Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br>C(O)(=O)C>[Br:13][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:12])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)C(=O)C(Br)c1ccccc1
Reaction time: 0.25 h
Yield: 69.1 %

Procedure:
12.31 g of phenyl-pyruvic acid and 50 ml of acetic acid were mixed together and then a solution of 12.34 g of bromine in 4 ml of acetic acid was added drop by drop over 1 hour. After the introduction was finished, stirring was continued for 15 minutes, followed by concentration to dryness under reduced pressure. The residue was taken up in 40 ml of dichloroethane and concentrated to dryness under reduced pressure, 30 ml of dichloroethane were added, and crystallization was allowed for 2 hours at 20° C. to obtain 12.6 g of 3-bromo-3-phenyl-pyruvic acid melting at 110° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N:11]=[C:12]=[O:13])[CH2:4][CH2:3]1.Cl.[CH3:15][O:16][NH2:17].C(N(CC)CC)C>CCOCC>[CH3:15][O:16][NH:17][C:12]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: CON
Reactant: O=C=NC1CCC(=O)c2sccc21
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
The crude ether solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanate prepared in Example 4 is added dropwise to a mixture of methoxyamine hydrochloride (9.02 g), triethylamine (13.67 g) and ether (50 ml) under a nitrogen atmosphere. After stirring for 36 hours at room temperature, the solid in the reaction mixture is collected and washed with water. The water-insoluble solid is recrystallized twice from acetone-hexane to afford the title urea, m.p. 185° to 188.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[C:5]([F:17])[CH:4]=1>CO.[Pd]>[NH2:9][C:8]1[C:3]([N:2]([CH3:1])[CH3:18])=[CH:4][C:5]([F:17])=[C:6]([S:12]([NH:15][CH3:16])(=[O:13])=[O:14])[CH:7]=1
Reactant: CNS(=O)(=O)c1cc([N+](=O)[O-])c(N(C)C)cc1F
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)c1cc(N)c(N(C)C)cc1F
Reaction time: 16 h
Yield: 70.7 %

Procedure:
A solution of 4-(dimethylamino)-2-fluoro-N-methyl-5-nitrobenzenesulfonamide (4.0 g, 14.3 mmol) in MeOH (100 mL) was treated with 10% Pd/C (400 mg) and stirred under H2 (50 psi) for 16 hours before being filtered, concentrated, and subjected to flash chromatography (33-50% EtOAc-petroleum ether) to give 5-amino-4-(d imethylamino)-2-fluoro-N-methylbenzenesulfonamide as a white solid (2.5 g, 71%). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (d, J=7.28 Hz, 1 H), 6.75 (d, J=11.69 Hz, 1 H), 4.58 (q, J=4.85 Hz, 1 H), 3.87 (br. s., 2 H), 2.66 (d, J=5.51 Hz, 3 H). MS (m/z) 248.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:19]=[C:18]([CH2:20][NH:21][CH3:22])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([CH:28]1[O:30]C1)[Cl:27]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:19]=[C:18]([CH2:20][NH:21][CH2:22][CH:28]([OH:30])[CH2:26][Cl:27])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1
Reactant: ClCC1CO1
Solvent: CCO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CNCC(O)CCl)oc21
Temperature: 80 °C

Procedure:
A sealed tube was charged with a mixture of N-(4-chlorobenzyl)-7-methyl-2-((methylamino)methyl)-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 62, 3.21 g), epi-chlorohydrin (0.90 mL), and ethanol (80 mL). The mixture was heated to 80° C. overnight and then concentrated. The crude product was purified by column chromatography (acetone/CHCl3/NH4OH, 1/1/0.5%) to yield 1.62 g of the title compound as a white solid. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.39, 7.33, 5.08, 4.54, 3.93, 3.84, 3.75-3.65, 3.56, 2.53, 2.39, 2.28.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>C(OCC)(=O)C>[C:24](=[O:25])([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 91.2 %

Procedure:
The alcohol 29 (135 mg, 0.56 mmol) is dissolved in ethyl acetate (0.82 ml). Pyridine (0.081 ml) is then added, followed by 4-nitrophenyl chloroformate (275 mg, 2.4 eq.). After one night at room temperature, the solvent is evaporated off. Chromatography on silica gel gives the carbonate 30 (206 mg, 91%).
Reaction SMILES: Cl.CO.COC[O:7][C:8]1[CH:17]=[C:16]([O:18]COC)[CH:15]=[C:14]2[C:9]=1[C:10](=[S:23])[CH:11]=[C:12]([CH3:22])[O:13]2.O>C1COCC1>[OH:7][C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[C:10](=[S:23])[CH:11]=[C:12]([CH3:22])[O:13]2
Reactant: COCOc1cc(OCOC)c2c(=S)cc(C)oc2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(=S)c2c(O)cc(O)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.9 %

Procedure:
Under cooling on ice, 70 ml HCl-methanol was added to 70 ml of 9.47 g (30.35 mmol) 5,7-bis(methoxymethoxy)-2-methylthiochromone in THF. The mixture was stirred overnight at room temperature. Subsequently, water was added to the solution thus reacted. The product was extracted twice with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled out under reduced pressure, whereby 6.88 g of 5,7-dihydroxy-2-methylthiochromone was obtained. This product was used without being purified in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](C(OCC)=O)=[C:5]([CH3:7])[N:6]=1.NC1SC=C(C)N=1.Cl[CH2:21][CH2:22][N:23]=[C:24]=[O:25]>>[CH3:7][C:5]1[N:6]=[C:2]([N:1]2[CH2:21][CH2:22][NH:23][C:24]2=[O:25])[S:3][CH:4]=1
Reactant: O=C=NCCCl
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: Cc1csc(N)n1
Product: Cc1csc(N2CCNC2=O)n1
Yield: 90 %

Procedure:
Following the procedure as described in Example 3, making variations as required to replace ethyl 2-amino-4-methylthiazole-5-carboxylate with 2-amino-4-methylthiazole to react with 2-chloroethyl isocyanate, the title compound was obtained as a colorless solid in 90% yield: 1H NMR (300 MHz, CDCl3) δ 6.41 (s, 1H), 5.79 (br s, 1H), 4.20-4.14 (m, 2H), 3.67-3.61 (m, 2H), 2.29 (s, 3H); MS (ES+) m/z 184.1.1 (M+1).
Reaction SMILES: C(OC(=O)C([O:8][C:9]1[CH:30]=[C:29]2[C:12]([N:13]=[CH:14][CH:15]=[C:16]2[CH:17]([OH:28])[C@@H:18]2[N:23]3[CH2:24][CH2:25][C@H:20]([C@@H:21]([CH:26]=[CH2:27])[CH2:22]3)[CH2:19]2)=[CH:11][CH:10]=1)CC)C.Br[CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[OH:28][C@@H:17]([C:16]1[C:29]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:30]=2)[N:13]=[CH:14][CH:15]=1)[C@@H:18]1[N:23]2[CH2:24][CH2:25][C@H:20]([C@@H:21]([CH:26]=[CH2:27])[CH2:22]2)[CH2:19]1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2C(O)c1ccnc2ccc(OC(CC)C(=O)OCC)cc12
Reactant: CCOC(=O)CCCBr
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCC(=O)O)cc12

Procedure:
The first step in the synthesis of the tracer of the present invention, as for the hapten, is the alkylation of 6-hydroxyquinidine using preferably one or less molar equivalent of alkylating reagent. The first step is the alkylation of 6-hydroxyquinidine(1) to (9S)-4-[(9-Hydroxycinchonan-6'-yl) oxybutanoic acid ethyl ester (5) using one molar equivalent of ethyl 4-bromobutyrate, most preferably using 0.9 molar equivalent of ethyl 4-bromobutyrate. The alkylated product (5) is hydrolyzed to obtain the corresponding acid (9S)-4-[9-Hydroxycinchonan-6'-yl)oxybutanoic acid (6). The acid is activated to form N-hydroxysuccinimide using a method well-known in the literature. This activated ester is coupled with 5-aminomethylfluorescein in the presence of pyridine to give the quinidine tracer (9S)-N-[(3',6'-dihydroxy-3-oxospiro[isobenzofuran-1(3H),9'-[9H]xanthen]-5yl) methyl]-4-[(9-hydroxycinchonan-6'-yl)oxy]butamide (7).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)[C:15](=[O:24])[CH:14]([NH:25][C:26](=[O:46])[C@H:27]([NH:32][C:33](=[O:45])[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:13]2.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:37][C:34]([CH3:35])([CH3:36])[C:33]([NH:32][C@H:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:26]([NH:25][CH:14]1[CH2:13][C:12]2[C:17](=[C:8]([N:3]3[C:2](=[O:1])[CH2:6][CH2:5][C:4]3=[O:7])[CH:9]=[CH:10][CH:11]=2)[N:16]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:15]1=[O:24])=[O:46])=[O:45]
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3C(=O)CCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3C(=O)CCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
tert-Butyl 1-((2R)-1-(8-(2,5-dioxopyrrolidin-1-yl)-2-oxo-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (30 mg) was added to ethyl acetate (0.3 mL), and 4N hydrochloric acid in ethyl acetate (230 μL) was added thereto, followed by stirring at 50° C. for six hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic layers were combined, and the combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (17 mg) was yielded.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].OO.O.S([O-])(O)=[O:18].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: O=S([O-])O
Reactant: CCOc1ccc(B(O)O)cc1F
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.3 g of the crude 3-fluoro-4-ethoxyphenyl boronic acid obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 23.6 g (208 mmol) of aqueous 30% hydrogen peroxide was added while being kept at about 35° C. in a warm bath. After addition and after stirring the reaction solution at a room temperature for 24 hours, the reaction solution was poured into 300 ml of water, then sodium hydrogen sulfite was added and stirred at a room temperature for one hour. The reaction solution was extracted with 300 ml of ethyl acetate and the extracted layer was washed with water and then with an aqueous saturated sodium chloride solution successively and, after dying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The concentrated residue was purified by silica gel column chromatography using a ethyl acetate/heptane mixed solvent as an eluent to obtain 17.6 g (113 mmol) of 3-fluoro-4-ethoxyphenol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]([CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]([CH2:29][N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
To a solution of 0.14 mL of oxalylchloride in 3 mL of CH2CI2 at -70° C. was added 0.16 mL of DMSO. After 5 min 270 mg of 1-Benzyl-3-(SR)-(4-hydroxypiperidin- 1-ylmethyl)-4-(SR)-phenylpyrrolidine (from Example 14) in 3 mL of CH2Cl2 was added. After stirring for 10 min, the reaction was warmed to 0 OC for 45 min. The reaction was quenched with H20 and partitioned between 100 mL H20 and 100 mL CH2C-2. After separating phases, the aqueous layer was extracted with 100 mL CH2C-2. The combined organic layers were washed with 100 mL brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography eluting with 2% MeOH in CH2C12 to provide 256 mg of the title compound as a light yellow oil. RF : 0.40 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ2.2-2.4 (m, 4H), 2.4-2.7 (m, 9H), 2.9-3.1 (m, 3H), 3.7 (ABq, 2H), 7.1-7.4 (m, 10H). Mass Spectrum (ESI): 349.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:8]=3[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:8]=3[CH:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)C(c1ccncc1)=Nc1cc(Cl)ccc1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(c1ccncc1)Nc1cc(Cl)ccc1O2

Procedure:
A 5.0 g. portion of 8-chloro-2-methoxy-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine (Example 1) is added to 2.5 g. of lithium aluminum hydride in 200 ml. of ether. The mixture is stirred and heated under reflux for 4 hours. Water is added dropwise to decompose the excess lithium aluminum hydride. The ether is decanted and the residue is extracted with methylene chloride which is then combined with the ether, dried and evaporated. The residue is crystallized from acetone-hexane giving 8-chloro-10,11-dihydro-2-methoxy-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine, mp. 186°-188° C.
Reaction SMILES: [K].[CH3:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH3:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])[C:6](=[O:8])[N:5]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])[C:4]1=[O:9]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Agent: [K]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)C(=O)N(S(=O)(=O)c2ccc3ccccc3c2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (1.00 g) was suspended in tetrahydrofuran (10 mL), 2-naphthalenesulfonyl chloride (1.02 g) was added slowly, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (100 mL) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 242 mg of white crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CC[C@@H](c2ccc(F)cc2)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
(5S)-2-Hydroxy-5-(4-fluorophenyl) tetrahydrofuran (211, 620 mg, 3.5 mmol), t-butyldimethylsilyl chloride (700 mg, 5.25 mmol) and imidazole (595 mg, 8.75 mmol) were dissolved in 2 mL of dry DMF. The resulting solution was stirred under dry argon overnight, poured into 200 mL of water, and extracted with a 2:1-mixture of ethyl acetate and hexane (3×100 mL). The combined organic extracts were washed with water (4×200 mL) and brine (100 mL), dried over sodium sulfate and the solvent was removed in vacuo to yield 1 g (96%) of (5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, mixture of cis and trains isomers) as a colorless oil, which did not need further purification. 1H-NMR (CDCl3) δ 7.40-7.50(2H, m, minor isomer), 7.25-7.35 (2H, m, major isomer), 7.00-7.10 (2H, m, both major and minor isomers), 5.71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90-4.98 (1H, m, minor isomer), 2.40-2.55 (1H, m, both major and minor isomers), 2.05-2.17 (1H, m, both major and minor isomers), 1.87-2.00 (1H, m, both major and minor isomers), 1.67-1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, both major and minor isomers), 0.16 (s, 6H, both major and minor isomers).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1.Cl[CH2:24][CH2:25][S:26][CH3:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH2:24][CH2:25][S:26][CH3:27])=[CH:19][CH:20]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(O)cc4)c3c2)o1
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCCOc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A suspension of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenol (693 mg, 2.37 mmol), 1-chloro-2-(methylthio)ethane (1.18 mL, 11.9 mmol), sodium iodide (355 mg, 2.37 mmol) and potassium carbonate (1.64 g, 11.9 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) and recrystallized from hexane/ethyl acetate to give the title compound (452 mg, yield 52%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]2[CH2:11][C:12](=[O:14])[O:17][C:16](=[O:18])[CH2:15]2)=[CH:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC(CCc1ccc(O)cc1)CC(=O)O
Product: CC(=O)Oc1ccc(CCC2CC(=O)OC(=O)C2)cc1

Procedure:
A solution of 3-[2-(4-hydroxyphenyl)ethyl]glutaric acid (600 mg) in acetic anhydride (15 ml) is heated in a bath at 120° C. for 2.0 hours. It is evaporated in vacuo and the residue is crystallized from dichloromethane-hexane to afford 495 mg of 3-[2-[4-(acetyloxy)phenyl]ethyl]glutaric anhydride, melting point 97°-99° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][C:2]1=[O:7].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:26][C:27]([F:34])([F:33])[C:28]([F:32])=[C:29]([F:31])[F:30]>>[F:30][C:29]([CH:6]1[CH2:5][CH2:4][O:3][C:2](=[O:7])[O:1]1)([F:31])[CH:28]([F:32])[C:27]([F:34])([F:33])[F:26]
Reactant: O=C1OCCCO1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1OCCC(C(F)(F)C(F)C(F)(F)F)O1
Temperature: 73 °C

Procedure:
Example 6 was prepared by combining 1,3-dioxan-2-one (240 g, 2.35 moles) (Richman Chemical Inc., Lower Gwynedd, Pa.) with benzoyl peroxide (5 g, 0.02 moles) in a 600 mL Parr reactor. The reactor was heated to 73° C. and hexafluoropropene (16 g, 0.1066 moles) was fed into the reactor over a 24 h period. The reactor was maintained at the set temperature for an additional 24 h. The reactor contents were collected and analyzed by GC/MS.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:30])=[C:24]([F:35])[CH:23]=1)#[N:2].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:38])[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:30])=[C:24]([F:35])[CH:23]=1)#[N:2]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OCC1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
After suspending 320 mg of N-(4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)-2-fluorophenyl)-N′-cyclopropylurea in 20 ml of tetrahydrofuran, there were added 1 ml of formaldehyde (37% aqueous solution), 80 mg of acetic acid and 280 mg of sodium triacetoxyborohydride while stirring at room temperature. After stirring for 20 minutes, a 2N aqueous sodium hydroxide solution and ethyl acetate were added for extraction. The extract was passed through a glass filter coated with NH type silica gel, and the silica gel was thoroughly washed with an ethyl acetate:methanol=20:1 mixed solvent. The organic solvents were combined and distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to obtain 130 mg of a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[O:7][C:6]=2[CH:14]=1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](=[O:12])(=[O:13])[NH2:11])[O:7][C:6]=2[CH:14]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2o1
Product: C=CCOc1ccc2cc(S(N)(=O)=O)oc2c1

Procedure:
The title compound is prepared by alkylation of 6-hydroxy-2-sulfamoylbenzo[b]furan with allyl bromide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]1[CH2:36][O:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:32]4[CH2:31][CH2:30][CH2:36][O:35][CH2:34][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C1CNCCOC1
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCCOCC4)c23)ccc1OCc1ccccn1
Yield: 20 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 13) and homomorpholine to give the title compound in 20% yield; NMR Spectrum: 1.74-1.79 (m, 2H), 2.75-2.78 (m, 4H), 2.97 (t, 2H), 3.56-3.58 (m, 2H), 3.61-3.64 (m, 2H), 4.41 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.55-7.58 (m, 2H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).