Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Br-]>O>[C:1]1([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Sc2ccccc2)cc1
Temperature: 20 °C

Procedure:
2.2 g of thiophenol and 2.8 g of potassium carbonate were added to 50 ml of N,N-dimethylformamide, and with stirring at about 20° C., 13.0 g of polyprenylbromide of general formula (II) in which n is 15 and A2 is Br was added dropwise. After the addition, the mixture was stirred overnight at room temperature. The reaction mixture was poured into about 100 ml of water and extracted with hexane. The hexane layer was washed with a 10% aqueous solution of sodium hydroxide and water, and then dried over anhydrous magnesium sulfate. The hexane was distilled off to give a yellow liquid. The yellow liquid was purified by silica gel column chromatography using methylene chloride as an eluent to give 8.6 g of a slightly yellow liquid. The NMR analysis of this liquid showed that a signal (doublet, δ=3.91) assigned to --CH2Br of the starting polyprenyl bromide disappeared, and a signal (doublet, δ=3.47) assigned to --CH2S-- and a signal (multiplet, δ =7.05-7.32) assigned to --SC6H5 newly appeared. The FD-MASS analysis gave m/e=1334.
Reaction SMILES: [CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18](Cl)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2]
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)c2c3ccccc3n(C=O)c12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c3c2c2ccccc2n3C=O)cc1
Yield: 65 %

Procedure:
Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 40 ml of chloroform. To it was added p-anisidine (0.21 g, 1.66 mM), 0.19 g triethylamine and the reaction was refluxed for 18 hrs. Solvent was evaporated and the residue was extracted in ethyl acetate. The organic layer was washed with 10% HCl solution, brine and then dried over anhydrous Na2SO4. It was then evaporated to obtain the crude residue which was then purified over silica gel column using ethylacetate-hexane system to obtain the desired compound as beige solid with a yield of 65% (0.16 g); mp 190-192° C.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br>CN(C)C=O>[O:20]1[CH2:19][CH:18]1[CH2:16][N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Powdered potassium hydroxide (3.36 g, 60 mmol) was added to a solution of carbazole (8.36 g, 50 mmol) in anhydrous N,N-dimethylformamide (50 mL) and stirred at ambient temperature for 1 hour. The reaction mixture was cooled in an ice bath and epibromohydrin (10.3 mL, 125 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 20 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude material was triturated with hexanes, and recrystallized from ethyl acetate/hexanes to yield the desired product as white needles (6.41 g, 58% yield). A second crop of crystals was crystallized from the mother liquor to give additional product (1.2 g, 11%). 1H NMR (CDCl3, 300 MHz) δ 8.11-8.08 (m, 2H), 7.46-7.44 (m, 4H), 7.28-7.25 (m, 2H), 4.68-4.62 (dd, 1H, J=3.1, 15.8 Hz) 4.45-4.38 (dd, 1H, J=4.8, 15.9 Hz), 3.37 (m, 1H), 2.84-2.81 (dd, 1H, J=4.2, 4.3 Hz), 2.60-2.57 (dd, 1H, J=2.5, 5.0 Hz). HPLC analysis: (C18, 5-95% acetonitrile in H2O+0.1% trifluoroacetic acid over 20 min: detention time, % area at 254 nm): 7.83 min, 98.7%.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[C:28]3[S:24][C:25](=[O:30])[NH:26][C:27]3=[O:29])=[CH:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)c1ccccn1
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)c1ccccn1
Yield: 86.2 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 610 mg (1.85 mmol) of 3′-[(methylpyrid-2-ylamino)methyl]biphenyl-4-carbaldehyde with 216 mg (1.85 mmol) of 2,4-thiazolidine dione, 640 mg (81%) of expected product are obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6].O>C(O)(=O)C>[N+:1]([C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:5][CH3:6])[C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3)([O-:4])=[O:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Temperature: 40 °C
Yield: 70.9 %

Procedure:
A solution of 7.3 g of 70% nitric acid (81.1 mmol) in 50 ml acetic acid was added dropwise to a cooled (19°-21° C) acetic acid (200 ml) solution of 15.0 g of N-ethylcarbazole (76.9 mmol). The green reaction solution was then heated on a water bath at 40° C for 2 hours. Upon cooling, addition to 400 ml of water gave a light green precipitate wgich was filtered and air dried. Recrystallization from acetone/methanol gave 13.1 g (71% yield) of 3-nitro-N-ethylcarbazole, mp 118.5°-20° C; the sulfur content (X-ray) was found to be <20 ppm, so that the sulfur in N-ethylcarbazole must be in the elemental or organic (no inorganic) form, most likely the latter, and is easily oxidized to a water soluble form.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH3:17].O>O1CCCC1>[F:15][C:13]1[CH:12]=[CH:11][C:10]([C:16](=[O:18])[CH3:17])=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:14]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
A solution of 1.75 g 2-methoxy ethanol in tetrahydrofuran (23 mL) was added dropwise to a suspension of 0.84 g of 60% sodium hydride in tetrahydrofuran (21 mL), and subsequently a solution of 3.0 g 2′,4′-difluoroacetophenone in tetrahydrofuran (19 mL) was added dropwise thereto. The temperature of the mixture was increased to room temperature, then the mixture was stirred for 24 hours, water was carefully added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was removed, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2.84 g of the title compound (yellow oil).
Reaction SMILES: [Mg:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][CH:16]=1.[CH3:18][OH:19]>>[CH2:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[O-:19])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2].[Mg+2:1].[CH2:7]([C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:18]=1[O-:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CO
Reactant: [Mg]
Product: CCCCCCCCCc1ccccc1[O-]
Product: [Mg+2]

Procedure:
Magnesium nonylphenoxide was prepared by reacting magnesium turnings (52 grams) with methanol (100 grams) in a three-liter three-neck flask fitted with stirrer, condenser, thermometer and nitrogen inlet. Magnesium turnings were added in 5-gram portions every 10 minutes and the exothermio reaction was controlled at 35° to 45° C. with the aid of an ice water bath. When all the magnesium was reacted, nonylphenol (880 grams) was added. The resulting solution contained 2.7% soluble magnesium according to atomic absorption analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][C:9]([OH:11])=O.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:9](=[O:11])[CH2:8][S:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: O=C(O)CSc1ncccn1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)CSc1ncccn1

Procedure:
Using the general method of Example 105 (2-pyrimidinylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide as a white solid, m.p. 156–160° C. (dec.).
Reaction SMILES: [Si](OCCCCCCOC1CCNCC1)(C(C)(C)C)(C)C.[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][N:39](C(OCC2C=CC=CC=2)=O)[CH2:38][CH2:37]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCN1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCNCC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCN1CCNCC1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 23, using Intermediate 24 as a substrate. ES/MS calcd. for C16H37N2OSi+ 301.3. Found m/z=301.3 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:3]=1.[C:13]([O-])([CH3:16])([CH3:15])[CH3:14].[K+]>CCOCC.O1CCCC1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)/C=C/c1cccnc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Ethereal HCl is added to a solution of 45 g of (2E)-3-(3-pyridyl)-2-propenoic acid in 300 ml of ether until the pH is acid. The precipitate obtained is filtered off, washed with ether and dried under reduced pressure. The product is then taken up in 600 ml of thionyl chloride and heated at reflux for 2 hours, and is then concentrated under reduced pressure and taken up successively in toluene and then ether. The residue obtained is then diluted with 1 liter of tetrahydrofuran, stirred at 5° C., and 67 g of potassium tert-butanolate in 2.5 liters of tetrahydrofuran are added. After reacting for 3 hours at 5° C. and for 1 hour at 20° C., the reaction mixture is subjected to customary treatment, allowing the expected product to be obtained after evaporation under reduced pressure.
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[OH:11])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:12]1[C:17](=[O:18])[N:16]([O:19][C:20](ON2C(=O)CCC2=O)=[O:21])[C:14](=[O:15])[CH2:13]1.CCN(CC)CC>CC#N>[CH2:1]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[O:11][C:20]([O:19][N:16]1[C:17](=[O:18])[CH2:12][CH2:13][C:14]1=[O:15])=[O:21])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)ON1C(=O)CCC1=O
Reaction time: 20 h

Procedure:
To a solution of (1R,2R)-2-pent-4-en-1-ylcyclopentanol (105 mg, 0.68 mmol) in MeCN (1.4 mL) was added N,N′-disuccinimidyl carbonate (174 mg, 0.68 mmol) and Et3N (0.19 mL, 1.36 mmol) and the mixture was stirred at 40 C for 20 hours. The reaction mixture was cooled, concentrated and purified by silica chromatography (gradient elution 0 to 100% EtOAc in hexane). LCMS (M+Na)+=318.1.
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH:27]([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:36].C[N:38]([CH:40]=[O:41])[CH3:39]>>[C:27]([O:36][C:40]([NH:38][C:39]1[N:22]=[CH:3][C:4]([CH2:9][C:27]([C:25]2[N:24]=[CH:23][N:22]([C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:26]=2)([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])=[CH:5][CH:6]=1)=[O:41])([CH3:32])([CH3:28])[CH3:25]
Reactant: O
Reactant: COC(=O)C(C(=O)OC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.12 g (5.12 mmol, 50%) of sodium hydride was added to a solution of 2.25 g (5.11 mmol) of the compound from example 12b in 40 ml of dry DMF at 0° C. and stirred at this temperature for 5 min. The mixture was then allowed to reach RT, was stirred for 1 h, was again cooled to 0° C. and then 1.47 g (5.11 mmol) of the compound from example 1b were added in one portion. Stirring was continued at this temperature for 30 min, then 50 ml of water were added while cooling in ice, and the mixture was extracted three times with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel. 3.15 g of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:10][CH:9]1[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC1CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 mmol of 3 5 mL of ethanol is added 2 mL of 1N NaOH and the mixture is stirred for 2 hours at ambient temperature. The mixture is partitioned between 25 mL of water and 25 mL of ether. The aqueous layer is acidified to pH 2 and extracted with 2×25 mL of ether. The combined either extracts are washed with brine, dried with anhydrous MgSO4, filtered and concentrated to yield 4.
Reaction SMILES: [CH2:1](N1C(=O)C2N(C)C=NC=2N(C)C1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(O)CCCCC=C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl.O>[CH3:29][S:30]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: C=CCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCCCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
This example illustrates the synthesis of 1-(6-Heptenyl)-3,7-dimethylxanthine (CT1534). To a solution of 6-hepten-1-ol (6.00 g, 52.6 mmol) in dichloromethane (120 ml) at 0° C. was added methanesulfonyl chloride (6.07 g, 4.0 ml, 53.0 mmol) followed by triethylamine (7.79 g, 77.0 mmol). After stirring for 10 min at 0° C., the reaction was allowed to warm to 25° C. and stirred for 2 hr. The reaction was poured into water (100 ml) and extracted with dichloromethane (2×100 ml). The organic portions were combined, dried (magnesium sulfate), and evaporated to give the 7-methanesulfonyl-1-heptene as a yellow oil (9.30 g, 93%), which was used without further purification.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=CC=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)=O.[CH3:19][CH:20](O)[CH3:21].S(=O)(=O)(O)O.C1OCOCO1.S([Cl:38])(=O)(=O)O>CCCCCC.CC(OC)(C)C>[Cl:38][CH2:19][C:20]1[CH:21]=[CH:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=1
Reactant: FC(F)(F)c1ccccc1C1CCCC1
Reactant: CC(C)O
Reactant: O=S(=O)(O)Cl
Agent: C1OCOCO1
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Temperature: -15 °C
Yield: 89 %

Procedure:
In a 1 L, 3-necked reaction flask fitted with a mechanical stirrer, a temperature probe, an addition funnel and a dry nitrogen inlet was placed 1-cyclopentyl-2-(trifluoromethyl)benzene (50 g, 233 mmol). The material was stirred and cooled to −12° C. (dry ice/IPA bath). Concentrated sulfuric acid (100 mL, 1877 mmol) was added dropwise so that the temperature was maintained between −12° C. to −10° C. The mixture was cooled to −15° C. and s-trioxane (27.3 g, 303 mmol) was added in 3 batches (9.1 g each batch) while the temperature was maintained at between −15° C. to −10° C. The mixture was stirred at −10° C. and almost immediately sulfurochloridic acid (28.1 mL, 420 mmol) was added slowly maintaining the temperature at between −10° C. to −5° C. The mixture was stirred for 20 min at −5° C. and 3 h between −2 to −3° C. The reaction mixture was slowly poured (with efficient stirring) into ice-water (1 L). MTBE (700 mL) was added and the mixture was stirred well. Celite (300 g) was added and stirred well. The celite slurry was filtered and the celite bed was washed with MTBE. The aqueous layer of the filtrate was separated and extracted with MTBE (1×700 mL). The combined MTBE layer was washed with water (1×500 mL) followed by saturated NaHCO3 (2′×350 mL). The MTBE layer was then washed with water (2×500 mL), dried (Na2SO4) and filtered. The filtrate was concentrated (at 38° C., bath temperature; 200 Torr) to give a yellow oil. The oil was taken up in hexane (500 mL) and filtered through a bed of silica; then the silica bed was washed with hexane. The filtrate was concentrated under reduced pressure (38° C., bath temperature; at 200 Torr) to give the title compound as a light yellow oil (36.2 g; 89% purity by LC at 214 nm). 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.72 (m, 4H), 1.78-1.89 (m, 2H), 1.94-2.04 (m, 2H), 3.19-3.28 (m, 1H), 4.82 (s, 2H), 7.62-7.72 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1([Li])C=CC=CC=1.C1[CH2:23][O:22]CC1.CN(C=[O:28])C.S(=O)(=O)(O)O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([OH:22])=[O:28])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Li]c1ccccc1
Product: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
A solution (250 mL) of 2,5-dibromo-1-nitrobenzene (4.32 g, 15.4 mmol) in THF was cooled to −105° C. and 0.88 M phenyllithium/THF solution (19.8 mL, 17.4 mmol) was slowly added dropwise. After 30 min, DMF (5.4 mL, 69.6 mmol) was slowly added dropwise and the temperature was slowly raised to −20° C. Dilute aqueous sulfuric acid solution (100 mL) was added to the reaction mixture and the mixture was concentrated. The product was extracted with ethyl acetate (80 mL×2). The organic layer was dried, concentrated and the resulting brown solid (5.66 g) was dissolved in acetone (50 mL). Jone's reagent (20 mL) was slowly added to this solution under ice-cooling, and the temperature was slowly raised to room temperature. Isopropanol was added to the reaction mixture and the mixture was concentrated. 2 mol/L Aqueous sodium hydroxide solution (100 mL) was added and the mixture was filtered. Concentrated hydrochloric acid was added to acidify the filtrate. The precipitate was collected by filtration and the residue was washed with water and dried to give 4-bromo-2-nitrobenzoic acid (1.95 g, 52%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.CC(C)([O-])C.[K+].[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:28]([N:41]=2)=[N:29][C:30]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH2:34])=[CH:31][CH:32]=3)=[C:21]([F:42])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:28]([N:41]=2)=[N:29][C:30]([C:33]2([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:2][CH2:34]2)=[CH:31][CH:32]=3)=[C:21]([F:42])[CH:20]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1ccccc1)c1ccc2sc(-c3ccc(C4OCCCO4)cc3F)nc2n1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2nc(C3(c4ccccc4)CC3)ccc2s1
Reaction time: 8 h

Procedure:
Trimethylsulfoxonium iodide (0.16 g, 0.72 mmol) and potassium tert-butoxide (0.080 g, 0.72 mmol) were combined in 1.5 mL DMSO to give a clear solution. A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[4,5-b]pyridine (0.200 g, 0.48 mmol) in 4 mL THF was added dropwise, rinsing with 1 mL THF. The reaction mixture was stirred overnight, and was then quenched with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (12 g) using 0-70% EtOAc/hexane. The product-containing fractions were concentrated to afford 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[4,5-b]pyridine as a pale yellow solid. MS (ESI) m/z: calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:44][C:45]([CH3:50])([CH3:49])[C:46]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)=[O:47]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise trimethylacetyl chloride (0.12 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.384 g oil. Crystallization as the oxalate salt from 2-propanol provided 0.297 g colorless crystals. Mp 194° C. Mass spectrum, m+ =413. Anal (C25H37N5O6) theory C, 59.63; H, 7.41; N, 13.91; found C, 59.47; H, 7.62; N, 13.63.