Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](F)[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C@H:14]1[CH2:18][CH2:17][NH:16][C@H:15]1[CH3:19].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([N:16]2[CH2:17][CH2:18][C@H:14]([OH:13])[C@@H:15]2[CH3:19])[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1O
Reactant: Cc1cc(C#N)c(Cl)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(Cl)c(Cl)c1N1CC[C@H](O)[C@@H]1C

Procedure:
Using 2,3-dichloro-4-fluoro-5-methylbenzonitrile (1.02 g), 0.9 M-dimethyl sulfoxide solution (5.56 ml) of (2S,3S)-3-hydroxy-2-methylpyrrolidine and lithium carbonate (370 mg), the title compound was obtained as a colorless solid (yield: 53 mg) by an operation similar to that in Example 3.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C1CC=CC=1.[C:11]1([CH3:17])[CH:16]=CC=[CH:13][CH:12]=1>COC1C=CC(O)=CC=1>[CH:3]12[CH2:17][CH:11]([CH:12]=[CH:13]1)[CH2:16][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: Cc1ccccc1
Agent: C1=CCC=C1
Agent: COc1ccc(O)cc1
Product: O=C(O)C1CC2C=CC1C2

Procedure:
To a four-necked flask having a capacity of 1 L and equipped with a stirrer, a thermometer, and a dropping funnel, 0.40 g of p-methoxyphenol, 108.1 g (1.50 mol) of acrylic acid, and 300 mL of toluene were added, and 109.1 g (1.65 mol) of cyclopentadiene was added dropwise to the flask from the dropping funnel at 40° C. or lower over 2 hours. After completion of the addition, the resultant mixture was stirred at room temperature for 10 hours, and then concentrated under reduced pressure, to thereby obtain 167.3 g (1.21 mol) of 5-norbornene-2-carboxylic acid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([C:14]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([C:27]2[C:36]([CH3:37])=[CH:35][C:30]([C:31](OC)=[O:32])=[C:29]([F:38])[CH:28]=2)[CH:21]=3)=[O:15])[CH2:13][CH2:12]1>C1COCC1>[F:38][C:29]1[C:30]([CH2:31][OH:32])=[CH:35][C:36]([CH3:37])=[C:27]([C:22]2[CH:21]=[C:20]3[C:25]([CH:26]=[C:17]([NH:16][C:14]([CH:11]4[CH2:13][CH2:12]4)=[O:15])[N:18]=[CH:19]3)=[CH:24][CH:23]=2)[CH:28]=1
Reactant: COC(=O)c1cc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(CO)c(F)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Diisobutylaluminum hydride (1.0 mol/L) in THF (1.1 mL, 1.06 mmol) was added dropwise to a solution of methyl 4-[3-(cyclopropanecarbonylamino)-7-isoquinolyl]-2-fluoro-5-methyl-benzoate (100 mg, 0.26 mmol) in THF (1 mL) cooled at −15° C. The reaction mixture warmed to room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid solution in water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (52 mg, 56%). 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.69 (dd, J=8.5, 1.6 Hz, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.11 (d, J=10.7 Hz, 1H), 5.26 (s, 1H), 4.58 (s, 2H), 2.26 (s, 3H), 2.13-2.03 (m, 1H), 0.92-0.77 (m, 4H). LCMS (Method E): RT=4.595 min, M+H+=351.2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)(Cl)Cl>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=3[O-:22])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(C2CCC3(CC2)OCCO3)nc1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccccc1C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
To an ice cold solution of 3 g (13.68 mmol) of 2-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine in chloroform (46 mL) was added 4.51 g (14.36 mmol) of meta-chloroperoxybenzoic acid (50-60%). The reaction mixture was stirred and allowed to come to room temperature over a four hour period. The volume of the reaction mixture was reduced by approximately 75% under reduced pressure and the residual material was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide solution. The organic phase was separated and washed with water and brine, then dried (sodium sulfate) and concentrated to yield 3 g of the product as an oil.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:34])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:33][CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[S:9][CH:10]=1)C.[Li+].[OH-].O.Cl>C1COCC1.C(Cl)Cl>[CH:31]1([S:28]([C:25]2[CH:24]=[CH:23][C:22]([CH:13]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:12]([NH:11][C:8]3[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[N:7]=3)=[O:34])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:32][CH2:33]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(Oc2ccc(F)cc2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1csc(NC(=O)C(Oc2ccc(F)cc2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Reaction time: 2.5 h

Procedure:
{2-[2-(4-Cyclopropanesulfonylphenyl)-2-(4-fluorophenoxy)acetylamino]thiazol-4-yl}-acetic acid ethyl ester (obtained in example A54) was taken in THF, to it was added aqueous solution of LiOH and stirred for 1-4 h. After completion of the reaction, water and DCM was added and stirred for 5 min. The aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:26](Br)[CH3:27]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:26][CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 400 g of 2-acetamido-5-nitrophenol in a 12-L, 4-necked flask equipped with a reflux condenser, nitrogen inlet, thermocouple, addition funnel, and mechanical stirrer was added 790 g of potassium carbonate and 2.0 L of dimethylformamide. The mixture was stirred at 60° C. as 294 g of ethyl bromide was added over 30 minutes. After 1 hour, an additional 27 g of ethyl bromide was added and the mixture was stirred at 60° C. for another hour. The mixture was cooled to room temperature and poured into 4 L of water. After 30 minutes, the product was collected by filtration and washed with water and heptane. The product was dried in a vacuum oven at 60° C. to give 457 g of the title compound.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:50]1([N:55]2[CH2:59][CH:58]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:57]3[NH:70][CH2:71][CH2:72][CH:56]23)[CH2:54][CH2:53][CH2:52][CH2:51]1>CN1C(=O)CCC1.CCOC(C)=O>[C:13]([O:12][C:10](=[O:11])[NH:1][CH:2]([C:7]([N:70]1[CH2:71][CH2:72][CH:56]2[N:55]([CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)[CH2:59][CH:58]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:57]12)=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: Fc1ccc2c(C3CN(C4CCCC4)C4CCNC34)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution containing Boc-L-Tle-OH (160 mg, 0.7 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (264 mg, 0.7 mmol) and DIPEA (148 mg, 0.7 mmol) were added followed by the addition of crude 37 (220 mg, 0.7 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel HPLC (2″ Dynamax SiO2, 20-100% EtOAc/hexanes over 30 min; Flow: 40 mL/min) to afford 280 mg (66%, 2 steps) of 38. 1H NMR (CDCl3, 300 MHz): δ8.37 (s, 1H), 7.58 (dd, J=5.7, 8.4 Hz, 1H), 7.12 (s, 1H), 6.73 (dd, J=1.8, 9.6 Hz, 1H), 6.65-6.58 (m, 1H), 5.07 (d, J=9.3 Hz, 1H), 4.76 (app t, J=8.4 Hz, 1H), 3.76 (d, J=9.3 Hz, 1H), 3.69 (app t, J=7.2 Hz, 1H), 3.41 (app t, J=8.7 Hz, 1H), 3.09 (app t, J=6.9 Hz, 1H), 3.00-2.94 (m, 2H), 2.66-2.50 (m, 2H), 1.69-1.51 (m, 5H), 1.39 (m, 3H), 1.18 (s, 9H), 0.01 (s, 9H) ppm. Mass spectrum, m/z [527.4] (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:23]#[C:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Na+].[Cl-].[NH4+].[OH-]>C1(C)C=CC=CC=1.[Cu]I.CCOCC>[C:15]([O:14][C:13](=[O:19])[N:12]([CH2:11][C:10]1[CH:20]=[CH:21][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:8][CH:9]=1)[C:23]#[C:24][Si:25]([CH:26]([CH3:28])[CH3:27])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)[Si](C#CBr)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCOCC2)cc1
Agent: [Cu]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)[Si](C#CN(Cc1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 90 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
A suspension of t-butyl 4-morpholinobenzylcarbamate (1.11 g, 3.80 mmol), bromoethynyl-triisopropyl-silane, CuI (225 mg, 1.17 mmol) and 1,10-phenantroline (250 mg, 1.40 mmol) in dry toluene (7.5 ml) was warmed to 90° C. under a nitrogen atmosphere. KHMDS (10 ml, 0.5 M in toluene) was added dropwise under nitrogen atmosphere and the mixture was stirred for 12 hours at this temperature. The reaction mixture was cooled to RT; Et2O (30 ml) and NaCl/NH4OH (60/30 ml) were added and the organic phase was extracted with Et2O (3×30 ml), washed with NaCl/NH4 and dried over Na2SO4. The solvent was removed under reduced pressure to afford the title compound which was purified by column chromatography (PE/AcOEt:95/5).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:5]([C:7]#[N:8])[N:6]=1.O.[Sn](Cl)[Cl:21]>C(O)(C)C.Cl>[ClH:21].[CH3:1][C:2]1[S:3][C:4]2[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:7]([NH2:8])[C:5]=2[N:6]=1
Reactant: Cc1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
Combine a suspension of 2-methyl-5-(2-nitroanilino)thiazole-4-nitrile (36 g, 138.5 mmol) in isopropanol (400 ml) in a 2.0 liter 3-necked RB flask equipped with a reflux condenser, thermometer, magnetic stirrer bar and heat with stirring to 65° C. (orange solution). Add tin (II) chloride hydrate (78.7 g, 415.4 mmol) in hydrochloric acid (400 ml; 5M) and heat the resulting solution at reflux. After 2.5 h., cool the reaction to 15° C., filter the suspension, wash with isopropanol/water (2:1) and dry at 50° C. under reduced pressure to leave a yellow solid (36.7 g). Evaporate the filtrate to around 200 mL to form a yellow slurry. Filter the slurry again and dry at 50° C. under reduced pressure to leave a yellow solid (10 g). Combine the solid and suspend in 1 N HCl (700 mL) and heat to reflux for 20 min, cool to 15° C. Filter the resulting yellow slurry and dry at 50° C. under reduced pressure to leave a yellow solid (32.4 g, 88%): mass spectrum (m/e): 231 (M+1); 1HNMR(300 MHz, DMSO-d6, ppm): δ 2.5(s, 3H), 6.78(dd, 1H), 6.85(dd, 1H), 6.98(t, 1H), 7.02(t, 1H), 8.80(s, 1H), 9.10(s, 1H), 9.98(s, 1H), 10.78(s, 1H). 13CNMR(75 MHz, DMSO, ppm): δ 19.6, 120.1, 120.8, 123.6, 125.8, 127.8, 129.2, 137.6, 154.4, 159.3, 160.4. Formula C11H11N4S.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[N:19]=2)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.[H][H]>[Pd].C(=O)([O-])[O-].[K+].[K+]>[NH2:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]3[N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[N:19]=[C:3]3[C:2]([CH3:1])=[CH:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1nc2c(C)cnc(-c3cccc([N+](=O)[O-])c3)n2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(C)cnc(-c3cccc(N)c3)n2n1

Procedure:
A 5.0 g portion of N-[8-methyl-5-(3-nitrophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]acetamide in a solution of 20 ml of trifluoroacetic acid containing 500 mg of 10% palladium on carbon catalyst was shaken under 46 lb. of hydrogen pressure on a Paar hydrogenator overnight. The mixture was filtered and the filtrate evaporated, giving an oil. This oil was neutralized with 20 ml of saturated aqueous potassium carbonate, saturated with salt and extracted into 100 ml of ethyl acetate. The organic phase was dried, filtered and evaporated. The residue was recrystallized from ethanol, giving 3.4 g of N-[5-(3-aminophenyl)-8-methyl[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]acetamide. A 282 mg portion of the above compound and 210 mg of p-toluene sulfonyl chloride were dissolved in 100 ml of pyridine with stirring and sealed overnight. A 105 mg portion of p-toluene sulfonyl chloride was added and the mixture was warmed under a drying tube on a steam bath for 1/2 hour. The mixture was cooled, evaporated and the residue taken up in chloroform and passed through a hydrous magnesium silicate pad. The filtrate was taken up in chloroform, washed with 0.1N hydrochloric acid, dried and evaporated. This residue was recrystallized from ethyl acetate-cyclohexane, giving the desired product as white crystals, mp 215°-218° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:19][CH:18]=1.Cl>C1COCC1.CCCCCC>[C:17]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=[CH:19][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A dispersion of sodium hydride in a mineral oil (60%) (0.22 mol) was treated with hexane under N2 flow to remove the oil and then dispensed in THF (100 ml) under N2 flow. Ethyl (diethylphosphono)acetate (0.22 mol) was added dropwise. The mixture was stirred for 30 minutes until the gas development has stopped. A mixture of (1,1′-biphenyl)-4-ylphenylmethanone (0.2 mol) in THF (100 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, then stirred and refluxed for 17 hours, cooled, poured out into HCl 10% and ice and extracted three times with DCM. The combined organic layer was washed once with a saturated K2CO3 solution, twice with H2O and once with a saturated NaCl solution, then dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc/hexane 1/1/98). Two pure fractions were collected and their solvents were evaporated. Fraction 2 was crystallized from 2-propanol. The precipitate was filtered off and dried. The mother layer was evaporated and combined with fraction 1, yielding 45 g of ethyl 3-[(1,1′-biphenyl)4-yl]-3-phenyl-2-propenoate (interm. 18).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1.[NH2:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14](/[CH:13]=[CH:12]/[C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]([NH:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24])=[O:9])=[CH:15][CH:16]=1
Reactant: NC(CO)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Br)cc1
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-43 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:36]2=[O:49])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:36]2=[O:49])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(CCCc3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CCCc3ccccc3)C2=O)sc1C(=O)O
Yield: 99 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(3-phenylpropyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 99% yield: mp 218-221° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.25-7.10 (m, 5H), 3.94-3.89 (m, 2H), 3.53-3.48 (m, 2H), 3.22 (t, J=6.9 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.83-1.73 (m, 2H); MS (ES+) m/z 346.2 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.ClCCl.CN(C1C=CC=CN=1)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)CCCCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nc(NC(=O)CCCCc2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a cooled mixture of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.10 g, 0.40 mmol), pyridine (0.096 g, 1.21 mmol), and dimethylaminopyridine (0.010 mg) in anhydrous tetrahydrofuran (5 mL) was added 5-phenylpentanoyl chloride (0.16 g, 0.81 mmol) in anhydrous dichloromethane (1 mL) dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate solution (2×5 mL), 1 N hydrochloric acid (5 mL), and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo. The residue was purified by column chromatography over silica gel, eluting with ethyl acetate/hexanes (1/1) to afford the title compound as a clear oil (0.16 g, 97%) %); 1H NMR (CDCl3, 300 MHz) δ 11.19 (s, br, 1H), 7.33-7.09 (m, 10H), 6.40 (t, J=4.8 Hz, 1H), 4.58 (d, J=5.8 Hz, 2H), 2.60-2.39 (m, 7H), 1.74-1.56 (m, 4H); MS (ES+) m/z 408.6 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:5]=[C:4]([NH2:25])[C:3]=1[N:26]1[CH2:30][CH2:29][CH2:28][S:27]1(=[O:32])=[O:31].C([O-])=O.[NH4+]>CO.[Pd]>[O:32]=[S:27]1(=[O:31])[CH2:28][CH2:29][CH2:30][N:26]1[C:3]1[C:4]([NH2:25])=[N:5][C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:7][CH:2]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(Cl)c1N1CCCS1(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1N1CCCS1(=O)=O
Temperature: 25 °C

Procedure:
Alternatively, 5-(1,1-dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinylamine (example 2) was prepared from 6-chloro-5(1,1-dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3yl]-4-pyrimidineamine (0.040 mg, 0.084 mmol) from example 1, which was dissolved in MeOH (4 ml) and to which Pd/C (10%, 0.009 g) and ammonium formate (0.053 mg, 0.84 mmol, 10 equivalents) were added. The mixture was heated under reflux for 2 days and then allowed to cool to room temperature, before the catalyst was filtered off. The crude product was concentrated in vacuo.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=[CH:2]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].CC1(C)[SiH2][SiH]=NC(C)(C)C1(C)C.C(O[CH:39]1[O:61][C@@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:40]1[O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C.[Sn](Cl)(Cl)(Cl)Cl>ClCCCl.ClCCl.C(OCC)(=O)C.CCCCCC>[C:42]([O:41][C@H:40]1[C@@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[O:61][C@@H:39]1[N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=[CH:2]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CCOC(=O)c1nc[nH]c1C(=O)OCC
Agent: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ncn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of diethyl imidazole-4,5-dicarboxylate (2.65 g, 12.50 mmol) and ammonium sulfate (50 mg) was heated at reflux at 135° C. for 6 h with hexamethyldisilazine (50 mL). The reaction mixture was evaporated to dryness and the residue was co-evaporated twice with dry toluene (2×50 mL) to remove last traces of hexamethyldisilazine. The solid that obtained was dried in vacuo for 6 h and used for the next step without further characterization. To a solution of the above residue (12.5 mmol) in 1,2-dichlorethane (60 mL) was added 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (5.06 g, 10 mmol) and tin tetrachloride (1.68 mL, 14.16 mmol) at 10° C. The reaction mixture was stirred under the atmosphere of argon at room temperature for 6 h. The reaction was checked by TLC using hexane and ethyl acetate (7:3). TLC indicated no starting material remained. The reaction mixture was diluted with dichloromethane (200 mL). The organic layer was washed with cold sat. sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and concentrated to yield a white foam. The residue was dissolved in dichloromethane (100 mL) and filtered through celite to remove tin salts. After evaporation in vacuo the residue (4.70 g) was dissolved in ethanol and filtered again through celite. The titled compound 47 was crystallized from the filtrate as needles. Yield 4.70 g (72%): mp 134-136° C.; 1H NMR (CDCl3) δ 1.28 (t, 3H, CH3), 1.37 (t, 3H, CHH3), 4.28-4.40 (m, 4H, 2 CH2), 4.65-4.88 (m, 3H, C4′H and C5′H), 5.85 (m, 2H, C2′H and C3′H), 6.68 (d, 1H, C1′H, J1′,2′=3.90 Hz) and 7.26-8.08 (m, 16H, C2H and PhH).