Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)OC(C)(C)C)cnc21
Reaction time: 66 h
Yield: 67.4 %

Procedure:
A suspension of Intermediate 17 (1.48 g), EDC (1.34 g) and HOBT (0.83 g) in DMF (20 ml) was stirred at room temperature for 30 min. t-Butyl carbazate (0.68 g) was then added and stirring continued under nitrogen for a further 66 h. The mixture was concentrated in vacuo and the residue divided into two portions for purification. Each portion was applied to an SPE cartridge (aminopropyl, 10 g) which was eluted with methanol and the combined eluents were concentrated in vacuo. Further purification was carried out by Biotage (silica, 40 g), eluting with cyclohexane:ethyl acetate (1:4). Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 18 (1.39 g). LCMS showed MH+=405; Tm=2.64 min.
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[O:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][NH2:51]>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:7][S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:51][O:50][CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][O:44]3)=[O:20])=[CH:12]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
0.295 g of (E)-3-(1-phenylmethansulfonyl-1H-pyrrol-3-yl)-acrylic acid (compound B1), 0.152 g of N-hydroxybenzotriazole hydrate (HOBt?H2O) and 561 μl of triethylamine are dissolved in 20 ml of N,N-dimethylformamide (DMF) at room temperature. Afterwards it is added 0.601 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC?HCl) and stirred for 1 hour at room temperature. Then is added 0.152 g of O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine and stirred for 2 hour. The DMF is evaporated under high vacuo. Water is added and the mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of dichloromethane/methanol from 99:1 to 98:2 to give 0.189 g of the title compound as a pale grey solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.IC(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH:37]([CH3:41])[CH3:38])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: COC(=O)C(c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C(C)C
Yield: 53.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 2-iodopropane (0.100 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.109 g (54%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[F:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1F
Yield: 46.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-fluoro-4-methylbenzenesulfonyl chloride (0.0410 g, 0.195 mmol) to obtain 4-(3-fluoro-4-methylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0191 g, yield 46%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([S:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[N:12]=1)([CH3:6])[CH3:5].[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[CH:25].O>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[C:4]([CH3:6])([S:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[N:12]=1)[CH3:5]
Reactant: COC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(C)(C)Sc1nc(CCOc2ccc(C#Cc3ccccc3)cc2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
Under nitrogen atmosphere, 2-({4-[2-(4-iodophenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid methyl ester (600 mg) synthesized in Example 144-2 and ethynylbenzene (145 mg) were dissolved in N,N-dimethylformamide (2 mL) and triethylamine (6 mL), dichlorobis(triphenylphosphine)palladium (10 mg) and copper(I) iodide (5 mg) were added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (400 mg) as a yellow oil.
Reaction SMILES: C=O.S([O-])([O-])(=O)=O.[Mg+2].[Br:9][C:10]1[CH:11]=[C:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:17][CH3:18])=[C:14]([CH:16]=1)[NH2:15].C[Si](C)(C)[O:25][C:26]([CH:28]=[CH2:29])=[CH2:27].[Al](Cl)(CC)[CH2:33]C>C(Cl)Cl.O.CCOCC>[Br:9][C:10]1[CH:11]=[C:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:17][CH3:18])=[C:14]([N:15]2[CH2:29][CH2:28][C:26](=[O:27])[CH2:25][CH2:33]2)[CH:16]=1
Reactant: COc1c(N)cc(Br)cc1C(C)(C)C
Reactant: CC[Al](Cl)CC
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COc1c(N2CCC(=O)CC2)cc(Br)cc1C(C)(C)C
Temperature: -70 °C
Reaction time: 4 h

Procedure:
After adding a 37% formaldehyde aqueous solution (7.6 ml, 94 mmol) and anhydrous magnesium sulfate (43 g) in that order to a solution of 5-bromo-3-(tert-butyl)-2-methoxyaniline (22 g, 85 mmol) in methylene chloride (170 ml) at room temperature, the mixture was stirred at the same temperature for 4 hours. The reaction mixture was filtered through celite, and then washing was performed with methylene chloride (100 ml). The obtained filtrate was cooled to −70° C. and 2-(trimethylsilyloxy)-1,3-butadiene (16.2 ml, 92.3 mmol) was added. A 1.0 M Et2AlCl-Hex. solution (94 ml, 94 mmol) was also slowly added dropwise, and the mixture was stirred for 12 hours while gradually raising the temperature to room temperature. After completion of the reaction, dilution was carried out with Et2O while cooling on ice, water (16 ml) was slowly added dropwise, and the mixture was stirred for an additional 2 hours at room temperature. After distilling off the solvent under reduced pressure, tetrahydrofuran (170 ml) was added, the pH was adjusted to 1 with a 1 N hydrochloric acid aqueous solution while cooling on ice, and the mixture was stirred for 1 hour. It was then diluted with water, and NaHCO3 powder was added to render the solution basic, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous Na2CO3, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (9.0 g) as a brown oil.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[OH:17])=[O:15])=[CH:10][CH:9]=1>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[O:17])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(O)C(=O)c2ccc(Br)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)C(=O)c2ccc(Br)cc2)cc1

Procedure:
Cupric sulfate, 90 g. (0.36 mole), is stirred and heated on the steam-bath with 110 ml. of pyridine and 45 ml. of water until complete solution is obtained. 4-Bromo-4'-methylbenzoin, 55 g. (0.18 mole), is added and the mixture is stirred and heated on the steam-bath for 3 hours. During this period, the yellow crystalline product separates. After cooling and dilution with water, the product is collected, washed with water, 1 N hydrochloric acid, and water, and dried; m.p. 132°-135°C. The analytical sample is obtained as yellow needles, m.p. 136°-137°C, after repeated recrystallizations from 95% ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH:10]([NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([OH:14])[CH:10]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(N)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
3-Amino-4-(4-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.116 g, 0.35 mmol) was dissolved in CH2Cl2. Propionyl chloride (0.034 mL, 0.39 mmol) and triethylamine (0.109 mL, 0.78 mmol) were added and the solution was stirred for 24 h at room temperature. The reaction was concentrated in vacuo, then purified by Biotage flash chromatography (30% ethyl acetate/70% hexane to 50% ethyl acetate/50% hexane) to yield the title compound (0.133 g, 97%). 1H-NMR (CDCl3): δ 0.87 (t, 3H), 1.44 (s, 9H), 1.78–1.95 (m, 3H), 2.20 (dt, 1H), 3.24 (t, 1H), 3.50 (d, 1H), 3.90 (t, 1H), 4.08 (q, 2H), 4.28 (d, 1H), 5.48 (bd, 1H), 7.26 (d, 2H), 7.37 (d, 2H). ESI-MS m/z: 383 (M+1), retention time 2.21.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N+:11]([O-])=O)=[C:5]2[CH:4]=[CH:3]1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[CH:4]=[CH:3]1
Reactant: [H][H]
Reactant: Cn1ccc2c([N+](=O)[O-])ccnc21
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccc2c(N)ccnc21

Procedure:
300 mg (1.69 mmol) of 1-methyl-4-nitro-1H-pyrrolo[2,3-b]pyridine are dissolved in a mixture of 20 ml of ethanol/THF (1:1). 38 mg (0.17 mmol) of platinum(IV) oxide are added, and the mixture is hydrogenated in a hydrogen atmosphere at atmospheric pressure overnight. The mixture is filtered through Celite and the solvent is removed under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15]C)=O)[NH:6]2.[CH3:17][C:18](C)([O-])C.[K+].C(OC)(=O)C=C>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:13](=[O:15])[CH2:18][CH2:17][N:6]3[C:7]=2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COC(=O)c1cc2c(Br)cc(OC)cc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COc1cc(Br)c2cc3n(c2c1)CCC3=O
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of the ester from Step 3 (0.5 g, 1.76 mmol) in toluene (7 mL) and THF (1 mL) at RT was added 1M potassium t-butoxide (1.76 mL, 1.76 mmol). After 15 minutes, methyl acrylate (0.32 mL, 3.5 mmol) was added, and the mixture was brought to reflux for 1.5 hours. The reaction was quenched by the addition of saturated NH4Cl solution, and the product was extracted with EtOAc/THF. The organic layer was washed with H2O and brine, dried (MgSO4), filtered, and evaporated. The intermediate was suspended in EtOH (10 mL), and concentrated HCl (2 mL) was added. After heating to reflux for 2 hours, the mixture was cooled and diluted with H2O (30 mL). The product was extracted with CH2Cl2 and the organic phase was washed with H2O before drying (MgSO4). Following filtration and removal of solvent under vacuum, the product was stirred with 1:2 EtOAc:hexane to give a tan-coloured solid (0.4 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[O:16])[C:5]1[C:6]([Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:8]([CH3:11])=[CH:9][C:10]=1[Cl:19])[CH3:18]
Reactant: CCN(CC)C(=O)c1ccc(C)cc1[Si](C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Product: CCN(CC)C(=O)c1c(Cl)cc(C)cc1[Si](C)(C)C

Procedure:
The title compound was prepared from the compound of Example 58 and 1.2 eq hexachloroethane according to General Method A. Purification by HPLC with 1:9 ethyl acetate/hexanes afforded 1.6 g of the title compound as a clear oil, a 54% yield.
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][CH:3]=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:19][Cl:20]>C(#N)C>[Cl-:20].[F:14][C:15]([F:28])([F:29])[C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:19][N+:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]2[C:2]([CH3:1])=[CH:3][S:4][C:5]=12
Reactant: Cc1csc2nc3ccccc3n12
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Solvent: CC#N
Product: Cc1csc2n1c1ccccc1[n+]2Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Cl-]
Reaction time: 18 h

Procedure:
198 mg of 3-methyl[1,3]thiazolo[3,2-a]benzimidazole were solubilised in acetonitrile (2 mL). Then 828 mg (3 eq) of 3,5-bis(trifluoromethyl)benzyl chloride were added and the solution stirred under reflux. After 18 h, 9-[3,5-bis(trifluoromethyl)benzyl]-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium chloride was recovered as a white powder (422 mg, 89%) by filtration. Mp>268° C.; 1H NMR (300 MHz, MeOD) δ=2.95 (3H, d, J=1.3, CH3), 6.03 (2H, s, CH2), 7.30 (1H, q, J=1.3, H5), 7.70-7.83 (2H, m, Ar), 8.02-8.04 (1H, m, Ar), 8.11 (1H, brs, Ar), 8.21 (2H, brs, Ar), 8.31-8.34 (1H, m, Ar); 13C NMR (75 MHz, MeOD) δ=14.11, 50.33, 112.73, 113.72, 115.13, 124.43 (1C, sept, J=4), 124.46 (2C, q, J=272), 126.67, 128.66, 129.20, 130.92 (2C, q, J=3), 133.72 (2C, q, J=34), 135.48, 136.62, 137.71, 156.38; HRMS m/z C19H13F6N2S [M−Cl]+ calcd: 415.0698, found: 415.0698.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CCOCC>[Br:9][C:10]1[C:11]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[OH:20])=[N:12][CH:13]=[N:14][CH:15]=1
Reactant: Brc1cncnc1
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: OC(c1ccccc1Cl)c1ncncc1Br

Procedure:
Slowly add freshly prepared lithium diisopropylamide (0.5 M in ether) to a refluxing solution of 5-bromopyrimidine (4.03 g, 25.3 mmol) and 2-chloro-benzaldehyde (3.55 g, 25.2 mmol) in ether (100 mL). After addition is complete, stir at reflux for an additional 2 hours, then quench with 2N HCl (50 mL). Wash the organic layer with water (4×50 mL), dry, filter, and concentrate. Purify the crude material by flash chromatography using a linear gradient of 100% hexanes to 50% EtOAc/hexanes to give the title compound: MS (IS) 298.9 (M+1); 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.77 (s, 1H), 7.40 (dd, 1H, J=1.4, 8.4), 7.23 (dt, 1H, J=1.9, 7.9), 7.15 (dt, 1H, J=1.4, 7.7), 6.92 (dd, 1H, J=1.5,7.9), 6.34 (d, 1H, J=6.4), 4.75 (d, 1H, J=6.7).
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:12]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C([OH:24])C>>[N+:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH+:21]([O-:24])[N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([O-:10])=[O:9]
Reactant: Nn1ccc2ccccc21
Reactant: CCO
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Product: O=[N+]([O-])c1ccncc1[NH+]([O-])n1ccc2ccccc21

Procedure:
A solution of 3-fluoro-4-nitro-pyridine-N-oxide (5 g) and 1H-indol-1-amine (4.2 g) in 25 ml of ethanol was stirred four hours at reflux. The solution was cooled and the product collected and dried to give 4 g of solid, d 195°. This material was recrystallized from ethanol/ether to give 2.2 g of solid, d 200°-201°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](I)[CH:3]=1.N#N.[CH3:12][CH2:13][OH:14].[Li][CH:16](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:12][C@H:13]([OH:14])[CH3:16])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1I
Reactant: CCO
Reactant: [Li]C(C)CC
Agent: FB(F)F
Agent: N#N
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C[C@@H](C)O
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of 4-chloro-2-iodo-1-methylbenzene (5.05 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.43 in EtOAc/hexane 3:7) to give (2R)-1-(5-chloro-2-methylphenyl)propan-2-ol (1.39 g, 38%) as pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.16 (s, 1H), 7.10 (m, 2H), 4.03 (m, 1H), 2.73 (m, 2H), 2.29 (s, 3H), 1.86 (s, 1H), 1.27 (d, J=6.24 Hz, 3H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.C(=O)(O)[O-].[Na+].C(OCC)C>CN(C)P(N(C)C)(N(C)C)=O>[CH:16]1[C:14](=[O:15])[N:13]=[C:11]2[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]3[O:12]2)[CH:17]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 135 °C
Yield: 91.8 %

Procedure:
To a suspension of uridine (200 g, 819 mmoles) in hexamethylphosphoramide (HMPA) (400 ml) was added sodium bicarbonate (5.3 g, 63.1 mmoles, 0.077 equivalents (eq.)) and diphenyl carbones (228.1 g, 1064.7 mmoles, 1.3 eq.). The mixture was heated to 135° C. for 11 h. After cooling to room temperature, diethyl ether (2 l) was added and the precipitate was filtered off. The solid was washed three times with ether (3×1l). Water (1 l) was added to the filtrate, the aqueous layer was separated and extracted three times with methylene chloride (3×1 l). The aqueous phase was evaporated to dryness. The combined solids were recrystallized from hot methanol to yield 170 g (92%) of 2,2′-anhydrouridine. The spectral properties agreed with those reported in the literature (Hampton and Nichol (1966) Biochemistry 5:2076).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CO
Temperature: 70 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (S)-3-chloro-propane-1,2-diol (366 mg, 3.31 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (95 mg) as a pale brown oil; LC-MS**: tR=0.88 min, [M+H]+=454.08; 1H NMR (CDCl3): δ1.34 (t, J=7.0 Hz, 3H), 1.67-1.79 (m, 2H), 1.82-1.96 (m, 4H), 2.04-2.15 (m, 2H), 2.43 (s, 3H), 2.79 (q, J=7.0 Hz, 2H), 3.18-3.29 (m, 1H), 3.81-3.99 (m, 4H), 4.01 (s, 3H), 4.15-4.22 (m, 1H), 7.30 (s, 1H), 7.49 (s, 1H), 7.93 (s, 1H), 7.94 (s, 1H).