Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)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>[F:12][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:19]=[O:20])[CH:21]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: O=Cc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1F
Temperature: 95 °C
Yield: 25.1 %

Procedure:
A mixture of 4-cyano-3-fluorophenylboronic acid (0.495 g, 3 mmol), 5-bromonicotinaldehyde (0.558 g, 3.00 mmol), sodium carbonate (2M in water, 3.00 mL, 6.00 mmol), bis(triphenylphosphine)palladium(II) chloride (0.053 g, 0.075 mmol) in DMF (10 mL) was heated to 95° C. for 3 h. After concentration, the residue was dissolved into CH2Cl2-MeOH and mixed with silica gel and concentrated. After flash column (MeOH—CH2Cl2, v/v, 0.5%-1%) yielded a colorless solid (170 mg) ESI-MS m/z: 227 [M+1]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].CO>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-chloropropanesulfonyl chloride (commercially available, for example, from Aldrich) (1 g, 6 mmol) in DCM (10 ml) in an ice-water bath was added t-butylamine (commercially available, for example, from Aldrich) (1.3 ml, 12 mmol). The solution was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was applied to a SCX-2 cartridge (50 g) (preconditioned with methanol) and the cartridge eluted with methanol (2 column volumes). The methanol fraction was concentrated in vacuo to give the title compound as a white waxy solid (1.17 g, 97%). LCMS RT=2.61 min, ES+ve m/z 214 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[N:20]=1)[C:7](=[O:13])[NH:8]2
Reactant: Cc1cccc(C=O)n1
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc(C=C2C(=O)Nc3cccc(CCO)c32)n1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (89 mg, 0.5 mmol), 6-methyl-2-pyridine-carbaldehyde (61 mg, 0.5 mmol) and piperidine (0.1 mL) in 1.0 mL of ethanol was heated at 100° C. for 1 hour and cooled to room temperature. The precipitate was filtered and recrystallized from ethyl acetate and hexanes to give 4-(2-hydroxy-ethyl)-3-(6-methyl-pyridin-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: C(O[CH2:4][N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:15](=[O:17])[C:16]=3[N:8]2[CH2:7][CH2:6]1)C.[H][H]>[Pd].C(O)(=O)C>[CH3:26][N:12]1[C:11]2[N:10]=[C:9]3[N:5]([CH3:4])[CH2:6][CH2:7][N:8]3[C:16]=2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13]1=[O:25]
Reactant: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O)c(=O)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3C)n(C)c1=O

Procedure:
A mixture of (R)-7,8-dihydro-8-ethoxymethyl-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (60 mg, 0.164mmol) and 10% palladium on carbon (50% water, 100 mg) in acetic acid (25 ml) was treated with hydrogen gas (50 psi) on a Parr sharker at room temperature for 18 hours. After filtration through a pad of celite, concentration of the filtrate under reduced pressure provided (R)-7,8-dihydro-1,8-dimethyl-3-(5-hydroxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-31878) as a white powder.
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][NH:38][CH2:37][CH2:36]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)([S:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1)[CH2:37][CH2:36]2
Reactant: COc1ccc(C(C#N)(Cc2cccc(CCl)c2)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(Cc2cccc(N3CCc4cc(OC)c(OC)cc4C3)c2)Sc2ccc(C)cc2)cc1OC
Temperature: 85 °C
Yield: 65.8 %

Procedure:
A mixture of 0.21 g of 3-(chloromethyl)-α-(3,4-dimethoxyphenyl)-α-[(4-methylphenyl)thio]benzene propane nitrile, 0.091 g of 6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline and 0.3 g of anhydrous potassium carbonate in 2.0 mL of N,N-dimethylformamide is heated at 85° C. for 4 hours, cooled, poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield an oil. This oil is purified by flash chromatography with 1.5% methyl alcohol in chloroform to yield 0.18 g of the desired product as a yellow glassy solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([N:15](C(C)C)[CH:16](C)C)[CH3:14].CNCC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH2:13][CH3:14])[CH3:16])(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CCNC
Solvent: ClCCl
Product: CCN(C)S(=O)(=O)c1ccc(Br)cc1C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a 0° C. solution of 4-bromo-2-methylbenzenesulfonyl chloride (1.00 g, 3.71 mmol) in CH2Cl2 (10 mL) was added N-ethyldiisopropylamine (0.71 mL, 4.31 mmol) and N-methylethylamine (0.96 mL, 11.13 mmol). The cold bath was removed and the reaction was stirred for 2 h. At completion, the reaction was concentrated, and the crude material was dissolved in CH2Cl2 (20 mL). The mixture was washed with 0.5 N aqueous HCl (3×10 mL), sat. aq. NaHCO3 (2×10 mL), water (10 mL), and saturated aqueous NaCl (5 mL), dried (Na2SO4), and concentrated to give 4-bromo-N-ethyl-2,N-dimethyl-benzenesulfonamide (0.91 g, 3.11 mmol, 85% yield). This material was directly dissolved in 1,4-dioxane (10 mL) and treated with bisboron pinacol ester (0.87 g, 3.43 mmol), PdCl2(dppf)-DCM (69 mg, 0.093 mmol), and KOAc (0.92 g, 9.34 mmol). The reaction was heated at 85° C. for 2 h. At completion, the reaction was cooled to room temperature and concentrated. The crude material was treated with CH2Cl2 (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL) and brine (5 mL), dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography over silica gel (5-20% EtOAc:hexane eluent) to give N-ethyl-2,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (0.64 g, 60% yield). 1H NMR (300 MHz, MeOH) δ ppm 7.80-7.88 (m, 1H), 7.68-7.77 (m, 2H), 3.26 (q, J=7.12 Hz, 2H), 2.83 (s, 3H), 2.61 (s, 3H), 1.37 (s, 12H), 1.17 (t, J=7.15 Hz, 3H). MS (EI) m/z: 340 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq NH4OAc, 2 min gradient) tR=2.48 min, 91% integrated area.
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]23[C:23](=O)[O:22][C:20](=[O:21])[CH:18]([CH2:19]2)[CH2:17]3)=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(O)(=O)C>[CH2:1]([N:6]1[C:20](=[O:21])[CH:18]2[CH2:19][C:16]([C:13]3[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=3)([CH2:17]2)[C:23]1=[O:22])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C1OC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: CC(C)(C)CN
Solvent: CC(=O)O
Product: CC(C)(C)CN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Reaction time: 20 h

Procedure:
2.4 ml of neopentylamine are added dropwise at room temperature to a suspension of 2.5 g of 1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acid anhydride in 6 ml of acetic acid. The mixture is stirred at 120° for 20 hours. After concentration by evaporation, the residue is chromatographed over silica gel with a 2:1 ether/hexane mixture. A fraction is obtained that is identical with the title compound of Example 4b.
Reaction SMILES: [OH:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.F[B-](F)(F)F.[CH3:17][O+](C)C>C(Cl)Cl>[CH3:17][O:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: C[O+](C)C
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1ncc([N+](=O)[O-])cc1Br

Procedure:
The title compound was synthesized from 2-hydroxy-3-bromo-5-nitropyridine by the method of H. J. W. van den Haak et al, Recl.Trav. Chim. Pays-Bas 99(3), p83-87 (1980) using trimethyloxonium tetrafluoroborate in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH:13](O)([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13]([O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: COc1ccc(CC(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)OC(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
Into an recovery flask, 16 mg (0.1 mmol) of 2-(4-methoxyphenyl)acetic acid, and 7 mg (0.1 mmol) of isopropanol were added, and dissolved in 5 ml of tetrahydrofuran. To this, 52 mg (0.2 mmol) of triphenylphosphine, and 177 mg (0.2 mmol) of the compound 14 of Example 8 were added, and stirred for 24 hours at room temperature. The solvent was distilled under a vacuum, acetonitrile was added, and filtration was carried out with an octadecylsilyl silica packed syringe, and from the filtrate, 16.7 mg of isopropyl-2-(4-methoxyphenyl)acetate was obtained. The yield was 70%.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1.[CH:32]1([CH:38]=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.O>[Cl:13][C:11]1[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH2:21][C:22]([NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:23])[CH3:20])[N:8]=[C:7]([CH2:6][C:5]2[CH:30]=[CH:31][C:2]([NH:1][CH2:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)CC(=O)NC1CCCC1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NCC3CCCCC3)cc2)nc1N(C)CC(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A mixture of methyl {2-(4-aminobenzyl)-4-chloro-6-[[2-(cyclopentylamino)-2-oxo-ethyl](methyl)amino]pyrimidin-5-yl}acetate (0.150 g, 0.336 mmol), cyclohexanecarbaldehyde (0.042 g, 0.370 mmol), acetic acid (0.019 mL, 0.336 mmol) and sodium triacetoxyborohydride (0.107 g, 0.505 mmol) in 1,2-dichloroethane (3 mL) was stirred overnight at room temperature. Water was then added and the mixture was neutralized with 1N NaOH followed by extraction with dichloromethane. The combined organic extracts was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed by preparative TLC to give methyl {4-chloro-2-{4-[(cyclo-hexylmethyl)amino]benzyl}-6-[[2-(cyclopentylamino)-2-oxoethyl](methyl)amino]pyrimidin-5-yl}acetate (0.092 g, 51% yield) as an amorphous solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](I)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[CH:26]1([OH:31])[CH2:30][CH2:29][CH:28]=[CH:27]1.C([O-])(=O)C.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:28]3[CH2:29][CH2:30][C:26](=[O:31])[CH2:27]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2I)cc1)c1nc2ccccc2[nH]1
Reactant: OC1C=CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: O=C1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 85 °C
Reaction time: 23 h

Procedure:
A suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-iodopyridin-2-yloxy)phenyl)methanone (4.138 g, 9.38 mmol), cyclopent-2-enol (3.16 g, 37.5 mmol), tetrabutylammonium chloride (2.87 g, 10.32 mmol), potassium acetate (1.841 g, 18.76 mmol) and palladium (II) acetate (0.211 g, 0.938 mmol) in acetonitrile (30 mL) (argon bubbled through for 30 min) and water (3.00 mL) in a round bottom flask was capped with a septum, degassed, backfilled with argon and heated to 85° C. After 23 h, the reaction was cooled to 23° C., diluted with dichloromethane (200 mL) and washed with brine (2×150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 35-50% EtOAc/hexane), affording the product as an off-white solid. MS (ESI, pos. ion) m/z: 398.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[C:17]([CH2:24][CH3:25])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH2:24]([C:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1)[CH3:25]
Reactant: CCc1nn(-c2ccc(OCc3ccccc3)cc2)c2ncccc12
Agent: [Pd]
Solvent: CCO
Product: CCc1nn(-c2ccc(O)cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A mixture of 1-[4-(benzyloxy)phenyl]-3-ethyl-1H-pyrazolo[3,4-b]pyridine (300 mg), 10% palladium on carbon (containing water (50%), 97 mg) and ethanol (10 ml) was vigorously stirred under a hydrogen atmosphere at room temperature for 5 hr. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (200 mg).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=[CH:11][CH:10]=1>>[C:1]([C:10]1[CH:11]=[N:12][C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[N:9]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cnc2c(n1)CCCC2
Reactant: O=Cc1ccccc1
Product: O=C(c1ccccc1)c1cnc2c(n1)CCCC2
Yield: 6 %

Procedure:
The reaction of benzaldehyde and 5,6,7,8-tetrahydroquinoxaline is carried out on the same molar scale and in the same manner as described in Example V. The crude reaction product is submitted to bulb-to-bulb distillation [oven temp. ~60° C. (0.1 mm Hg)] to remove volatiles. Column chromatography (30 g silica gel developed in 3% acetone/hexane), followed by high performance liquid chromatography (Magnum®9, Partisil®10, developed in 4% acetone/2,2,4 trimethylpentane) provides 6% yield of 2-benzoyl-5,6,7,8-tetrahydroquinoxaline as a solid (m.p. 61.5°-63.5° C.). The structure is confirmed by IR and NMR spectroscopy, and by elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 13.5 h
Yield: 43.8 %

Procedure:
A mixture of 10.05 g of 1-t-butoxycarbonyl-4-hydroxypiperidine and 50 ml of tetrahydrofuran was stirred with 2.6 g of sodium hydride at room temperature for 30 minutes and then cooled to 0° C. A liquid mixture of 10.02 g of ethyl bromoacetate and 50 ml of tetrahydrofuran was added, and the reaction solution was stirred for 13.5 hours. After addition of saturated ammonium chloride, the reaction solution was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the insolubles were filtered off, and the solvent was removed by evaporation. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/normal hexane=1:3→1:1) to give 6.28 g of the title compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].[CH3:11][C:12]([CH3:16])=[CH:13][CH2:14]O>O1CCOCC1>[CH3:1][C:2]1[C:8]([CH2:14][CH2:13][CH:12]([CH3:16])[CH3:11])=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[OH:4]
Reactant: CC(C)=CCO
Reactant: Cc1cc(O)c(C)cc1O
Solvent: C1COCCO1
Product: Cc1cc(O)c(C)c(CCC(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
2,5-Dimethylbenzoquinone (5 g) in ethyl acetate was shaken with an aqueous solution of sodium hydrosulfite. The organic layer was separated, washed, dried and evaporated to yield 2,5-dimethylhydroquinone. To a solution of 2,5-dimethylhydroquinone (5 g), prepared as described above, and 3-methyl-2-buten-1-ol (3.1 g) in dioxane (20 mL) was added BF3-ether (4.5 mL) at room temperature under nitrogen. The solution was stirred at room temperature for one hour, extracted with ethyl acetate, washed with water and dried. The mixture containing starting material and alkylated product was hydrogenated in methanol (100 mL) with 5 drops of concentrated HCl in the presence of Pd/C (10%, 200 mg) at60 psi for 18 hours. Workup and chromatography (silica gel hexane-ethyl acetate 5% to 12%) gave 2 g of the desired product, 2,5-dimethyl-3-(3-methyl-butyl)-hydroquinone.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:33][O:32][C:30]([CH:27]1[CH2:28][CH2:29][CH:25]([C:9]2[NH:8][C:16]3[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH3:24])[C:11]=3[N:10]=2)[CH2:26]1)=[O:31]
Reactant: CCCn1c(=O)c2c(nc(C3CCC(C(=O)OC)C3)n2Cc2ccccc2)n(CCC)c1=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)OC)C3)nc2n(CCC)c1=O

Procedure:
2.29 g (5.1 mmol) of 7-benzyl-8-(3-methyloxycarbonyl-cyclopentyl)-1,3-dipropylpurine-2,6-dione are hydrogenated in 40 ml of methanol with the addition of 0.5 g of dry Pearlman catalyst until the uptake of hydrogen has ceased at 20° C. under 5.0 bars. After filtering over kieselguhr the solution is evaporated down and the residue is recrystallised from isopropanol. 1.54 g (83.2% of theory) of the title compound are obtained in the form of colourless crystals, melting point 188°-194° C.
Reaction SMILES: [C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:14][CH2:15][C:9]1([C:18]([NH2:20])=O)[CH2:10][CH2:11]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.C(Cl)(Cl)Cl.CO.O.O>C(Cl)Cl.N1C=CC=CC=1>[C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:11][CH2:10][C:9]1([C:18]#[N:20])[CH2:15][CH2:14]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C(N)=O)CC2
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C#N)CC2
Reaction time: 1.5 h

Procedure:
A solution of 7.52 g (26.6 mmol) of the product from step C in 50 ml of CH2Cl2 and 80 ml of anhydrous pyridine was treated with 11.12 g of (methoxycarbonylsulfamoyl)-triethylammonium hydroxide inner salt (Burgess reagent) in 1-g portions over 5 min. After stirring for 1.5 hr, TLC (90-10-1, CHCl3 -CH3OH-H2O) showed complete conversion to product, and the solution was evaporated to give a paste, to which H2O was added, up to 400 ml, with trituration and stirring to afford, after standing 20 hr at 0° C., filtration and drying in vacuo, the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:13])([CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C@H:25]3[O:29]C(C)(C)[N:27]([C:32](=[O:36])[CH:33]([F:35])[F:34])[C@@H:26]3[CH2:37][F:38])=[CH:21][CH:20]=2)=[CH:15][N:14]=1)=O)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O.O>C1(C)C=CC=CC=1>[F:35][CH:33]([F:34])[C:32]([NH:27][C@H:26]([CH2:37][F:38])[C@H:25]([OH:29])[C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:15]=[N:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:18][CH:17]=2)=[CH:24][CH:23]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3CCCN3)nc2)cc1)C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a stirred solution of 2-(5-{4-[(4S,5R)-3-(2,2-Difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 0.94 mmol) and CH2Cl2 (20 mL), cooled to 0° C., is added trifluoroacetic acid (3 mL) and water (100 ul). The reaction is allowed to warm to ambient temperature, and is stirred for a further 2 hours. Toluene (20 mL) is added and the reaction mixture concentrated under vacuum to give the crude product. Purification by preparative HPLC gave the title compound (217 mg): 1H NMR (400 MHz, CDCl3), 1.88-2.06 (m, 3H), 2.38-2.48 (m, 1H), 3.22-3.40 (m, 3H), 4.25-4.37 (m, 1.5H), 4.4-4.47 (m, 0.5H), 4.52-4.59 (m, 0.5H), 4.63-4.70 (m, 0.5H), 4.71-4.78 (m, 1H), 4.86-4.94 (m, 1H), 5.89-6.01 (m, 1H), 6.20 (t, 1H), 7.43-7.53 (m, 2H), 7.58-7.63 (1H, m), 7.71-7.77 (m, 2H), 8.15-8.24 (m, 1H), 8.82-8.88 (m, 1H), 8.9-8.94 (m, 1H). m/z M+H 394.