Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([O:14]C)=[O:13])=[CH:4][C:3]=1[Cl:16].[OH-].[Li+].[CH3:19]O>>[CH3:19][C:8]1[N:7]2[C:2]([NH2:1])=[C:3]([Cl:16])[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]2=[N:10][C:9]=1[CH3:11]
Reactant: COC(=O)c1cc(Cl)c(N)n2cc(C)nc12
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Yield: 96 %

Procedure:
A mixture of methyl 5-Amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylate (EXAMPLE 26, Step 4, 10.5 g, 43.9 mmol,) and 1 N lithium hydroxide (87.7 mL, 87.7 mmol) in methanol (100 mL) was stirred under reflux for 1 h. After removal of the solvent in vacuo, the residue was suspended with water and treated with 2 N hydrochloric acid to adjust to pH 4. The resulting solid was filtered, washed with water and diethyl ether and dried in vacuo with heating to give 9.5 g (42.2 mmol, 96%) of the title compound as a brown solid.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12](C(O)=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[C:19]=[O:20].[CH2:21]([CH:23]([NH:26][OH:27])[CH2:24][CH3:25])[CH3:22]>>[OH:27][N:26]([CH:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[C:19]([NH:18][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)=[O:20]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CCC(CC)NO
Reactant: [N-]=C=O
Product: CCC(CC)N(O)C(=O)Nc1ccc(C(=O)c2ccccc2)cc1

Procedure:
Using the method of Compound 76, 4-benzoylbenzoic acid (1.47 g, 6.5 mmole) was converted to the corresponding isocyanate then reacted with N-(1-ethylpropyl)hydroxylamine (1.0 g, 10 mmole) to provide 0.58 g of the desired product as white crystals, m.p. 156°-157° C. Analysis: Calculated for C19H22N2O3 : %C, 69.92; %H, 6.79; %N, 8.58; Found: %C, 69.7; %H, 6.61; %N, 8.64.
Reaction SMILES: C(OC([N:6]([CH2:13][CH:14]([CH3:24])[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[O:7]C(OCC)=O)=O)C.[ClH:25].C(OCC)(=O)C.N>CO.O>[ClH:25].[OH:7][NH:6][CH2:13][CH:14]([CH3:24])[CH2:15][P:16](=[O:17])([OH:23])[OH:20]
Reactant: CCOC(=O)ON(CC(C)CP(=O)(OCC)OCC)C(=O)OCC
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CNO)CP(=O)(O)O

Procedure:
A mixture of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-methylpropylphosphonate (28.3 g.). and conc. hydrochloric acid (280 ml.) was refluxed for 18 hours and then concentrated under reduced pressure to give an oily residue. To the residue was added a mixture of water (100 ml.) and ethyl acetate (100 ml.). From the resultant mixture, the aqueous layer was separated, treated with activated charcoal and concentrated under reduced pressure to give an oily residue. The residue was dissolved in a mixture of methanol (30 ml.) and water (15 ml.). The solution was adjusted to pH 4.0 with aqueous ammonia under ice-cooling and concentrated under reduced pressure to give a residue, which was passed through a column of anion exchange resin, Amberlite IRA-400 (OH- form). The column was washed with water and then the object compound was eluted with 1 N hydrochloric acid. The eluate was concentrated under reduced pressure to give oily hydrochloric acid salt of 3-(N-hydroxyamino)-2-methylpropylphosphonic acid (9.6 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:15]2[CH:16]=[CH:17][C:12]([S:18][CH3:19])=[CH:13][CH:14]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CSc1ccccc1
Product: CSc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and thioanisole.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](O)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[N:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: O=C(O)c1cn(C2CC2)c2nc(O)c(F)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 0.19 g (0.72 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid in 2 ml of phosphorus oxychloride was heated at reflux for one-half hour. The resulting solution was cooled to room temperature and the solvent was removed in vacuo. The residue was triturated with ice water and the resulting solid was removed by filtration, washed with water, then ether, and dried in vacuo to give 0.11 g of the title compound, mp 209°-212° C.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([C:21](=[O:23])[CH3:22])[C:18](F)=[C:17]([F:25])[C:16]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]>C1COCC1>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([C:21](=[O:23])[CH3:22])[C:18]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])=[C:17]([F:25])[C:16]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)c(ON=C(C)C)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
t-BuOK (0.47 mL, 1.0 M in THF) was added to propan-2-one oxime (35 mg, 0.47 mmol). After stirring for 30 minutes, THF (0.5 mL) was added, and the reaction mixture was cooled to −78° C. A solution of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (6) (50.0 mg, 0.147 mmol) in THF (1 mL) was added. The reaction mixture was slowly warmed to 0° C. and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 5-acetyl-2-(2-chlorophenylamino)-3-fluoro-4-isopropylideneaminooxybenzoic acid methyl ester. The recovered oxime was suspended in a 1:1 mixture of 5% aqueous HCl and MeOH (30 mL) and heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (40% methylene chloride in hexanes) provided 17 mg (35% for two steps) of the desired product (7).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N.C([O:17]CC)C>>[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:17]
Reactant: N#Cc1cccc(OC(F)(F)F)c1
Reactant: CCOCC
Agent: Cl
Product: O=Cc1cccc(OC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
103 g (0.544 mol) of stannous chloride and 400 ml of diethyl ether are introduced into a one liter three-necked flask equipped with a condenser, a mechanical stirrer and a gas bubbler tube. This mixture is cooled and saturated with hydrogen chloride gas until the stannous chloride is completely dissolved. A solution of 72.7 g (0.388 mol) of 3-trifluoromethoxy-benzonitrile in 75 ml of anhydrous diethyl ether is added dropwise but fastly via the dropping funnel, while the mixture is cooled with ice-water. The mixture is allowed overnight, then the aldehyde is steam distilled. The distillate is extracted several times with diethyl ether and the extracts are combined. 250 ml of a solution of sodium bisulphite (d=1.32-1.33) are added to the extracts and allowed overnight. The bisulfite compound is filtered off, washed with a small quantity of ice-water and then with diethyl ether. The compound is introduced into a one liter flask which contains solution of 60 g of potassium carbonate in 250 ml of water. The mixture is heated at 100° C. so as to decompose the bisulfite compound and to steam distil the aldehyde as it is formed. The distillate is extracted several times with diethyl ether. The combined ether phases are dried over sodium sulphate and filtered and the solvent is evaporated. 32 g (44% yield) of 3-trifluoromethoxy-benzaldehyde are obtained as a colourless oil.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]12[CH2:18][O:17][C:14]([CH3:19])([O:15][CH2:16]1)[O:13][CH2:12]2.[CH:32]1(C23OCC(CO)(CO2)CO3)[CH2:35]C[CH2:33]1>>[Na:1].[CH:19]1([C:14]23[O:15][CH2:16][C:11]([CH2:10][O:9][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]5[NH:24][C:25]6[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=6[N:27]=5)=[O:22])[C:3]=4[CH3:2])([CH2:12][O:13]2)[CH2:18][O:17]3)[CH2:35][CH2:32][CH2:33]1
Reactant: Cc1c(OCC23COC(C)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: OCC12COC(C3CCC3)(OC1)OC2
Agent: [Na]
Product: Cc1c(OCC23COC(C4CCC4)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 2.3 %

Procedure:
The same procedure as in the steps (24b) to (24f) of Example 24 was repeated using (1-cyclobutyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl)methanol obtained in the step (38a) above to obtain the title compound (56 mg, 2.3%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23]Cl)[N:11]=1)=[O:9].C(Cl)Cl.[OH2:38]>>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:34])([F:33])[F:1])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23][N:7]2[CH2:8][CH2:10][O:38][CH2:5][CH2:6]2)[N:11]=1)=[O:9]
Reactant: O
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(CCl)ncc1-c1ccccc1Cl
Solvent: ClCCl
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(CN2CCOCC2)ncc1-c1ccccc1Cl
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 0.58 g (1.11 mmol) 2-chloromethyl-5-(2-chloro-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml CH2Cl2 0.24 ml (2.78 mmol) morpholine were added. The reaction mixture was stirred for 16 hrs. at RT and than poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 200:10:1) to give 0.40 g (62%) 5-(2-chloro-phenyl)-2-morpholin-4-ylmethyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 573.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[OH:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH2:14][NH2:15].O>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:15][CH2:14][CH:13]([OH:12])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(O)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 0.67 h

Procedure:
A mixture of 1-(4-hydroxyphenyl)propan-2-one (4.6 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (5.2 g) in dry benzene (150 ml) was heated under reflux using a Dean and Stark head until the required amount of water had been collected. The solution was cooled, the solvent evaporated, the residue dissolved in methanol (20 ml), cooled in ice and treated portionwise with sodium borohyride (6.1 g) over 30 minutes. The mixture was stirred for 40 minutes, and the solvent removed under reduced pressure. Water was added to the residue and the mixture adjusted to pH 5 by addition of acetic acid followed by extraction with ethyl acetate. The extracts were washed with water, aqueous sodium bicarbonate and brine, dried (magnesium sulphate), filtered and evaporated to dryness. Chromatography of the residue on silica gel in 5% methanoldichloromethane gave N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine mp 50°-5° C., of analytical purity as a 53:47 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)=[O:6].[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([N:36]=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:15][CH3:16])=[O:6])=[CH:8][CH:9]=2)=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Reactant: CCC(C)COC(=O)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(N=Cc2ccc(C(=O)OCC(C)CC)cc2)cc1

Procedure:
44.3 g of said p-(2-methylbutoxycarbonyl)benzaldehyde, 32 g of p-n-tetradecyloxyaniline, and 0.1 g of p-toluenesulfonic acid were dissolved in toluene. The solution was heated under reflux, and water generated in the dehydrating condensation was removed with a Dean-Stark condenser. After the reaction solution was cooled, the organic layer was washed with water, and the solvent (toluene) was distilled off in vacuum. The solid residue was recrystallized from ethanol to obtain yellow crystals.
Reaction SMILES: C(O)C.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH3:24])=[CH:14][C:13]=1[CH3:25].[S-:26][C:27]#[N:28].[K+].CCCCCC>C(OCC)(=O)C>[S:26]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH3:24])=[CH:14][C:13]=1[CH3:25])[C:27]#[N:28]
Reactant: N#C[S-]
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCBr
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCSC#N
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To 60 ml of ethanol were added 1.87 g (4.68 mmol) of 6-bromohexyl-[2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenyl]ether and 2.28 g (23.46 mmol) of potassium thiocyanate. The mixture was refluxed for 8 hours under heating. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Then extraction was conducted by adding ethyl acetate and water. The organic phase obtained was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=20:1), to obtain 1.37 g (yield: 77%) of an intended product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.[F:8][C:9]1[C:37]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:36][C:12]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[F:8][C:9]1[C:37]([N:38]2[CH2:39][CH2:40][N:41]([C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH2:42][CH2:43]2)=[CH:36][C:12]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=3)[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: COCCC(=O)O
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: COCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
0.020 ml 3-methoxy-propionic acid (0.2 mmol) and 40 mg 1,1-carbonyldiimidazole (0.24 mmol) were refluxed in 4 ml dichloromethane under nitrogen for 40 minutes. 100 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.2 mmol) were added and the resulting mixture refluxed for additional 4.5 h. The reaction mixture was then diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 129 mg yellow solid. This residue was purified by column chromatography (40 g silicagel, dichloromethane/methanol 24:1) leading to 44 mg off-white solid (37%). MS (ISP) 587.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]=1.C(O[C@@H:12]1[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]1[O:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)C.[K].FC(F)(S(O)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C[Si](N[Si](C)(C)C)(C)C>C(OCC)(=O)C.CO.C(#N)C>[C:15]([O:14][C@@H:13]1[C@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:34][C@H:12]1[N:1]1[CH:2]=[CH:3][C:4](=[O:7])[CH:5]=[CH:6]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C1C=CN=CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: O=C(OC[C@H]1O[C@@H](n2ccc(=O)cc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
0.47 g. (5 mmol) of 4-pyridone, 2.52 g. (5 mmol) of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, and 4.06 g. (12 mmol) of the potassium salt of perfluorobutanesulfonic acid were refluxed with 0.29 g. (1.75 mmol) of HMDS and 1.49 g. (13.75 mmol) of TCS in 70 ml. of absolute acetonitrile for 12 hours. The usual working-up step (Example 1) yielded after chromatography on silica gel with ethyl acetate-methanol (95:5) 65% of amorphous 1-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-4-pyridone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:18]3[C:19](=[O:21])[CH2:20][S:16][C:17]3=[O:22])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: ClCCCCSc1cccc2nccn12
Reactant: O=C1CSC(=O)N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 8.35 g (35.4 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 4.15 g (35.4 mmol) of thiazolidine-2,4-dione in 200 ml of N,N-dimethylformamide, 5.30 ml (35.4 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate). The resulting crude crystal was purified by recrystallization (solvent: chloroform/diethyl ether) to yield 10.01 g (88.0%, light orange crystal) of the desired product.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3]C.[OH-].[Na+].[CH2:8]([P:10](CCC#N)(=[O:12])[OH:11])[CH3:9].S(=O)(=O)(O)[OH:18]>O>[CH2:8]([P:10]([OH:11])([CH2:3][CH2:2][C:1]([OH:5])=[O:18])=[O:12])[CH3:9]
Reactant: CCP(=O)(O)CCC#N
Reactant: CCCCO
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(O)CCC(=O)O
Temperature: 120 °C
Yield: 97.8 %

Procedure:
A stirred apparatus is initially charged with 150 g of butanol, 65 g of water, 150 g (3.75 mol) of sodium hydroxide and 183 g (1.25 mol) of ethyl(2-cyanoethyl)-phosphinic acid (produced as in Example 5). The efficiently stirred mixture was heated to about 120° C. and reacted at that temperature for about 6 hours. Then, 250 ml of water were added and the butanol was removed from the reaction mixture by distillation. Following the addition of a further 500 ml of water, the mixture is neutralized by addition of about 184 g (1.88 mol) of concentrated sulfuric acid. The water is then distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo and the residue is recrystallized from acetone to obtain 203 g (98% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid as a solid material.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.O1CCCC1.C([O:24][C:25]([C:27]1[S:31][C:30]2=[CH:32][N:33]=[C:34]([C:35](OCC)=[O:36])[N:29]2[CH:28]=1)=O)C>CO>[OH:24][CH2:25][C:27]1[S:31][C:30]2=[CH:32][N:33]=[C:34]([CH2:35][OH:36])[N:29]2[CH:28]=1
Reactant: CCOC(=O)c1cn2c(C(=O)OCC)ncc2s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cn2c(CO)ncc2s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A 9.4 ml portion of a 1.5N diisobutylaluminum hydride/n-hexane solution was added to 10 ml of an anhydrous tetrahydrofuran solution containing 0.758 g of 2,5-diethoxycarbonylimidazo[5,1-b]thiazole, and the mixture was then stirred at -78° C. for 2 hours. Then, 10 ml of methanol was added to the reaction solution, and after stirring for 30 minutes, the solution was subjected to Celite filtration. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by a silica gel column chromatograph to obtain 383.3 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9](=[O:18])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:5]=[CH:6][CH:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9](=[O:18])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)c1c(F)cccc1F)c1cccc(Br)c1
Reactant: COc1cccc(OC)c1B(O)O
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: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1-c1cccc(N(CC(=O)OC(C)(C)C)C(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 2-(N-(3-bromophenyl)-2,6-difluorobenzamido)acetate (0.55 mmol) is mixed with 2,6-dimethoxyphenyl boronic acid (6.13 mmol) and Pd(Ph3P)4 (0.024 mmol). To the solid mixture under nitrogen, Na2CO3 2M (0.83 mL) is added followed by DMF (5.6 mL). The reaction mixture is stirred at room temperature for 1 hour and then heated at 85° C. for 12 hours. The reaction mixture is purified by automated column chromatography (gradient of hexanes and ethyl acetate) to give tert-butyl 2-(N-(3-(2,6-dimethoxyphenyl)phenyl)-2,6-difluorobenzamido)acetate: 1H NMR (400 MHz, CDCl3) δ7.19 (m, 6H), 6.69 (t, J=7.2 Hz, 2H), 6.58 (d. J=8.4 Hz, 2H), 4.46 (s, 2H), 3.64 (s, 6H), 1.48 (s, 9H); MS: (ES+) 484.1 (M+23)+.