Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]1[O:7][CH2:6]1)Cl.[CH3:8][C:9]([O:12][C:13](=[O:40])[CH2:14][CH2:15][C@H:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][C@@H:34]2[OH:37])[C@:30]2([CH3:31])[C@@H:25]([CH2:26][C@H:27]([OH:38])[CH2:28][CH2:29]2)[CH2:24][C@H:23]3[OH:39])[CH2:20][CH2:19]1)[CH3:17])([CH3:11])[CH3:10]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:8][C:9]([O:12][C:13](=[O:40])[CH2:14][CH2:15][C@H:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][C@@H:34]2[OH:37])[C@:30]2([CH3:31])[C@@H:25]([CH2:26][C@H:27]([O:38][CH2:3][CH:5]4[O:7][CH2:6]4)[CH2:28][CH2:29]2)[CH2:24][C@H:23]3[OH:39])[CH2:20][CH2:19]1)[CH3:17])([CH3:10])[CH3:11]
Reactant: ClCC1CO1
Reactant: C[C@H](CCC(=O)OC(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CCC(=O)OC(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OCC5CO5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 37 %

Procedure:
A mixture of 50% NaOH (10 ml), epichlorohydrin (6 ml) and tetrabutylammonium hydrogen sulfate (0.3 g) kept at 0° C. was added drop by drop to a solution of (3α,5β,7α,12α)-3,7,12-trihydroxy-cholan-24-oic acid 1,1-dimethylethyl ester (prepared according to the procedure described by R. P. Bonar-Law et al., J. Chem. Soc. Perkin Trans. I, 1990, 2245) (0.0045 mol) in CH2Cl2 (10 ml). When the addition was completed the mixture was left to react at room temperature by 24 h. The organic phase was separated, washed with H2O to neutral, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography to obtain 0.86 g of desired product (0.0017 mol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[F:26][C:27]1[C:28](B(O)O)=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:28]5[C:27]([F:26])=[CH:32][N:31]=[C:30]([O:33][CH3:34])[CH:29]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1cc(B(O)O)c(F)cn1
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(F)cn1
Yield: 20.8 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 5-fluoro-2-methoxypyridin-4-ylboronic acid (44 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (19 mg, 20%). ESI-MS m/z calc. 457.12. found 458.3 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH2:9]([Mg]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: BrCCCCCCBr
Solvent: C1CCOC1
Product: BrCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
To a stirred solution of 1500 mL (0.15 mol) of 0.1M Li2CuCl4 and 1,6-dibromohexane (456.8 g, 1.87 mol, 1.25 eq) in tetrahydrofuran, at -5 to 0° C., was added a solution of benzyl magnesium chloride (750 mL, 2M in tetrahydrofuran, 1.5 mol) over a 90 min period. The reaction mixture was stirred at 0° C. for 90 min, then quenched carefully with 2.0 L of saturated aqueous ammonium chloride. The internal reaction temperature was kept below 20° C. during the quench. The mixture was stirred for 1 h at room temperature and the layers separated. The organic layer was washed with 20% aqueous sodium chloride (4×500 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo at 45°-50° C. to an amber oil. Purification by fractional vacuum distillation through a 12-inch vacuum-jacketed Vigreux column gave the desired product as a colorless oil (198.2 g, 52%). An analytical sample was prepared by redistillation: bp 123°-124° C. (1.5 mm Hg); FT-IR (neat film) 3100-3000, 3000-2800, 2000-1700, 1604, 1496, 748, 699, 644 cm-1 ; 1H NMR (CDCl3, 400 MHz) δ 7.29-7.16 (m, 5 H), 3.40 (t, 2 H), 2.60 (t, 2 H), 1.88-1.81 (m, 2 H), 1.63-1.60 (m, 2 1.32 (m, 6 H); 13C NMR (CDCl3, 100 MHz) δ 142.7, 128.4, 128.2, 125.6, 35.9, 34.0, 32.8, 31.4, 29.1, 28.6, 28.1. Anal. Calcd for C13H19Br: C, 61.19; H, 7.50; Br, 31.31. Found: C, 61.25; H, 7.59; Br, 31.47.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:20]=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17]>C(#N)C>[N+:16]([C:19]1[CH:20]=[N:21][N:22]([CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])[CH:23]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C1CCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCN1CCn1cc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
1-(2-Chloroethyl)pyrrolidin-2-one (0.72 g, 4.8 mmol) was added to a solution of potassium carbonate (1.2 g, 8.7 mmol), 4-nitro-1H-pyrazole (0.5 g, 4.4 mmol) in dry acetonitrile (4 mL) and the reaction was stirred at 60° C. overnight. The solvent was concentrated in vacuo, then the residue was slurried in water, collected by filtration and dried in vacuo to afford 1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrrolidin-2-one (0.21 g, 0.9 mmol). LC-MS (Method H), RT=1.23 min. (ES+) 225.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][NH2:19].[CH:20]([C:22]1[NH:26][N:25]=[N:24][N:23]=1)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][N:19]=[CH:20][C:22]1[NH:26][N:25]=[N:24][N:23]=1
Reactant: O=Cc1nnn[nH]1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CON)c1Cl
Product: Cc1ccc(Cl)c(Nc2ccccc2CON=Cc2nnn[nH]2)c1Cl

Procedure:
The title compound is prepared by the reaction of O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl]hydroxylamine, prepared as in Example 1, steps 1-3, with 5-formyltetrazole.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[C:24](=[O:25])[C@:23]3([CH3:26])[C@H:19]2[CH2:20][CH2:21][CH2:22]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[C:24](=[O:25])[C@:23]3([CH3:26])[C@H:19]2[CH2:20][CH2:21][CH2:22]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C[C@]12CCC[C@H]1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@]12CCC[C@H]1N(S(=O)(=O)c1ccc(O)cc1)C2=O

Procedure:
According to the procedure of Example 47, Step 6, using (1S,5R)-6-{[4-(benzyloxy)phenyl]sulfonyl}-1-methyl-6-azabicyclo[3.2.0]heptan-7-one (354 mg, 0.954 mmol) and catalytic 10% Pd/C, with ethyl acetate added to aid solubility, (1S,5R)-6-[(4-hydroxyphenyl)sulfonyl]-1-methyl-6-azabicyclo[3.2.0]heptan-7-one was obtained (291 mg, 100%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.24-1.35 (m, 4H) 1.46-1.56 (m, 1H) 1.75 (dt, J=12.32, 6.09 Hz, 1H) 2.02 (dd, J=12.63, 5.56 Hz, 1H) 2.07-2.16 (m, 1H) 4.09 (d, J=4.04 Hz, 1H) 6.93 (s, 1H) 6.97 (d, J=8.84 Hz, 2H) 7.81 (d, J=8.84 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH3:20]>CN(C=O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]2[CH3:1])[CH3:20])=[CH:22][CH:23]=1
Reactant: CC(Br)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)n(C(C)c2ccc(Cl)cc2)c2ccccc12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of ethyl 2-methyl-1H-indole-3-carboxylate (250 mg, 1.23 mmol) in anhydrous DMF (2 mL) was added NaH (60% in mineral oil, 74 mg, 1.85 mmol) at room temperature under N2. The reaction was stirred at 50-60° C. for 30 min. Then the reaction was cooled to 0° C. and a solution of 1-(1-bromoethyl)-4-chlorobenzene (from Example 35; 400 mg, 1.85 mmol) in DMF (1 mL) was added drop-wise. The reaction was stirred at room temperature overnight. Then the mixture was diluted with water and extracted with EtOAc. The organic extract was combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography using an eluent of petroleum ether/EtOAc (60:1) to afford the title compound as a yellow oil. (210 mg, yield 50.1%) 1H NMR (Methanol-d4, 400 MHz) δ 8.07-8.04 (m, 1H), 7.33-7.29 (m, 2H), 7.16-7.15 (m, 2H), 7.14-7.08 (m, 1H), 7.07-6.96 (m, 2H), 5.97 (q, J=7.2 Hz, J2=14.4 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 2.76 (m, 3H), 1.95 (d, J=6.8 Hz, 3H), 1.43 (d, J=14.0 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1.O>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(C#N)(c1ccccc1)c1ccccc1

Procedure:
To a solution of diphenylacetonitrile (1 g) in tetrahydrofuran (10 ml) was added 60% sodium hydride (0.25 g) portionwise under ice-cooling and stirring. After completion of portionwise addition, the mixture was further stirred for 15 minutes. Then, ethyl bromoacetate (0.69 ml) was added dropwise and the mixture was further stirred for 30 minutes. The reaction mixture was then diluted with water and the organic layer was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to provide the title compound (1.2 g) as colorless powder.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16][CH2:15]1>C1(C)C=CC=CC=1>[C:3]([CH:5]=[C:20]1[CH2:21][CH2:22][C:17]2([O:24][CH2:14][CH2:15][O:16]2)[CH2:18][CH2:19]1)#[N:4]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC=C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (50% in mineral oil, 1.15 g, washed with hexane) in toluene (50 ml) is added a solution of diethyl cyanomethylphosphonate (4.25 g) in toluene (50 ml) dropwise under nitrogen and the mixture is stirred 30 minutes longer. A solution of 1,4-cyclohexanedione monoethylene ketal (3.12 g) in toluene (50 ml) is added dropwise under nitrogen at room temperature. After 10 minutes, ice water is added under vigorous stirring. The aqueous layer is collected and extracted several times with ether. The combined toluene-ether extracts are washed with water, then brine, dried over sodium sulphate and concentrated to dryness at reduced pressure. The residual oil is chromatographed through a 25×140 mm column of silica gel, using methylene chloride as solvent to afford an oil which gradually crystallizes to give 8-cyanomethylene-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: Cl.[NH2:2][N:3]1[C:12]2[N:11]=[C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:24])[C:5](=[O:25])[CH:4]1[CH2:26][CH3:27].Br[CH2:29][CH2:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:26]([CH:4]1[N:3]([N:2]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:12]2[N:11]=[C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[CH:8][C:7]=2[N:6]([CH3:24])[C:5]1=[O:25])[CH3:27]
Reactant: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccccc3)nc2N1N
Reactant: BrCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccccc3)nc2N1N1CCCC1
Temperature: 80 °C

Procedure:
8-amino-7-ethyl-5-methyl-2-(2-phenyl-1H-imidazol-1-yl)-7,8-dihydropteridin-6(5H)-one hydrochloride salt (Example 278, 28 mg, 0.073 mmol) was combined with 1,4-dibromobutane (0.05 mL, 0.42 mmol) and potassium carbonate (38 mg, 0.27 mmol) in 0.2 mL of CH3CN. This mixture was heated to 80° C. for 19 h, then filtered, washed with EtOAc, and the filtrate concentrated under reduced pressure. The residue was purified by HPLC to give the title compound. 1H NMR (CD3OD) δ: 8.01 (s, 2H), 7.73 (d, J=1.8 Hz, 1H), 7.70-7.50 (m, 5H), 4.43 (t, J=4.1 Hz, 1H), 3.36 (s, 3H), 2.98-2.83 (m, 2H), 2.83-2.70 (m, 2H), 2.12-1.95 (m, 2H), 1.60-1.40 (m, 4H), 0.79 (t, J=7.5 Hz, 3H); LCMS [M+H]: 404.1 m/z (M+H)+; ret. Time: 6.82 min (Analytical Method C).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[ClH:18].[O-:19][C:20]#[N:21].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[ClH:18].[ClH:18].[NH2:16][C:15](=[N:14][C:11]1[S:12][CH:13]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:20]([NH2:21])=[O:19])[N:8]=2)[N:10]=1)[NH2:17]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.64 g), 1N-hydrochloric acid (5.15 ml) and potassium cyanate (0.21 g) in water (6.4 ml) was stirred for 19 hours at ambient temperature. The solution was made basic with aqueous potassium carbonate and the resulting precipitate was collected by filtration. The free base was converted to the hydrochloride in a usual manner followed by recrystallization from aqueous methanol to give 2-(diaminomethyleneamino)-4-(6-ureidomethylpyridin-2-yl)thiazole dihydrochloride (0.45 g).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:15]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[O:16])[CH:3]=2)[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Product: O=C(O)COc1ccc(-c2cc(F)cc(F)c2)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and 3,5-difluorophenylboronic acid according to GP4: LC/MS (an10n8): Rt 3.03 min, m/z 434.5 [M+H]+; 1H NMR (CDCl3): δ 4.85 (s, 2H), 6.81 (td, J=8.9, 2.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.9 Hz, 1H), 7.41 (d, J=6.6 Hz, 1H), 7.48 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.66-7.78 (m, 4H), 8.23 (s, 1H), 8.57 (s, 1H)
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1)[CH3:2].Cl[CH2:23][C@H:24]([OH:27])[CH2:25][OH:26]>C(O)(C)C.[OH-].[Na+].O>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:23][C@H:24]([OH:27])[CH2:25][OH:26])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: OC[C@@H](O)CCl
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1ccc(-c2nc(-c3cc(C)c(OC[C@H](O)CO)c(C)c3)no2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (79 mg, 0.263 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.6 mL), (R)-3-chloro-propane-1,2-diol (148 mg, 1.31 mmol) is added. The mixture is stirred at rt for 2 h, then at 65° C. for 16 h before another portion of (R)-3-chloro-propane-1,2-diol (119 mg, 1.05 mmol) is added. Stirring is continued at 65° C. for 24 h. The reaction mixture is diluted with water and extracted with diethyl ether. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 4% of 7 N NH3 in methanol to give (2R)-3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol as an off-white solid; LC-MS: tR=0.99 min; [M+1]+=375.13; 1H NMR (CDCl3): δ 7.83 (s, 2H), 7.80 (d, J=3.8 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 4.20-4.11 (m, 1H), 3.97-3.93 (m, 1H), 3.91 (dd, J=11.5, 4.3 Hz, 1H), 3.85 (dd, J=11.5, 5.5 Hz, 1H), 2.97 (q, J=7.5 Hz, 2H), 2.39 (s, 6H), 1.41 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N+:19]([O-])=[C:18]([CH3:23])[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.C(OC(=O)C)(=[O:34])C>>[CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:23][OH:34])[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(CCOc2cc[n+]([O-])c(C)c2C)OCC2(CO1)OCCO2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCC1(CCOc2ccnc(CO)c2C)OCC2(CO1)OCCO2
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
The 4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethoxy)-2,3-dimethylpyridine 1-oxide (947 mg, 2.79 mmol) obtained in the step (4f) was mixed with acetic anhydride (10 ml). To the mixture, triethylamine (0.6 ml, 4.3 mmol) was added and stirred at 50° C. for 2 hours. The reaction mixture was concentrated and methanol (10 ml) was added to the residue and thereafter, a 5N aqueous sodium hydroxide solution (7 ml) was added and stirred at room temperature for one hour. To the mixture, a saturated aqueous ammonium chloride solution (7 ml) was added and the pH of the resultant solution was adjusted to about 10. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with a 2N aqueous sodium hydroxide solution, water, and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol=1/0-4/1 gradient) and a desired fraction(s) was concentrated to obtain the title compound (564 mg, yield: 59.6%) as a light yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.IC(F)(F)C(F)(F)C(F)(F)C(F)([F:12])I.[F:20][C:21]1([F:31])[C:26]([F:28])([F:27])[C:25]([F:30])(F)[O:24][C:22]1=[O:23]>>[F:27][C:26]([F:28])([C:21]([F:31])([F:20])[C:22]([F:12])=[O:23])[C:25]([F:30])=[O:24]
Reactant: O=C1OC(F)(F)C(F)(F)C1(F)F
Reactant: FC(F)(I)C(F)(F)C(F)(F)C(F)(F)I
Agent: O=S(=O)(O)O
Product: O=C(F)C(F)(F)C(F)(F)C(=O)F
Temperature: 85 °C
Reaction time: 6 h
Yield: 11 %

Procedure:
Into a four necked flask equipped with a thermometer, a reflux condenser, a dropping funnel and a magnetic stirrer, 4950 g (18.5 moles as SO3) of fuming sulfuric acid containing 30% of SO3 were charged. The flask was heated to 85° C. and then, 990 g (2.2 moles) of 1,4-diiodoperfluorobutane having the forumla I (CF2)4I were added dropwise to the flask. The reaction was conducted for 6 hours while maintaining the temperature in the reactor at 85° to 95° C. The reaction mixture discharged from the reflux condenser, was passed through a gas washing bottle containing concentrated sulfuric acid and was collected in a flask cooled with a dryice-ethanol coolant. The collected reaction products in the flask were separated by distillation whereby 247 g of a fraction of a boiling point of 18° C. were obtained. According to F19NMR analysis of the fractions, the fraction having a boiling point of 18° C. consisted of 200g (yield of 47%) of perfluoro- γ-butyrolactone and 47 g (yield of 11%) of perfluorosuccinic difluoride. Another fraction having a boiling point of 1° C., 45 g (yield of 11% ) of perfluoroetrahydrofuran was also obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[Br:12]Br>O1CCOCC1>[Br:12][CH2:11][C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][CH3:1])[CH:8]=1)=[O:10]
Reactant: BrBr
Reactant: CCc1cccc(C(C)=O)c1
Solvent: C1COCCO1
Product: CCc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a stirred solution of 3-ethylacetophenone (Maybridge Chemical Company Ltd.; 1.103 g, 7.44 mmol) in dry 1,4-dioxane (15 mL) was added, bromine (383 μL, 7.44 mmol). The solution was stirred at room temperature for 30 min. and then the solvent was removed on a rotary evaporator. The residue was chromatographed on a Foxy 200 machine (Isco, Inc., P.O. Box 82531, Lincoln, Nebr. 68501, USA.; eluent, 5% CH2Cl2/Hexane, 0–2 min. then 20–30% CH2Cl2/Hexane, 2–20 min.) to give 2-bromo-1-(3-ethylphenyl)ethanone (1.15 g, 68%) as a clear oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:13][O:14][C:15]([C:17]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccc2c(Cl)ncnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(F)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
A mixture of 4-chloro-7-fluoro-quinazoline (2.87 g, 15.4 mmol) (WO 9609294 A1) and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (4.15 g, 17.1 mmol), as prepared in Example 1b, was placed in a −78° C. bath for 5 min under argon before adding a 1.08 M LiHMDS/THF solution (17.8 mL, 19.2 mmol) rapidly by syringe along the sides of the flask (to allow cooling and dispersion of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was manually swirled in the −78° C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 2.5 h stirring at rt, the dark brown homogeneous solution was quenched with 1.0 M NaH2PO4 (38 mL) and extracted with DCM (1×150 mL and 1×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure, and subject to high vacuum at 90° C. with toluene chasers (3×10 mL) to provide the crude title compound as an opaque thick yellow oil that was used in the next step without further purification (6.83 g, “114%” crude yield). 1H-NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.11 (dd, 1H), 7.70 (dd, 1H), 7.36 (ddd, 1H), 3.74-3.64 (m, 2H), 3.62-3.51 (m, 2H), 3.61 (s, 3H), 2.47-2.38 (br m, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 389.2, found 390.1 (MH)+.