Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].ClCCCC(Cl)=O.C(C1C=CC=CC=1CC(O)=O)C.C([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[C:28]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39]Cl)[CH:27]=1)C.[Li+].[OH-]>C(Cl)Cl.O.C(O)C>[CH:37]1([C:36]([C:28]2[CH:27]=[CH:26][CH:31]=[CH:30][C:29]=2[CH2:32][C:33]([OH:35])=[O:34])=[O:41])[CH2:38][CH2:39]1
Reactant: CCc1ccc(CC(=O)O)c(C(=O)CCCCl)c1
Agent: CCc1ccccc1CC(=O)O
Agent: O=C(Cl)CCCCl
Agent: [Al+3]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1ccccc1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
To a slurry of AlCl3 (210 g, 1.6 mol) in methylene chloride (200 mL) cooled in an ice bath is added 4-chlorobutyryl chloride (121 g) dropwise while maintaining the pot temperature below 10° C. After 10 minutes, ethyl benzeneacetic acid (118 g, 0.72 mol) is added dropwise maintaining the pot temperature below 10° C. The mixture is stirred at room temperature for 1 hour, then heated to 40° C. After 4 hours, the solution is cooled to room temperature and poured onto crushed ice (2 L). Methylene chloride (1 L) is added. The organic phase is separated. The aqueous phase is extracted with two 1 L portions of methylene chloride. The combined organics are dried (MgSO4) and concentrated. Toluene (1 L) is added and the solution is concentrated to ca. 500 mL. Ethanol (500 mL) is added. The solution is heated to 70° C. and HCl (g) is bubbled through for 20 minutes. The solution is sparged with N2 and concentrated. Chromatography through silica gel (2.5 L) using an ethyl acetate/heptane gradient gives a 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (119 g). To a slurry of LiOH (23.5 g, 0.56 mol) in water (100 mL) and ethanol (100 mL) is added the 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (50 g, 0.19 mol). The reaction becomes exothermic and is cooled with an ice bath. After 1 hour, the solution is allowed to warm to room temperature. After 18 hours, the mixture is concentrated. Water (400 mL) and conc. HCl are added (until pH 4). Ethyl acetate (600 mL) is added. The organic phase is separated, washed with brine and dried (MgSO4). The solution is heated on a steam bath and charcoal (ca. 3 g) is added. The mixture is filtered through Celite and concentrated. The residue is dissolved in ethyl acetate (300 mL) and heptane (600 mL) with heating. Seed crystals are added. After cooling an organic oil appears. Heptane (500 mL) is added and the mixture is heated to reflux, treated with charcoal (ca. 5 g), filtered and seeded. A solid forms and is collected. 1H NMR shows ca. 4:1 mixture of para:meta isomers. Recrystallization from ethyl acetate/heptane gives 4 (cyclopropylcarbonyl)benzeneacetic acid (4.3 g, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:11]1([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H](CC1CC1)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@@H](CC2CC2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.33 g) in dimethyl sulfoxide (20 mL) were added 3-cyclopropyl-L-alanine (1.00 g) and cesium carbonate (3.28 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 2.05 g, 100%).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([CH2:14][C:15]([NH2:17])=[S:16])#[N:13]>>[CH3:11][C:2]1[S:16][C:15]([CH2:14][C:12]#[N:13])=[N:17][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: N#CCC(N)=S
Product: Cc1sc(CC#N)nc1-c1ccccc1
Yield: 56 %

Procedure:
This compound was synthesized from 2-bromo-1-phenylpropan-1-one and 2-cyanothioacetamide as described in example 1 step 1 (1.7 g, 56% yield %). MS (ESI) m/z: Calculated for C12H10N2S: 214.06. found: 215.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[NH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CCNC(=O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reaction time: 24 h
Yield: 103.5 %

Procedure:
2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (200 mg, 0.78 mmol), EDCI (372.7 mg, 1.94 mmol), methyl 3-aminopropionate (16.7 mg, 1.17 mmol), HOBt (157.6 mg, 1.17 mmol) and ethyldiisopropylamine (352.6 mg, 2.7 mmol) dissolved in dichloromethane (15 mL) were stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the desired compound (265 mg, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]([OH:21])=[C:6]([C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[CH:7]=1.[C:23](OC(=O)C)(=O)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:22])[O:21][C:23]([CH3:24])=[C:9]([C:10]1[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=1)[C:8]2=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccc2c(c1)OCCO2)c1cc(Cl)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc2c(c1)OCCO2

Procedure:
This compounds was synthesised in the same manner as described above. 1-(5-Chloro-2,4-dihydroxy-phenyl)-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (1.1.2.5) (0.3 g, 0.9 mmol), acetic anhydride (0.5 ml), potassium carbonate (0.5 g 3.6 mmol). 6-Chloro-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-hydroxy-2-methyl-chromen-4-one was obtained an off white solid (0.3 g, 96.8%).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:5][N:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[CH2:17]1[O:25][C:24]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=2[O:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[O:18]1[C:19]2[CH:20]=[CH:21][C:22]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=4)=[N:5][N:4]4[CH2:14][CH2:15][CH2:16][C:3]=34)=[CH:23][C:24]=2[O:25][CH2:17]1
Reactant: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
Reactant: OB(O)c1ccc2c(c1)OCO2
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: Cc1ccccc1
Solvent: CO
Product: Cc1cccc(-c2nn3c(c2-c2ccc4c(c2)OCO4)CCC3)n1
Temperature: 80 °C

Procedure:
A mixture of 3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (99 mg, 0.36 mmol), 3,4-methylenedioxyphenylboronic acid (65 mg, 0.39 mmol), (PPh3)4Pd (20 mg, 0.02 mmol), 1 N aqueous sodium carbonate solution (500 μL, 0.5 mmol) in toluene (5 mL) and methanol (1 mL) is purged with argon for 10 min and heated at 80° C. under nitrogen for 30 h. The mixture is cooled and partitioned between water and ethyl acetate, and the organic portion washed with water and brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The crude residue is chromatographed on SiO2 (ethyl acetate) to yield the title compound, 10 mg (9%), as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(N(C(C)C)CC)(C)C.C1(P([N:37]=[N+:38]=[N-:39])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([N:37]=[N+:38]=[N-:39])=[O:13]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnc2ccccc2n1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(=O)c1cnc2ccccc2n1
Reaction time: 8 h

Procedure:
A stirred solution quinoxaline-2-carboxylic acid (348 mg, 2 mmol) in THF (6 mL) at rt under nitrogen was treated with diisopropylethylamine (365 μL, 2.1 mmol) followed by diphenylphosphoryl azide (410 μL, 1.9 mmol). After stirring overnight the reaction was diluted to 60 mL with Et2O and washed 2×60 mL with sat. NaCl. There was an insoluble brown oil, which was drained off with the aqueous layer and assumed to be a diphenyl phosphate impurity. The organics were dried (MgSO4), filtered and concentrated to a tan solid, which corresponds to the acyl azide (350 mg, 92%). 1H-NMR (400 MHz, CDCl3) δ9.58 (s, 1H), 8.32 (d, 1H), 8.21 (d, 1H), 7.94 (m, 2H)
Reaction SMILES: C([SiH2]OC([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[N:24][C:25]([O:28][C@@H:29]3[CH2:34][O:33][C:32]4=[N:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][N:31]4[CH2:30]3)=[N:26][CH:27]=2)=[C:18]([F:41])[CH:17]=1)(C)C)(C)(C)C.C([SiH2][O:47][C:48](C)(C)[C@@H]1OC(=O)N(C2C=CC(B3OC(C)(C)C(C)(C)O3)=C(F)C=2)C1)(C)(C)C>>[F:41][C:18]1[CH:17]=[C:16]([N:11]2[CH2:10][C@@H:14]([CH2:48][OH:47])[O:13][C:12]2=[O:15])[CH:21]=[CH:20][C:19]=1[C:22]1[CH:23]=[N:24][C:25]([O:28][C@H:29]2[CH2:34][O:33][C:32]3=[N:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][N:31]3[CH2:30]2)=[N:26][CH:27]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1COC(=O)N1c1ccc(-c2cnc(O[C@@H]3COc4nc([N+](=O)[O-])cn4C3)nc2)c(F)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Product: O=C1O[C@H](CO)CN1c1ccc(-c2cnc(O[C@H]3COc4nc([N+](=O)[O-])cn4C3)nc2)c(F)c1

Procedure:
5 (R)-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{3-fluoro-4-[2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxy)-pyrimidin-5-yl]-phenyl}-oxazolidin-2-one. The title compound was prepared by following the same procedure as described in the preparation of Example 8, except 5(R)-(tert-butyl-dimethyl-silanyloxymethyl)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-2-one was used in place of N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-acetamide. ESI MS m/z 587 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(N)c([N+](=O)[O-])c2)ccn1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added (4-chloro(2-pyridyl))-N-methylcarboxamide (1 eq) and potassium carbonate (1.2 eq) and stirred at 90° C. for 3 days. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered, and concentrated in vacuum to give brown solid. Purification on silica gel (2% triethyl amine/50% ethyl acetate in hexane) gave 4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carboxamide as an orange solid. The product gave satisfactory NMR. HPLC, 3.39 min; MS: MH+=289.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]([C@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11](=[O:23])[C:12]2[C:18]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:16]=[CH:15][C:13]=2[N:14]=1.B(Cl)(Cl)Cl.N(CCO)CCO>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]([C@H:24]([CH3:32])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:11](=[O:23])[C:12]2[C:18]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COc1ccccc1-c1nc2ccnc(C(F)(F)F)c2c(=O)n1[C@H](C)Cc1ccccc1
Agent: ClB(Cl)Cl
Solvent: OCCNCCO
Solvent: ClCCl
Product: C[C@H](Cc1ccccc1)n1c(-c2ccccc2O)nc2ccnc(C(F)(F)F)c2c1=O
Temperature: 0 °C
Reaction time: 0.06 h
Yield: 65.7 %

Procedure:
(R)-2-(2-methoxyphenyl)-3-(1-phenylpropan-2-yl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (6.6 g, 15.02 mmol) was dissolved in anhydrous dichloromethane (75 mL) and cooled to 0° C. in an ice bath. To this was added a 1M dichloromethane solution of boron trichloride (31.5 mL, 31.5 mmol) slowly to maintain temperature. After addition, the reaction mixture was stirred for 2-5 minutes. The reaction mixture was transferred via canulla to a 0° C. aqueous solution of diethanolamine (10.3 g, 97.6 mmol in 150 mL water) with stirring. The reaction mixture was allowed to come to room temperature and stir for 1 hour. The reaction mixture was diluted with dichloromethane, and the layers separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a foam. This foam was purified by silica gel column chromatography using 20-40% ethyl acetate/hexanes as eluant to give a colorless foam which was then crystallized from ethyl acetate/hexanes to provide the product (4.2 g). 1H NMR (400 MHz, CDCl3) δ 8.79 (d, 1H), 7.6 (d, 1H), 7.45 (m, 1H), 7.00 (m, 6H), 6.90 (m, 2H), 3.60 (m, 2H), 3.10 (m, 2H), 1.99 (t, 3H). MS m/z 426.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and methanesulfonyl chloride (40 mg, 0.35 mL) at ice-bath. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 365.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@@H:12]34)[CH:17]=2)=[C:5]([CH3:33])[CH:4]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]34)[CH:17]=2)=[C:5]([CH3:33])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CCSC3)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C)c1

Procedure:
To a solution of tert-butyl (7bR,11aS)-6{4-methoxy-2-methylphenyl)-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate (34 mg, 0.07 mmol) in CH2Cl2 (5 ml) at 25° C. was added trifluoroacetic acid (1 mL). The mixture was stirred at ambient temperature for 1 hour before saturated NaHCO3 (10 mL) was added and then extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford the title compound of EXAMPLE 9. 1H NMR (CDCl3, 300 MHz): δ 7.16 (d, 1H, J=8.0 Hz), 6.88 (s, 1H), 6.75 (m, 3H), 3.80 (s, 3H), 3.80 (m, 1H), 3.65 (m, 1H), 3.52 (m, 1H), 3.23-2.85 (m, 6H), 2.61 (m, 1H), 2.24 (s, 3H), 2.90 (m, 4H). LRMS (ES+): 367 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][CH2:16][C:17](=O)[CH3:18])[CH:6]=1)[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:26]3[C:25](=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[NH:29][C:17]=2[CH3:18])[CH:6]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(SCC(C)=O)cc(C(F)(F)F)c1
Agent: Cl
Product: CCOC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: 3-(2-oxo-propylsulfanyl)-5-trifluoromethyl-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+].C1COCC1>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:11]2[CH:10]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:35])=[O:2])[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:12]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A solution of 2-[2,6-bis-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pentanoic acid methyl ester (250 mg, 0.5 mmol) in NaOH (1N, 1 mL) and THF (5 mL) was stirred at 40° C. overnight. The mixture was cooled to room temperature, acidified with 10% citric acid, and extracted with CH2Cl2 (3×). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (5-25% ethyl acetate in CH2Cl2) to give the product as a white solid (190 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=8.29 Hz, 4H), 7.68-7.83 (m, 6H), 3.85 (t, J=7.72 Hz, 1H), 2.05-2.17 (m, 1H), 1.79 (dt, J=7.06, 13.75 Hz, 1H), 1.53-1.64 (m, 1H), 0.98 (d, J=6.40 Hz, 6H). MS m/e 482.2 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CN(C=O)C.[Cl-].[Na+].O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(CCl)cc1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(CN(c2ccc(I)cc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (68 mg) in anhydrous DMF (1.0 ml) was added dropwise to a solution of sodium hydride (16 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 4-acetoxybenzyl chloride (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=6/1) to obtain (4-acetoxybenzyl)-(4-iodophenyl)pyrimidin-2-ylamine (67 mg). NMR (HL, CDCl3): δ 2.28 (3H, s), 5.22 (2H, s), 6.63 (1H, t, J=4.6 Hz), 6.98-7.02 (4H, m), 7.26 (2H, d, J=8.1 Hz), 7.64-7.67 (2H, m), 8.34 (2H, d, J=4.6 Hz)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(OC1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H]1OC(=O)C)(=O)C>>[S:10]1[C:5]2[CH:4]=[N:3][CH:2]=[N:7][C:6]=2[NH:8][C:9]1=[O:11]
Reactant: O=c1[nH]c2nc(Cl)nc(Cl)c2s1
Agent: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: O=c1[nH]c2ncncc2s1

Procedure:
In an effort to study the thiazolo[4,5-d]pyrimidine ring system with respect to the order of nucleophilic substitution at the 2,5, and 7 positions and possibly use this information to synthesize the adenosine analog, chlorination of the readily available 2-chlorothiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (21) using refluxing POCl3 and N,N-dimethylaniline (Scheme IV) was effected. The desired 2,5,7-trichlorothiazolo[4,5,-d]pyrimidine (22) was obtained along with a small amount of 5,7-dichloro-2-(N-methylanilino)thiazolo[4,5-d]pyrimidine (23). The trichloro compound, 22, was carefully hydrolyzed in 1N NaOH at 60° C. in order to obtain the mono-oxo derivative, 5,7-dichlorothiazolo[4,5-d]pyrimidin-2(3H)-one (24), the structure of which was verified by single crystal X-ray analysis. Reaction of 24 with 1,2,3,5-tetra-O-acetyl-D-ribofuranose (25) under fusion glycosylation conditions produced 5,7-dichloro-3-2,3,5-tri-O-acetyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidin-2-one (26). Attempts to use 26 for further modification to obtain the adenosine analog were unsuccessful due to the labile nature of the thiazole ring toward nucleophilic ring-opening.