Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18]O)[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[Br:30]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][Br:30])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCBr)[C@H]1Oc1ccccc1
Reaction time: 1.17 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (700 mg, 1.718 mmol) in CH2Cl2 (17 mL) at 0° C. (icewater bath) were added perbromomethane (627 mg, 1.890 mmol) and triphenylphosphine (541 mg, 2.061 mmol). After 70 min, TLC (2:1 hexanes:acetone) showed incomplete conversion so additional CBr4 and Ph3P (64 mg and 54 mg, respectively) were added and the reaction was stirred for an additional 20 min. The reaction was concentrated and purified by column chromatography on SiO2 (5→20% acetone/hexanes) to provide the title compound as a hard white foam (712 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 2H), 7.03-6.82 (m, 3H), 5.18-4.99 (m, 2H), 4.21 (q, J=8.7 Hz, 2H), 3.44 (ddd, J=10.0, 7.4, 5.0 Hz, 1H), 3.33 (ddd, J=9.9, 8.4, 6.9 Hz, 1H), 2.28 (dt, J=13.0, 6.6 Hz, 1H), 2.10 (dtd, J=12.6, 7.9, 4.5 Hz, 1H), 2.05-1.96 (m, 1H), 1.85-1.73 (m, 2H), 1.73-1.61 (m, 1H), 1.44 (s, 10H), 1.30 (d, J=6.5 Hz, 3H), 1.28-1.20 (m, 1H), 1.20-1.09 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 173.20, 159.18, 154.89, 129.74, 121.33, 115.37, 80.94, 79.95, 74.57, 53.02, 41.18, 34.13, 33.95, 31.54, 28.33, 19.13, 18.29; HRMS-ESI (m/z) ([M+Na]+) calcd for C22H32BrNNaO5, 492.1356; found, 492.1352.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:34][CH3:35])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH2:30][CH2:31][CH3:32])[C:17]=4[CH2:18]3)[C:13]=2[CH:33]=1)C1C=CC=CC=1>[Ni]>[OH:8][C:9]1[C:10]([O:34][CH3:35])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH2:30][CH2:31][CH3:32])[C:17]=4[CH2:18]3)[C:13]=2[CH:33]=1
Reactant: CCCOc1c(OC)cc(Cl)c2c1CN1CCc3cc(OC)c(OCc4ccccc4)cc3C1C2
Agent: [Ni]
Product: CCCOc1c(OC)cc(Cl)c2c1CN1CCc3cc(OC)c(O)cc3C1C2

Procedure:
A product obtained in Example 12 (0.045 g, 0.09 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4, 7 or 10. The crude product was purified by silica chromatography to give the product (0.026 g, 70.7%). 1HNMR (CDCl3) δ: 1.03 (3H, t, CH3), 1.79 (2H, q, CH2), 2.64˜2.71 (3H, m, CH2), 3.19˜3.53 (5H, m, CH2 and N—CH), 3.82 (3H, s, Ar—OCH3), 3.88 (3H, s, Ar—OCH3), 3.93˜3.97 (2H, t, OCH2), 4.24 (1H, d, CH2), 5.54 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.85 (1H, s, ArH), 6.88 (1H, s, ArH).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])=[N:8][C:7]=1[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:5])C.[Na].[OH-].Cl>C1COCC1.CO>[C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[O:13])=[N:8][C:7]=1[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: Cl
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)O)s1)c1ccncc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
Compound 24 (840 mg, 2.45 mmol) was dissolved in THF (5 mL) and methanol (5 mL), and a 4 mol/L aqueous sodium of hydroxide solution (3 mL) was added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was allowed to cool down, and neutralized with 2 mol/L hydrochloric acid added thereto. The precipitated solid was collected by filtration to afford the entitled Compound 95 (411 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:31]1([C:34]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Yield: 68.3 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[3-(trifluoromethyl)phenyl]benzamide (429 mg, 1.00 mmol), cyclopropanecarbonyl chloride (525 mg, 5.0 mmol) and N,N-dimethylpyridine-4-amine (610 mg, 5.00 mmol) in pyridine (5 mL) was stirred at room temperature for 2 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (340 mg, 68%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH2:25]Cl)=[CH:23][CH:24]=1)=[O:19]>CN(C)C=O>[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH2:25][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:14][CH:13]=2)=[CH:23][CH:24]=1)=[O:19]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 47491.2 %

Procedure:
N,N-Dimethylformamide (400 mL) was added to sodium hydride (60% dispersion; ˜16 g, 0.4 mol) which had been washed with hexanes. The mixture was cooled to −5° C., and then a solution of 4-phenylphenol (73.12 g, 0.43 mmol) in N,N-dimethylformamide (150 mL) was added. The mixture was allowed to stir at room temperature for 2.5 h, and then a solution of 5-chloromethylfuran-2-carboxylic acid methyl ester (25 g, 0.14 mmol) in N,N-dimethylformamide (100 mL) was added. The reaction mixture was heated at ˜105° C. for 2 h, and then it was allowed to cool, evaporated under reduced pressure, and water was added. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine, dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 75 L purification system, eluting with 0-10% methylene chloride/toluene to give 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid methyl ester (20.5 g, 46%).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.[CH2:19]([O:21][C:22](=[O:27])[CH:23]=[C:24](Cl)[CH3:25])[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22](=[O:27])/[CH:23]=[C:24](/[O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]([F:17])([F:18])[F:7])[CH:11]=1)\[CH3:25])[CH3:20]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OC(F)(F)F)c1
Temperature: 23 °C
Yield: 68.9 %

Procedure:
Potassium t-butoxide (1.23 g, 0.013 mol) was added to a stirred solution of 3-trifluoromethoxy-phenol (1.19 g, 0.007 mol) in tetrahydrofuran (15 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 1.00 g, 0.007 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 72%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(Nc1ccc(Cl)cc1)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(c1cccnc1)N(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 3.5 g. portion of 3-[1-(4-chlorophenylamino)ethyl]pyridine was dissolved in dichloromethane, and 2.7 g. of potassium carbonate and 2.55 ml. of benzenesulfonyl chloride were added. The mixture was stirred at ambient temperature for 1 day, and was then diluted with 10 ml. of dichloromethane and extracted with 20 ml. of aqueous sodium bicarbonate and 20 ml. of water. The organic layer was dried over magnesium sulfate and evaporated under vacuum to an oil. The oil was dissolved in diethyl ether, and the insolubles were separated. The solvent was then evaporated away under vacuum, and the resulting oil was taken up in chloroform and chromatographed over a silica gel column, eluting with chloroform. The product-containing fractions were evaporated to obtain 3.1 g. of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=4)=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 160 °C
Yield: 24.8 %

Procedure:
A mixture of N-(3-hydroxy-phenyl)-acetamide (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(3-acetylamino-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 26%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: CN(C)c1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: CNc1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine and methyl amine by a procedure similar to example 46. 1H NMR (CDCl3): 7.42-7.42 (m, 1H), 7.34 (ddd, J=8.1, 6.9, 4.0, 1H), 7.04 (m, 2H), 6.94 (m, 1H), 6.63-6.71 (m, 3H), 5.13 (s, broad, 1H), 3.49 (s, 3H), 3.10 (d, J=4.8, 3H), 2.97 (s, 6H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:1][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:3])[CH:10]=1
Reactant: BrBr
Reactant: Nc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
Cycle 1. Methylene chloride, 125 ml, and 32.2 g (0.1 mol) tetrabutylammonium bromide were mixed in a 200-ml, 3-necked roundbottom flask, equipped with a mechanical stirrer, a thermometer, an additional funnel and a water condenser leading to a mineral oil bubbler. Bromine, 16.0 g (0.1 mol), was added to the mixture over 15 minutes at room temperature. The temperature of the mixture rose from 24° C. to 30° C. The contents of the flask were stirred for 30 minutes. 2-fluoroaniline, 11.1 g (0.1 mol), at room temperature, was added to the mixture in one portion. The temperature of the mixture rose to 40° C. The orange solution immediately turned yellowish. After stirring for 15 minutes, the solution turned milky and the temperature was 32° C. After 30 more minutes, solids were observed. The solution was filtered and the solids washed with ice-cold methylene chloride until white. On air-drying 9 g of product (Solid I) was obtained. The melting point was >200° C. LC analysis showed only desired product with a trace of impurity. LC analysis of the mother liquor (I) showed that it contained some desired product and some dibrominated compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.Cl[CH2:22][C:23]([NH:25][C:26]([NH2:28])=[O:27])=[O:24]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:22][C:23]([NH:25][C:26]([NH2:28])=[O:27])=[O:24])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: NC(=O)NC(=O)CCl
Product: CC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-8-isopropyl-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with chloroacetylurea according to the method of Example 2; m.p. 164°-166°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2)[CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: COC(=O)COCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methoxy)acetate (0.040 g, 0.089 mmol) in THF (2.00 mL) was added a solution of lithium hydroxide (0.011 g, 0.45 mmol) in 1.0 mL of water. The reaction mixture was stirred for 10 min. The THF was removed, and the reaction mixture acidified to pH 1 with 5N HCl. The resulting solid was rinsed with water and diethyl ether, and the solid was dried in vacuo at 50° C. for 2 h to give 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyloxy)acetic acid. MS (ESI) m/z: calculated: 434.1; Observed: 435.0 (M++1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][CH:12]([CH2:23][CH3:24])[C:13]([CH2:21][CH3:22])([C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:16])[N:15]=2)[CH:7]=[C:6]([Cl:25])[N:5]=1.[C:26]1(C)[CH:31]=CC=C[CH:27]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]([CH2:31][C:26]#[CH:27])[C:14](=[O:16])[C:13]([CH2:21][CH3:22])([C:17]([O:19][CH3:20])=[O:18])[CH:12]([CH2:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([Cl:25])[N:5]=1
Reactant: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1(CC)C(=O)OC
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(CC)(C(=O)OC)C(CC)N=C1c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To 3.15 g (78 mmol) of sodium hydride in 50 mL of dimethylformamide at 0° C. was added dropwise over 1.5 hr a solution of 26.9 g (75 mmol) of 2-(2,6-dichloro-4-pyridyl)-5,6-diethyl-5-methoxycarbonyl-5,6-dihydropyrimidin-4-one in 200 mL of dimethylformamide. When this addition was complete 12.5 mL (16.73 g, 112.5 mmol) of 80% propargyl brmide in toluene was added and the reaction stirred at room temperature overnight. Upon completion the reaction was quenched onto 600 mL of ice/water, extracted with ethyl acetate (3×400 mL), the organics were combined, washed with water (2×300 mL) and saturated sodium chloride (2×500 mL), dried over Na2SO4, filtered and evaporated to dryness in vacuo to give 29.23 g (73.8 mmol, 98%) of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[Br:17])=O)[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[Br:17])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1ccc(OC)cc1Br
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)CCCc1ccc(OC)cc1Br
Temperature: 55 °C
Yield: 87.5 %

Procedure:
A solution of 4-(2-bromo-4-methoxy-phenyl)-4-oxo-butyric acid ethyl ester (Intermediate 150, 6.45 g, 20.5 mmol) in trifluoroacetic acid (32 mL, 409 mmol) was treated with triethylsilane (14.4 mL, 90 mmol) and the resulting reaction mixture was heated at 55° C. for 3 h. The reaction mixture was then cooled to ambient temperature, neutralized with solid sodium bicarbonate, diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (5.4 g, 88%) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>ClCCl.Cl>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][N:8]([C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc2c(n1)CCNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CC1)N1CCc2nc(Cl)ccc2C1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
To a room temperature stirred suspension of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (50 mg, 0.24 mmol) in dichloromethane (2 ml) under a nitrogen atmosphere was added DIPEA (0.12 ml, 0.73 mmol) followed by cyclopropyl carbonyl chloride (24 μl, 0.27 mmol). The resulting mixture was stirred for 16 hours, diluted with dichloromethane (30 ml) and 1M aq. HCl (2 ml). The organic layer was separated and washed with saturated aqueous NaHCO3 (15 ml) and brine (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure to provide the title compound (60 mg, 95%) which was used without further purification.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23]2[O:27][N:26]=[C:25]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[S:34]([CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)(=[O:36])=[O:35])[N:24]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1>ClCCl>[CH:38]1([CH2:37][S:34]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C@H:28]2[C:25]2[N:24]=[C:23]([CH2:22][O:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[O:27][N:26]=2)(=[O:36])=[O:35])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=S(=O)(CC1CCCCC1)N1CCCC[C@H]1c1noc(COC2CCN(Cc3ccccc3)CC2)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=S(=O)(CC1CCCCC1)N1CCCC[C@H]1c1noc(COC2CCNCC2)n1
Yield: 63.4 %

Procedure:
α-Chloroethyl chloroformate (95 μl) was added to a solution of 5-[(1-benzyl-4-piperidyl)oxymethyl]-3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1,2,4-oxadiazole (325 mg) [see Example 16] in dichloromethane (20 ml) at 0° C. The reaction mixture was stirred for 1.5 hours after which time the dichloromethane was removed under reduced pressure and the residue dissolved in methanol. The mixture was then heated under reflux for 2 hours, the solvent removed under reduced pressure and the residue partitioned between diethyl ether and 2N aqueous hydrochloric acid solution. The aqueous layer was washed twice with diethyl ether and then neutralised (pH7) with sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-5-[4-piperidyloxymethyl]-1,2,4-oxadiazole (170 mg) as a brown oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>C(#N)C>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CCl)cc1
Solvent: CC#N
Product: COc1ccc(Cn2ccnc2)cc1
Yield: 69.3 %

Procedure:
To a stirred solution of imidazole (25.35 g, 375 mmole) in acetonitrile (625 ml) was added p-methoxybenzyl chloride (16.95 ml, 125 mmole). The reaction was refluxed for 16 hours, evaporated to dryness, and redissolved in methylene chloride and saturated sodium bicarbonate. The organic layer was extracted with water twice. Standard acid/base workup gave N-p-methoxybenzylimidazole (16.3 g, 69%) which was used without further purification:
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:3]([OH:22])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1
Temperature: 47.5 °C
Yield: 59.6 %

Procedure:
A solution of 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (1.00 g, 3.08 mmol) in ethanol (15 ML) was treated with a 1N aqueous sodium hydroxide solution (6 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×40 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (570 mg, 60%) as a white solid: mp 139-143° C.; EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1241.