C. (R)-1-Indanol (98% ee) (3.0 g, 22 mmol), 1,1′-(azodicarbonyl)dipiperidine (5.66 g, 22 mmol) and tributylphosphine (5.6 mL, 22 mmol) were added and the mixture was stirred at −30° C. for 23 hrs. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure and the obtained oil was purified by silica gel chromatography (hexane to hexane/ethyl acetate=10:1) to give the title compound (4.4 g, yield 66%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[Na+].Cl>>[Cl:1][C:2]1[NH:10][C:9](=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(=O)[nH]c1Cl
Temperature: 129 °C
Yield: 88 %

Procedure:
A 500-mL round-bottom flask was charged with 2,6-dichloronicotinic acid (25.0 g, 130 mmol), NaOH solution (325 mL, 2N) and the solution was refluxed at 129° C. for 4 hours. The reaction mixture was cooled to room temperature and acidified with a 6N aq. HCl solution. The resulting precipitate was filtered and dried under reduced pressure yielding to the desired product (19.87 g, 88%).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2C=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[K].[Na].I[CH3:22].[CH2:23]([CH2:26]OC)OC>>[CH3:5][CH:18]1[CH:17]=[C:16]2[C:7](=[N:8][C:9]3[C:14](=[N:15]2)[CH:13]=[CH:12][CH:11]([CH3:22])[CH:10]=3)[C:6]2[CH:1]=[CH:2][CH:3]=[CH:23][C:26]1=2
Reactant: CI
Reactant: COCCOC
Reactant: c1ccc2c(c1)ccc1nc3ccccc3nc12
Agent: [K]
Agent: [Na]
Product: CC1C=Cc2nc3c(nc2=C1)-c1ccccc1C(C)C=3

Procedure:
This phenazine was reduced with a 3:1 potassium/sodium metal alloy in dimethoxyethane, to the brick red alkali metal adduct. Alkylation occurred over 1 hour with addition of iodomethane. Residual K/Na alloy was quenched with addition of ethanol. The product was isolated with column chromatography and was recrystallized from ethylacetate/hexane. 2.0 grams of product was isolated for a 38% overall yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1COCC1.C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>CCCCCCC>[CH3:21][Si:20]([CH3:23])([CH3:22])[N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a flask equipped with a reflux condenser, a nitrogen inlet, mechanical stirrer, and a thermowell was charged 4-iodopyrazole (200 g, 1.03 mol) and THF (2 L) at ambient temperature. To this solution was added triethylamine (TEA, 158 mL, 1.13 mol, 1.1 equiv) and the resulting solution was cooled to 0° C. in an ice-brine bath. To this solution was added chlorotrimethylsilane (TMS-Cl, 137 mL, 1.08 mol, 1.05 equiv) with vigorous stirring allowing the temperature to reach 18° C. (The reaction becomes very thick and difficult to stir, but becomes manageable after over time). When the exothermic process had subsided, the cold bath was removed and the reaction was warmed to room temperature. The reaction was followed by GC and was found to be deemed complete after about 1 hour (sampling of reaction must be done out of air and diluted with dry solvent to prevent TMS hydrolysis). The reaction mixture was then diluted with n-heptane (2 L) before being filtered under nitrogen. The solvent was removed from the filtrate under reduced pressure venting the rotovap with nitrogen. The residual oil was diluted with n-heptane (1 L) and re-concentrated. If the solids formed upon adding the n-heptane, a second filtration was necessary. The residue was then distilled under the reduced pressure (70-90° C. at about 0.5 Torr) using a Kugelohr to afford 1-trimethylsilyl-4-iodopyrazole (263 g, 274.1 g theoretical, 96%) as a colorless oil. This material must be kept under nitrogen at all times since the TMS group rapidly hydrolyzes. Subsequently, it was found that 1-trimethylsilyl-4-iodopyrazole can be prepared by heating the iodopyrazole with 2 equivalents of hexamethyldisilazane for 1 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[C:14]([CH2:16]C(OC)=O)#[N:15].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[C:10]([OH:12])[C:16]([C:14]#[N:15])=[C:7]2[OH:9]
Reactant: COC(=O)CC#N
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(O)nc2ccc(Cl)cc2c1O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 300 ml, three neck flask, equipped as described in Example 1, was charged with 39.5 g 5-chloroisatoic anhydride (molecular weight 198.5:assay 95 percent), 21.8 g methyl cyanoacetate, 150 ml triethylamine and four drops of DMF. Agitation was commenced, and continued until reaction was discontinued. A slight exotherm caused the temperature of the reaction mixture to increase from 20° C. to about 38° C., and to remain at about 38° C. for approximately one hour, during which time there was a steady and vigorous evolution of gas. At the end of one hour the temperature began to drop, and the rate of gas evolution slowed as the consistency of the reaction mixture became jelly-like. The reaction mixture was then heated to a temperature of 90° C. and maintained at a temperature within the range of 85° to 90° C. for one-half hour. The heating to 90° C. occurred over a period of one-half hour. The temperature of the reaction mixture was then raised to approximately 100° C., and maintained at about such temperature for an additional 30 minutes. Gas evolution reached a maximum during the time that the reaction mixture was at a temperature between 85° and 100° C. and then gradually decreased and stopped. The reaction mixture became jelly-like and gummy during the time that the temperature was being maintained between 85° and 90° C.; to facilitate stirring a 20 ml addition of DMF was made when this occurred. After the reaction mixture had been maintained at approximately 100° C. for one-half hour, agitation was stopped and the reaction mixture separated into an upper colorless layer consisting mainly of triethylamine and a lower layer of a tan oil. The excess of triethylamine was recovered by distillation, after which the oily remainder was dissolved in 700 ml water and treated with 3 g activated charcoal at reflux. Concentrated hydrochloric acid at a temperature of 60° to 70° C. was then added to the beaker to bring the pH to 1.0 and to form a precipitate. The precipitate was recovered by filtration; the filter cake was washed with water, was reslurried in warm water, refiltered, and finally dried at 60° C. The yield was 39.34 g (93.9 percent of theory based upon the pure 5-chloro-isatoic anhydride charged) 6-chloro-3-cyano-2,4-dihydroxyquinoline, melting point 275°-277° C. Examination of the product by infrared spectroscopy and nuclear magnetic resonance indicated that it was of high purity.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7]([C:11]2[NH:12][C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:15]=23)[CH2:8][CH:9]=[CH2:10])[S:5][CH:6]=1.C[N+]1([O-])CC[O:35]CC1.[OH2:39]>C(#N)C.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]([C:11]2[NH:12][C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:15]=23)[CH2:8][CH:9]([OH:35])[CH2:10][OH:39])[S:5][CH:6]=1
Reactant: O
Reactant: C=CCC(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO)c3nc(Cl)cs3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
Osmium tetroxide (2.5% w.t., 2.032 mL, 0.162 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)but-3-en-1-yl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (720 mg, 1.618 mmol) and N-methyl morpholine oxide (284 mg, 2.427 mmol) in acetonitrile (20 mL,) and water (2 mL). The mixture was stirred at room temperature for 105 mins. The reaction was quenched with saturated aqueous sodium metabisulfite solution and extracted with chloroform (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7]([CH2:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:30](OCC)C.Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7]([CH2:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:30])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Agent: Cl
Solvent: CO
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 48 h
Yield: 90 %

Procedure:
A solution of 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid [Example 8] (0.5 g) was dissolved in methanol (100 mL) and treated with excess diethyl ether saturated with dry hydrochloric acid. The mixture was kept at 25° C. for 48 hours. The solvents were evaporated, the residue dissolved in a small amount of methanol. Crystallization was induced with diethyl ether. The solid was collected, washed with diethyl ether, and dried to afford 0.47 g (90%) of the title compound; mp 118.5°-120.5° C.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:13](=[O:48])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:45]([CH3:46])[CH3:47])[C:29](=[O:44])[C:30]([F:43])([F:42])[C:31](=[O:41])[NH:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccccc1
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
To a solution of 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-phenethylcarbamoyl)propyl]acetamide (0.451 g) in dichloromethane (7 mL) and anisole (0.22 mL) was added trifluoromethanesulfonic acid (0.30 mL). After 1.5 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, and the extracts were washed (saturated sodium bicarbonate, brine), dried, and evaporated. The crude product was purified by chromatography, twice, with dichloromethane:methanol (first column: gradient, 99:1, 92:8; second column: gradient, 99:1, 92:8) as the eluent. The resulting material was crystallized from ether and petroleum ether to give the title compound (0.119 g) as a tan solid; TLC: Rf =0.27, dichloromethane:methanol (98:2); 300 MHz NMR: 9.20 (t,1), 8.42 (d,1), 7.38-7.18 (m,10), 6.51 (d,1), 5.97 (d,1), 5.15 (d,2), 4.80 (dd,1), 4.43 (broad s,2), 3.43- 3.29 (m,2), 2.76 (t,2), 2.29-2.13 (m,1), 0.85 (d,3), 0.74 (d,3); MS: m/z=525(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:7]([C:5]5[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)[nH]n1
Yield: 71 %

Procedure:
In the same manner as in Example 261 and using 3-methyl-1H-pyrazole-5-carboxylic acid (160 mg, 1.2 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2 mmol), triethylamine (190 mg, 1.9 mmol) and N,N-dimethylformamide (3 mL) as starting materials, the title compound (190 mg, 70%) was obtained as a white solid.