Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[NH:32][C:31]=3[C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)=[CH:29][C:24]=2[O:23][CH2:22]1>C1COCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[N:34]=[C:33]([CH:35]4[CH2:36][CH2:37][N:38]([S:8]([CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:10])=[O:9])[CH2:39][CH2:40]4)[NH:32][C:31]=3[C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1cccc(-c2[nH]c(C3CCNCC3)nc2-c2ccc3c(c2)OCO3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(C3CCN(S(=O)(=O)Cc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.9 %

Procedure:
α-Toluenesulfonyl chloride (0.032 g, 0.17 mmol) and diisopropylethylamine (0.036 mL, 0.21 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine (0.050 g, 0.14 mmol; see Example 9) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.005 g (7%) of the title compound as a yellow solid. MS (ESP+) m/z 517.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.73 (t, 1H, J=7.7 Hz), 7.42 (m, 5H), 7.33 (d, 1H, J=7.3 Hz), 7.27 (d, 1H, J=7.3 Hz), 6.07 (s, 2H), 4.40 (s, 2H), 3.82 (m, 2H), 3.19 (m, 1H), 2.85 (m, 2H), 2.66 (s, 3H), 2.10 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)C.[CH3:15][C:16]1[CH:17]=[C:18]([NH2:21])[NH:19][N:20]=1>CCOC(C)=O>[CH3:15][C:16]1[CH:17]=[C:18]2[NH:21][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:5][C:4](=[O:14])[N:19]2[N:20]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Solvent: CCOC(C)=O
Product: Cc1cc2[nH]c(-c3ccccn3)cc(=O)n2n1
Temperature: 25 °C
Yield: 79 %

Procedure:
(prepared according to an analogous procedure described in Polish J. Chem., 56 (1982) p 963) 3-Oxo-3-(pyridin-2-yl)propionic acid ethyl ester (2 g, 0.01035 mol) and 5-methyl-2H-pyrazol-3-ylamine (1 g, 1 eq) were heated together at 140° C. for 2 h; after cooling to rt, the solid residue was stirred with EtOAc and the solid collected by filtration to give 1.84 g of 2-methyl-5-pyridin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Step B: The product of step A (1.84 g) was dissolved in POCl3 (24 ml) and cooled to 0° C. N,N-dimethylaniline (3.1 ml, 3 eq) was added and the mixture heated at 60° C. for 16 h. The mixture was cooled to rt and the volatiles removed. The resulting residue was dissolved in CH2Cl2, poured onto ice, and taken to pH 8 with NaHCO3 (s). The CH2Cl2 layer was removed, washed with water, and dried (MgSO4). The mixture was concentrated under reduced pressure and the residue chromatographed (SiO2, hexane-EtOAc/hexane 1:1) to give 1.2 g of the title compound. 1H NMR (CDCl3) δ 8.71 (m, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.87 (t, J=9.6 Hz, 1H), 7.41 (m, 1H), 6.64 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11]Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.[Cl:14]CCC1CCCCC1>>[Cl:1][CH2:2][CH2:3][C:4]1([CH:10]([Cl:14])[CH3:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: ClCCC1CCCCC1
Reactant: ClCCC1(CCCl)CCCCC1
Agent: Cl
Product: CC(Cl)C1(CCCl)CCCCC1

Procedure:
In this example 100.0 grams of cyclohexane, 17.0 grams of vinyl chloride, 6.0 grams of di-t-butyl peroxide and 21.0 grams of concentrated 37% hydrochloric acid in 21.0 grams of water were added to an 850 ml rotating autoclave. The rotating autoclave was heated to a temperature of between 130° and 140° C. at an initial pressure of 30 atmospheres of nitrogen for a period of time comprising 4 hours. At the end of this time, heating was terminated thereby allowing the autoclave to return to room temperature, and the autoclave was vented. The product was recovered and distilled. The material boiling higher than the unreacted cyclohexane was analyzed by means of preparatory gas-liquid chromatography and infrared spectroscopy. The major product showed infrared absorption at 2860 cm-1 and 2930 cm-1, thereby indicating the presence of a cyclohexyl ring and at 660 cm-1 and 730 cm-1, thereby indicating the presence of a primary alkyl chloride. It should be noted that the infrared analysis failed to disclose an absorption at 1375 cm-1, thereby indicating an absence of methyl grouping. It was determined as a direct conclusion from the infrared analysis that the product (2-chloroethyl)cyclohexane was produced in 30 mole percent yield. The product obtained in lower yield showed infrared absorption at 2860 cm-1 and 2940 cm-1, thereby indicating the presence of a cyclohexyl grouping, at 450 cm-1, thereby indicating the presence of a CH2 bonding and at 615 cm-1 and 670 cm-1, thereby indicating the presence of a secondary alkyl chloride. It was determined by mass spectroscopy that the largest significant ion found had a molecular weight of 172-174 atomic mass units. It may be concluded from the above infrared and mass spectroscopy data that the product was x-(1-chloroethyl)-y-(2-chloroethyl)cyclohexane which eliminated hydrogen chloride (loss of chlorine attached to the secondary carbon atom) during the mass spectroscopy analysis to form x-vinyl-y-(2-chloroethyl)cyclohexane, the molecular weight of which is 172.8 atomic mass units, in 17 mole percentage yield. It seems probable that bis-(2-chloroethyl)cyclohexane loses hydrogen chloride more readily than does (2-chloroethyl)cyclohexane. In the presence of hydrogen chloride the resulting vinyl compound adds hydrogen chloride to form a (2-chloroethyl)-(1-chloroethyl)cyclohexane. In the absence of hydrogen chloride, the vinyl compound polymerizes.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:35](OCC)=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:35]([C:27]1[N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=1)=[O:36]
Reactant: CCCCCCCCCCCCCCCCCCn1c(C(=O)OCC)nc2ccccc21
Reactant: CN(C)CCCN
Product: CCCCCCCCCCCCCCCCCCn1c(C(=O)NCCCN(C)C)nc2ccccc21
Temperature: 125 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (0.818 g) was added to ethyl 1-octadecyl-1H-benzimidazole-2-carboxylate (1.771 g) and the mixture was stirred for 15 hours at 125° C. The reaction mixture was purified by silica gel column chromatography (silica gel 60 g, chloroform:methanol=30:1), thereby yielding the entitled compound (1.746 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10]Cl)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:14][NH2:15]>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10][NH:15][CH3:14])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CN
Reactant: ClCC1COc2cc(Cl)ccc2O1
Product: CNCC1COc2cc(Cl)ccc2O1

Procedure:
14.8 g (0.0675 mol) of 6-chloro-2-chloromethylbenzo-1,4-dioxane and 31.0 g of methylamine are heated in a pressure tube for 24 hours at 120°. Evaporating off the excess methylamine and distilling under reduced pressure yield 6-chloro-2-methylaminomethylbenzo-1,4-dioxane having a boiling point of 70°-73° (at 0.001 mbar).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[Na+]>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])=[CH:19][CH:20]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 155 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1.5 g (4.7 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate, 0.68 g (5.8 mmole) 2,4-thiazolidinedione and 0.96 g (11.8 mmole) sodium acetate were mixed and heated under vacuum to 155° C. The reaction mixture melted and was removed from the heat after 15 minutes. Water/acetone (2:1) was added and the mixture was stirred for 1 h. Filtration gave 1.67 g (yield 83%) of 5-(4-[2-(4-methanesulfonyloxyphenyl)-ethoxy]benzylidene)thiazolidine-2,4-dione as yellow crystals.
Reaction SMILES: [K].[SH:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.Br[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16]>CC(C)=O>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=[C:3]1[S:2][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Cn1c(S)nc2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: Cn1c(SC(C(=O)O)c2ccccc2)nc2ccccc21
Yield: 87 %

Procedure:
An acetone solution of 6.5 g (0.032M) of the potassium salt of 2-mercapto-1-methyl-benzimidazole and 9.7 g (0.045M) of α-bromophenylacetic acid is stirred at room temperature overnight. The solid which is collected is washed with water and the filtrate is concentrated to remove the solvent. The combined materials are recrystallized from acetonitrile. The recrystallized material weighs 8.3 g (87% yield) and melts at 157°-9° C.
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][N:11]1[CH2:15][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:12]1=[O:24])C1C=CC=CC=1.[NH3:26]>CO>[CH2:17]([O:16][C:14]1[CH2:15][N:11]([CH2:10][C:9]([NH2:26])=[O:8])[C:12](=[O:24])[CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CN1CC(OCc2ccccc2)=CC1=O)OCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)CN1CC(OCc2ccccc2)=CC1=O

Procedure:
25.0 g of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester was dissolved in 500 ml of methanol and stirred at 40° C. with passing of gaseous NH3 for 5 hours. Then the reaction solution was evaporated and the residue was mixed with 50 ml of acetone. The precipitated crystals were filtered by suction and dried. 15.2 g of TLC pure product with a melting point of 174.5° to 175.5° C. was obtained. For the product:
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.COC(C)(C)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CC(C)CCO
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 180 mg (0.768 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 8A in 7 ml of dry tetrahydrofuran was admixed with 0.167 ml (1.537 mmol) of 3-methylbutan-1-ol (CAS 123-51-3), 423.2 mg (1.614 mmol) of triphenylphosphine and 0.32 ml (1.614 mmol) of diethyl azodicarboxylate. The resulting mixture was stirred at room temperature for 1 h. Some of the solvent was drawn off under reduced pressure and the residue was admixed with 5 ml of tert-butyl methyl ether. The resulting precipitate was filtered off and the mother liquor was partitioned between dichloromethane (15 ml) and water (10 ml). The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 225 mg (69% of theory, 72% pure) of the target compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(-c2nc(CI)c(C)o2)c1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: COc1cccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)c1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-methoxyphenyl)4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 53 of molecular weight 465.55 (C27H31NO6), MS(ESI): 466.37 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([N:13]=[C:14]=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:18]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:13][C:14]([NH2:18])=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: S=C=NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: N
Solvent: CCOCC
Product: NC(=S)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-chlorobenzhydryl isothiocyanate [5.2g (0.02M)] in 50 mls of dry ether at 0° C is treated with NH3 (anhyd.) for 1/2 hour while maintaining a temperature of 0° C with stirring. Stirring is continued an additional 1.5 hours at 9° to 10° C. during which time a white solid appears. The crude thiourea is filtered and washed thoroughly with ether; mp 173°-5° C. The filtrate is concentrated in vacuo to yield additional product. The combined crops of N-(4-chlorobenzhydryl) thiourea are used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.[OH-].[K+]>CO>[NH:10]1[CH2:11][CH:12]=[C:13]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:14][CH2:15]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C1=C(c2c[nH]c3ncccc23)CCNC1
Yield: 83.8 %

Procedure:
7-Azaindole (10 g, 85 mmol), 4piperidone (34 g,0.22 mol) and potassium hydroxide (16.83 g, 0.3 mol) were heated to reflux in 150 ml methanol overnight. The reaction was cooled, filtered and concentrated to give an orange slurry. The slurry was then extracted with methylene chloride and washed with water. The organic layer was dried over anhydrous magnesium, filtered and concentrated to afford 14.2 g (84%) of product as a solid: mp 195-199° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][N:12]([CH3:40])[C:13]1[C:18]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]3[C:31]4[N:32]=[C:33]([NH2:35])[S:34][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[CH:17][CH:16]=[C:15]([C:36]([F:39])([F:38])[F:37])[N:14]=1)[CH:2]([CH3:4])[CH3:3].[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][N:12]([CH3:40])[C:13]1[C:18]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]3[C:31]4[N:32]=[C:33]([NH:35][C:41](=[O:43])[CH3:42])[S:34][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[CH:17][CH:16]=[C:15]([C:36]([F:38])([F:37])[F:39])[N:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1CCCCC1CN(C)c1nc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(N)nc23)ncn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4N(C)CC4CCCCN4CC(C)C)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(6-(2-(((1-isobutylpiperidin-2-yl)methyl)(methyl)amino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine, Example 24(d), (0.14 g, 0.24 mmol) and acetic anhydride (5 mL, Aldrich) in pyridine (20 mL) was stirred at 25° C. for 24 h. The reaction mixture was partitioned between aqueous solution of NaHCO3 and EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel column chromotography (gradient: 50-100% EtOAc/hexane) afforded the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 614 (M+1). Mp: 123.2-125.4° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18]([C@@H:20](/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:39])=[O:38])[C@@:21]([OH:28])([CH2:25][CH2:26]C)[C:22]([OH:24])=[O:23])=[O:19])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1C=CC(C[C@H](NC([C@@H](/C=C/CCCCCCC(F)([F:91])CCCCCCC)[C@@](O)(CCC)C(O)=O)=O)C(O)=O)=CC=1)C#CC>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18]([C@@H:20](/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:39])=[O:38])[C@:21]([CH2:25][CH2:26][F:91])([OH:28])[C:22]([OH:24])=[O:23])=[O:19])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCC)C(=O)O)C(=O)O)cc1
Reactant: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)O)[C@@](O)(CCC)C(=O)O
Product: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)O)[C@@](O)(CCF)C(=O)O

Procedure:
(E)-(2S,3S)-3-[(S)-2-(4-Butoxy-phenyl)-1-carboxy-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-propyl-undec-4-enoic acid (No. 5527300) was synthesized by the synthetic method of (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-carboxy-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-propyl-nonadec-4-enoic acid (No. 5501825), using (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(2-fluoro-ethyl)-11-(heptane-1-sulfonyl)-2-hydroxy-2-undec-4-enoic acid (No. 5514421) as a starting material.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([NH2:13])=O)[N:10]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]#[N:13])[N:10]=1
Reactant: NC(=O)c1csc(-c2ncc[nH]2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1csc(-c2ncc[nH]2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic acid amide (120 mg) in 2 mL of anhydrous pyridine is added 0.25 mL of POCl3 dropwise at 0° C. The reaction mixture is stirred at the same temperature for 2 hours, poured into ice water, neutralized with solid NaHCO3, and extracted with 5% MeOH in CH2Cl2. The extract is washed with brine, dried and concentrated to a solid. 1H NMR (DMSO): δ 13.45 (br, 1H), 8.82 (s, 1H), 7.38 (s, 1H), 7.12 (s, 1H). LRMS calcd 176, found 177 (MH+).
Reaction SMILES: [C:1](=O)([O-])OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2CC)(=O)=O)=CC=1.IC.[CH2:30]([C@@H:32]1[N:41]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[C:38](F)[CH:39]=2)[N:34]([CH2:53]CC)[C:33]1=[O:56])[CH3:31]>>[CH2:30]([C@@H:32]1[N:41]([S:42]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)(=[O:43])=[O:44])[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH3:1])[CH:39]=2)[N:34]([CH3:53])[C:33]1=[O:56])[CH3:31]
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2ccc(C)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with iodomethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-3-ethyl-4-[(4-hydroxyphenyl)sulfonyl]-1,6-dimethyl-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−123° (c=0.0057 G/ML, DMSO); MS (ESI) m/z 361 ([M+H]+); MS (ESI) m/z 359 ([M−H]−); Anal. Calcd for C18H20N2O4S: C, 59.98; H, 5.59; N, 7.77. Found: C, 57.75; H, 5.20; N, 7.42.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.CCN(CC)CC>C(Cl)Cl>[CH:35]1([C:38]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:24][CH2:23]2)=[O:39])[CH2:37][CH2:36]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-ylmethyl-9H-purine (230 mg, 0.50 mmol), cyclopropyl carbonyl chloride (50 μL, 0.55 mmol) and NEt3 (140 μL, 1.00 mmol) in DCM (10 mL) was allowed to stir at r.t. for 5 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-5%) then further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 40-98%) affording 852 as a white solid (46 mg, 17%). LCMS (method I): RT 3.59 min, [M+H]+ 529.4. 1H NMR (DMSO, 400 MHz): δ 8.03-7.99 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 4.45-4.10 (6 H, m), 3.77-3.75 (6 H, m), 3.27-3.24 (3 H, m), 3.16-3.00 (1 H, m), 2.86 (2 H, d, J=7.07 Hz), 2.64-2.47 (1 H, m), 2.20-2.08 (1 H, m), 2.01-1.93 (1 H, m), 1.79-1.71 (2 H, m), 1.33 (3 H, t, J=7.43 Hz), 1.30-1.07 (2 H, m), 0.74-0.66 (4 H, m)
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[C:8]([CH3:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>C1COCC1.O>[CH3:30][C:8]1[N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[C:6]([Sn:35]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:31][CH2:32][CH2:33][CH3:34])[N:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reaction time: 2 h
Yield: 117.3 %

Procedure:
3 M Ethyl magnesium bromide in THF (6.0 ml, 18.0 mmol) was added dropwise to a solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (5.30 g, 11.8 mmol) in THF (100 ml) at −78° C. After stirring for 2 h, tributyltin chloride (5.0 ml, 18.4 mmol) was added. After stirring for an additional 2 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 8.49 g of impure 2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole as a orange liquid. Method [7]Retention time 11.32 min by HPLC (MH+ 615).